WO2002012447B1 - Isolation and use of solid tumor stem cells - Google Patents

Isolation and use of solid tumor stem cells

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Publication number
WO2002012447B1
WO2002012447B1 PCT/US2001/024243 US0124243W WO0212447B1 WO 2002012447 B1 WO2002012447 B1 WO 2002012447B1 US 0124243 W US0124243 W US 0124243W WO 0212447 B1 WO0212447 B1 WO 0212447B1
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WO
WIPO (PCT)
Prior art keywords
solid tumor
tumor stem
stem cells
cells
population
Prior art date
Application number
PCT/US2001/024243
Other languages
French (fr)
Other versions
WO2002012447A3 (en
WO2002012447A2 (en
Inventor
Michael F Clarke
Sean J Morrison
Max S Wicha
Muhammad Al-Hajj
Original Assignee
Univ Michigan
Michael F Clarke
Sean J Morrison
Max S Wicha
Muhammad Al-Hajj
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to ES01956101.8T priority Critical patent/ES2553796T3/en
Priority to CA2417909A priority patent/CA2417909C/en
Priority to AU7813401A priority patent/AU7813401A/en
Priority to EP10179961.7A priority patent/EP2359863B1/en
Priority to AU2001278134A priority patent/AU2001278134B2/en
Priority to EP01956101.8A priority patent/EP1343871B1/en
Priority to JP2002517738A priority patent/JP5352037B2/en
Priority to US10/343,692 priority patent/US7115360B2/en
Application filed by Univ Michigan, Michael F Clarke, Sean J Morrison, Max S Wicha, Muhammad Al-Hajj filed Critical Univ Michigan
Publication of WO2002012447A2 publication Critical patent/WO2002012447A2/en
Publication of WO2002012447A3 publication Critical patent/WO2002012447A3/en
Publication of WO2002012447B1 publication Critical patent/WO2002012447B1/en
Priority to US11/529,869 priority patent/US7850961B2/en
Priority to US11/607,780 priority patent/US7754206B2/en
Priority to US11/651,214 priority patent/US20090004205A1/en
Priority to US11/788,489 priority patent/US20080194022A1/en
Priority to US11/776,935 priority patent/US8044259B2/en
Priority to US12/758,540 priority patent/US20110033481A1/en
Priority to US12/979,991 priority patent/US8357491B2/en
Priority to US13/241,701 priority patent/US8420885B2/en
Priority to US13/563,884 priority patent/US20120295350A1/en
Priority to US13/714,921 priority patent/US20140011274A1/en
Priority to US13/795,381 priority patent/US9089556B2/en

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    • C12N5/0693Tumour cells; Cancer cells
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
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    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574Immunoassay; Biospecific binding assay; Materials therefor for cancer
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    • C07K14/70585CD44
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07ORGANIC CHEMISTRY
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    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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    • C12N2501/00Active agents used in cell culture processes, e.g. differentation
    • C12N2501/40Regulators of development
    • C12N2501/42Notch; Delta; Jagged; Serrate
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    • C12N2503/00Use of cells in diagnostics
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    • C12N2503/02Drug screening

Abstract

A small percentage of cells within an established solid tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. Thus, solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. We have developed a xenograft model in which we have been able to establish tumors from primary tumors via injection of tumors in the mammary gland of severely immunodeficient mice. These xenograft assay have allowed us to do biological and molecular assays to characterize clonogenic solid tumor stem cells. We have also developed evidence that strongly implicates the Notch pathway, especially Notch 4, as playing a central pathway in carcinogenesis.

Claims

AMENDED CLAIMS[Received by the International Bureau on 21 January 2003 (21.01.03): new claims 186-449 added; remaining claims unchanged; (51 pages)]
1. An isolated solid tumor stem cell, wherein:
(a) the solid tumor stem cell is derived from a solid tumor; and
(b) the solid tumor stem cell is tumorigenic.
2. The isolated solid tumor stem cell of claim 1 , wherein the solid tumor stem cell expresses at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
3. The isolated solid tumor stem cell of claim 1 , wherein the solid tumor stem cell expresses the cell surface marker CD44.
4. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell expresses the cell surface marker epithelial specific antigen (ESA).
5. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell expresses the cell surface marker B38.1.
6. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell expresses lower levels of the marker CD24 than the mean expression of CD24 by non- tumorigenic cancer cells derived from the solid tumor.
7. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell does not express detectable levels of one or more LINEAGE markers, wherein a LINEAGE marker is selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
8. The isolated solid tumor stem cell of claim 7, wherein the solid tumor stem cell does not express detectable levels LINEAGE markers, wherein the LINEAGE marker comprises CD2, CD3, CD 14, CD 16, and CD64. 115
9. The isolated solid tumor stem cell of claim 8, wherem the LINEAGE markers further comprise CD 10, CD31, and CD 140b.
10. The isolated solid tumor stem cell of claim 1, wherein the solid umor is a sarcoma or an epithelial cancer.
11. The isolated solid tumor stem cell of claim 10, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
12. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell contains a polynucleotide vector.
13. The isolated solid tumor stem cell of claim 12, wherein the polynucleotide vector is a viral vector or a plasmid.
14. The isolated solid tumor stem cell of claim 12, wherein the polynucleotide vector contains a reporter polynucleotide.
15. The isolated solid tumor stem cell of claim 14, wherein the reporter polynucleotide is provides a detectable signal when active in a solid tumor stem cell.
16. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell further comprises a recombinant polynucleotide.
17. The isolated solid tumor stem cell of claim 16, wherein the recombinant polynucleotide is integrated into a chromosome of the solid tumor stem cell.
18. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell is introduced into a host mammal.
19. The isolated solid tumor stem cell of claim 18, wherein the solid tumor stem cell forms a new tumor upon transplantation into the host animal. 116
20. The isolated solid tumor stem cell of claim 19, wherein the animal is an immunocompromised animal.
21. The isolated solid tumor stem cell of claim 19, wherein the animal is a mammal.
22. The isolated solid tumor stem cell of claim 21, wherein the mammal is an immunocompromised mammal.
23. The isolated solid tumor stem cell of claim 21 , wherein the mammal is a mouse.
24. The isolated solid tumor stem cell of claim 23, wherein the mouse is an immunocompromised mouse.
25. The isolated solid tumor stem cell of claim 24, wherein the immunocompromised mouse is selected from the group consisting of nude mouse, SCID mouse, NOD/SCID mouse, Beige/SCID mouse; and β2 microglobin deficient NOD/SCID mouse.
26. The isolated solid tumor stem cell of claim 1, further comprising a culture medium, in which culture medium the solid tumor stem cell is situated.
27. The isolated solid tumor stem cell of claim 26, wherein the culture medium comprises a Notch ligand.
28. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell is affixed to a substrate.
29. The isolated solid tumor stem cell of claim 1, wherem the solid tumor stem cell has been treated to reduce proliferation.
30. The isolated solid tumor stem cell of claim 1, wherein the solid tumor stem cell has been treated to increase proliferation. 117
31. An enriched population of solid tumor stem cells, wherein:
(a) the tumor cells are derived from a solid tumor;
(b) the solid tumor stem cells are tumorigenic; and
(c) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells.
32. The enriched population of claim 31 , wherein the solid tumor is a sarcoma or an epithelial cancer.
33. The enriched population of claim 32, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
34. The enriched population of claim 31 , wherein the solid tumor stem cells in the enriched population express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
35. The enriched population of claim 31 , wherein the solid tumor stem cells in the enriched population express the cell surface marker CD44.
36. The enriched population of claim 31, wherein the solid tumor stem cells in the enriched population express the cell surface marker epithelial specific antigen (ESA).
37. The enriched population of claim 31 , wherein the solid tumor stem cells in the enriched population express the cell surface marker B38.1.
38. The enriched population of claim 31 , wherein the solid tumor stem cells in the enriched population express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
39. The enriched population of claim 31 , wherein solid tumor stem cells in the enriched population fail to express at least one lineage marker selected from the group consisting of CD2, CD3, CD14, CD16, CD45, CD64, and CD140b. 118
40. The enriched population of claim 31 , wherein the enrichment is in the ability to form new tumors relative to unfractionated tumor cells.
41. The enriched population of claim 31 , wherein the population is at least 5-fold enriched.
42. The enriched population of claim 31 , wherein the population is at least 10-fold enriched.
43. The enriched population of claim 31, wherein the population is at least 50-fold enriched.
44. A population of cells that have been enriched for non-tumorigenic solid tumor cells, wherein:
(a) the population is derived from a solid tumor; and
(b) the population is depleted for the ability to form tumors relative to unfractionated solid tumor cells.
45. The enriched population of claim 44, wherein the solid tumor is a sarcoma or an epithelial cancer.
46. The enriched population of claim 45, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
47. A method for enriching a population of cells for solid tumor stem cells, comprising the steps of:
(a) dissociating a solid tumor to form a cell suspension;
(b) contacting the dissociated cells with at least one reagent, wherein the reagent either selectively binds to a solid tumor stem cell positive marker or negative marker; and
(c) selecting cells that bind to the reagent that selectively binds to a positive marker and/or that do not bind to the reagent that selectively binds to a negative marker, wherein the selected cells are enriched in tumor stem cells as compared with the unfractionated population of solid tumor cells.
48. The method of claim 47, wherein the solid tumor is a sarcoma or epithelial cancer. 119
49. The method of claim 48, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
50. The method of claim 47, wherein the reagent is an antibody or a lectin.
51. The method of claim 47, wherein the reagent is conjugated to a fluorochrome or to magnetic particles.
52. The method of claim 47, wherein the solid tumor stem cell positive marker is a marker selected from the group consisting of CD44, B38.1 and ESA.
53. The method of claim 47, wherein the solid tumor stem cell negative marker is a marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
54. The method of claim 47, wherein the cell selection is performed is by flow cytometry, fluorescence activated cell sorting, panning, affinity column separation, and/or magnetic selection.
55. The method of claim 47, wherein steps (b) and (c) comprise:
(b) contacting the dissociated cells with a combination of reagents, wherein each reagent in the combination either selectively binds to either a solid tumor stem cell positive marker or negative marker; and
(c) selecting cells that bind to reagents that selectively bind to the positive marker or that do not bind to reagents that selectively bind to the negative marker or a combination thereof, wherein the selected cells are enriched in tumor stem cells as compared with the population of unfractionated cells.
56. The method of claim 47, further comprising the step of:
(d) isolating the selected solid tumor stem cells. 120
57. The method of claim 47, further comprising the steps of:
(d) introducing at least one selected cell to a culture medium that supports the growth of tumor stem cells; and
(e) proliferating the selected cell in the culture medium.
58. The method of claim 57, further comprising the step of:
(f) introducing the proliferated cell into a host mammal.
59. The method of claim 57, further comprising the steps of:
(f) contacting the proliferated cell with a test compound; and
(g) determining the effect of the test compound on the proliferated cell.
60. The method of claim 57, further comprising the steps of:
(f) mixing a population of non-tumorigenic tumor cells with the solid tumor stem cells in culture, wherem the population of non-tumorigenic tumor cells
(i) is derived from a solid tumor;
(ii) is depleted for the ability to form tumors relative to unfractionated solid tumor cells.
61. The method of claim 60, further comprising the steps of:
(g) transplanting the mixture into a host animal.
62. The method of claim 60, further comprising the steps of:
(g) analyzing the mixture for an increase or decrease in the ability of the solid tumor stem cells to survive or proliferate.
63. The method of claim 57, further comprising the step of: (f) isolating the proliferated solid tumor stem cell. 121
64. A method for stimulating an immune response to a solid tumor stem cell, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells; wherein: (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) treating the population to prevent cell replication; and
(c) administering the treated cell to a human or animal subject in an amount effective for inducing an immune response to solid tumor stem cells.
65. The method of claim 64, wherein the solid tumor is a sarcoma or epithelial cancer.
66. The method of claim 65, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
67. The method of claim 64, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
68. The method of claim 64, wherein the treatment kills the solid tumor stem cells.
69. The method of claim 64, wherein the administration is by injection or by oral administration.
70. The method of claim 64, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
71. The method of claim 64, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44. 122
72. The method of claim 64, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
73. The method of claim 64, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1.
74. The method of claim 64, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
75. The method of claim 64, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
76. The method of claim 64, further comprising the step of:
(d) obtaining antibodies or antibody secreting hybridomas from the human or animal subject.
77. The method of claim 76, further comprising the step of:
(e) testing the obtained antibody for the ability to specifically bind to solid tumor stem cells.
78. The method of claim 76, further comprising the step of:
(e) testing the obtained antibody for the ability to bind to a polypeptide present on solid tumor stem cells.
79. The method of claim 76, further comprising the step of:
(e) immunologically identifying a polypeptide present on solid tumor stem cells.
80. The method of claim 76, further comprising the step of:
(e) immunologically identifying a polynucleotide encoding a polypeptide present on solid tumor stem cells. 123
81. The method of claim 76, further comprising the step of:
(e) testing the obtained antibody for the ability to reduce tumor growth.
82. A method for stimulating an immune response to a solid tumor stem cell, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells; wherein: (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) mixing the tumor stem cells in an in vitro culture with immune effector cells;
(c) removing the immune effector cells from the culture; and
(d) transplanting the immune effector cells into a host animal in a dose that is effective to stimulate an immune response in the animal.
83. The method of claim 82, wherein the solid tumor is a sarcoma or epithelial cancer.
84. The method of claim 83, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
85. The method of claim 82, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
86. The method of claim 82, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
87. The method of claim 82, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1. 124
88. The method of claim 82, wherem, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
89. The method of claim 82, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
90. The method of claim 82, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
91. A purified population of polynucleotides, wherein the polynucleotides have been purified from an enriched population of solid tumor stem cells, wherein:
(a) the tumor cells are derived from a solid tumor;
(b) the solid tumor stem cells are tumorigenic; and
(c) the solid tumor stem cell population is enriched at least at least 2-fold relative to unfractionated tumor cells.
92. The polynucleotide population of claim 91, wherein the solid tumor is a sarcoma or an epithelial cancer.
93. The polynucleotide population of claim 92, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
94. The polynucleotide population of claim 91 , wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
95. The polynucleotide population of claim 91 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
96. The polynucleotide population of claim 91, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
97. The polynucleotide population of claim 91 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cell expresses the cell surface marker B38.1.
98. The polynucleotide population of claim 91, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
99. The polynucleotide population of claim 91, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
100. The polynucleotide population of claim 91 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD 10, CD 14, CD 16, CD31, CD45, CD64, and CD 140b.
101. The polynucleotide population of claim 91, wherein the polynucleotides are affixed to a solid surface.
102. The polynucleotide population of claim 101, wherein the polynucleotides are affixed to the solid surface in an orderly array.
103. The polynucleotide population of claim 102, wherein the orderly array is a microarray.
104. The polynucleotide population of claim 91 , wherein the polynucleotides are in a cDNA library. 126
105. The polynucleotide population of claim 91 , wherein the polynucleotides have been amplified.
106. The polynucleotide population of claim 91 , wherein the polynucleotides are labeled.
107. The polynucleotide population of claim 91 , wherein the polynucleotides are used as a hybridization probe.
108. The polynucleotide population of claim 107, further comprising a microarray of polynucleotide sequences.
109. A purified population of polypeptides, wherein the polypeptides have been purified from an enriched population of solid tumor stem cells, wherein:
(a) the tumor cells are derived from a solid tumor;
(b) the solid tumor stem cells are tumorigenic; and
(c) the solid tumor stem cell population is enriched at least at least 2-fold relative to unfractionated tumor cells.
110. The polypeptide population of claim 109, wherein the solid tumor is a sarcoma or an epithelial cancer.
111. The polypeptide population of claim 110, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
112. The polypeptide population of claim 109, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
113. The polypeptide population of claim 109, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
114. The polypeptide population of claim 109, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker CD44. 127
115. The polypeptide population of claim 109, wherein, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
116. The polypeptide population of claim 109, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
117. The polypeptide population of claim 109, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
118. The polypeptide population of claim 109, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
119. The polypeptide population of claim 109, wherein the polypeptides are affixed to a solid surface. ι
120. The polypeptide population of claim 109, wherein the polypeptides are affixed to the solid surface in an orderly array.
121. The polypeptide population of claim 120, wherein the orderly array is a microarray.
122. The polypeptide population of claim 109, wherein the polypeptides are labeled.
123. The polypeptide population of claim 109, wherein the polypeptides are used as a probe.
124. The polypeptide population of claim 123, further comprising a microarray of components, wherein the components are selected from the group consisting of cells, polynucleotides, polypeptides, and test compounds. 128
125. A method for analyzing a population of cells enriched for solid tumor stem cells for gene expression patterns, comprising the steps of:
(a) obtaining an population of cells enriched for solid tumor stem cells; wherein: (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(b) analyzing the population of cells for gene expression patterns.
126. The method of claim 125, wherein the analysis is by a method selected from the group consisting of resequencing, high throughput screening, use of a microarray, use of analytical software for data collection and storage, use of analytical software for flexible formatting of data output, use of analytical software for statistical analysis of individual spot intensities to provide grouping and cluster analyses, and use of analytical software for linkage to external databases.
127. The method of claim 125 wherein the solid tumor is a sarcoma or an epithelial cancer.
128. The method of claim 127, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
129. The method of claim 125, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
130. The method of claim 125, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
131. The method of claim 125, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44. 129
132. The method of claim 125, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
133. The method of claim 125, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
134. The method of claim 125, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tiimor.
135. The method of claim 125, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
136. A method for analyzing a population of cells enriched for solid tumor stem cells for protein expression patterns, comprising the steps of:
(a) obtaining an population of cells enriched for solid tumor stem cells; wherein: (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(b) analyzing the population of cells for protein expression patterns.
137. The method of claim 136, wherein the analysis is by a method selected from the group consisting of mass spectrometry, high throughput screening, use of a microarray, use of analytical software for data collection and storage, use of analytical software for flexible formatting of data output, use of analytical software for statistical analysis of individual spot intensities to provide grouping and cluster analyses, and use of analytical software for linkage to external databases.
138. The method of claim 136, wherein the solid tumor is a sarcoma or an epithelial cancer. 130
139. The method of claim 138, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
140. The method of claim 136, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
141. The method of claim 136, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
142. The method of claim 136, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
143. The method of claim 136, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
144. The method of claim 136, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1.
145. The method of claim 136, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
146. The method of claim 136, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b. 131
147. A method for dete-rmining the effect of a test compound on a solid tumor stem cell, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells, wherein: (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) contacting the obtained cells with the test compound; and
(c) determining the response of the contacted cells to the test compound.
148. The method of claim 147, wherein the solid tumor is a sarcoma or an epithelial cancer.
149. The method of claim 148, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
150. The method of claim 147, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
151. The method of claim 147, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
152. The method of claim 147, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
153. The method of claim 147, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
154. The method of claim 147, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1. 132
155. The method of claim 147, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
156. The method of claim 147, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
157. The method of claim 147, wherein the solid tumor stem cells are localized in a manner selected from the group consisting of in monolayers in culture, in suspension in culture, and affixed to a solid surface.
158. The method of claim 147, wherein the contacting is effected at more than one concentration of the test compound being tested.
159. The method of claim 147, wherein the contacting is effected using micro fluidic methods.
160. The method of claim 147, wherein the determination of the response of the contacted cells to the test compound comprises assaying for an effect selected from the group consisting of tumor formation, tumor growth, tumor stem cell proliferation, tumor cell survival, tumor cell cycle status, and tumor stem cell survival.
161. The method of claim 147, wherein the test compound is attached to a solid surface.
162. The method of claim 161, wherein the test compound is attached to a solid surface as a microarray.
163. The method of claim 147, wherein the test compound is in a set of other molecules.
164. The method of claim 147, wherein the test compound is in an array of other molecules. 133
165. The method of claim 147, further comprising the step of.
(d) identifying the target in the contacted cells with which the test compound interacts.
166. A method for determining the effect of a test compound on a solid tumor stem cell, comprising the steps of:
(a) contacting a population of solid tumor cells with the test compound;
(b) obtaining an enriched population of solid tumor stem cells from the contacted solid tumor cells, wherein:
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(c) determining the response of the contacted cells to the test compound.
167. The method of claim 166, wherein the solid tumor is a sarcoma or an epithelial cancer.
168. The method of claim 167, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
169. The method of claim 166, wherein the solid tumor is a sarcoma or an epithelial cancer.
170. The method of claim 166, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
171. The method of claim 166, wherein the solid tumor cells are in vivo.
172. The method of claim 166, wherein the solid tumor cells are in vitro.
173. The method of claim 166, wherein the solid tumor cells are in raw tumor tissue.
174. The method of claim 166, wherein the solid tumor cells are a cell line. 134
175. The method of claim 166, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
176. The method of claim 166, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
177. The method of claim 166, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
178. The method of claim 166, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
179. The method of claim 166, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
180. The method of claim 166, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
181. The method of claim 166, wherein the solid tumor stem cells are localized in a manner selected from the group consisting of in monolayers in culture, in suspension in culture, and affixed to a solid surface.
182. The method of claim 166, wherem the contacting is effected at more than one concentration of the test compound being tested.
183. The method of claim 166, wherein the contacting is effected using microfluidic methods. 135
184. The method of claim 166, wherein the determination of the response of the contacted cells to the test compound comprises assaying for an effect selected from the group consisting of tumor formation, tumor growth, tumor stem cell proliferation, tumor cell survival, tumor cell cycle status, and tumor stem cell survival.
185. The method of claim 166, wherein the test compound is attached to a solid surface.
186. The method of claim 185, wherein the test compound is attached to a solid surface as a microarray.
187. The method of claim 166, wherein the test compound is in a set of other molecules.
188. The method of claim 166, wherein the test compound is in an array of other molecules.
189. The method of claim 166, further comprising the step of.
(d) identifying the target in the contacted cells with which the test compound interacts.
190. A method for determining the effect of a test compound on a solid tumor stem cell, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells, wherein; (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) transplanting the obtained cells into an animal;
(c) administering a test compound to the animal; and
(d) determining the response of the transplanted solid tumor stem cells to the test compound.
191. The method of claim 190, wherein the animal is an immunocompromised animal.
192. The method of claim 190, wherein the animal is a mammal . 136
193. The method of claim 192, wherein the mammal is an immunocompromised mammal.
194. The method of claim 192, wherein the mammal is a mouse.
195. The method of claim 194, wherein the mouse is an immunocompromised mouse.
196. The method of claim 195, wherein the immunocompromised mouse is selected from the group consisting of nude mouse, SCID mouse, NOD/SCID mouse, Beige/SCID mouse; and β2 microglobin deficient NOD/SCID mouse.
197. The method of claim 190, wherein the solid tumor is a sarcoma or an epithelial cancer.
198. The method of claim 197, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
199. The method of claim 190, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
200. The method of claim 190, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
201. The method of claim 190, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
202. The method of claim 190, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
203. The method of claim 190, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1. 137
204. The method of claim 190, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
205. The method of claim 190, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
206. A method for determining the effect of a test compound on a solid tumor stem cell, comprising the steps of:
(a) administering a test compound to an animal;
(b) obtaining from the animal an enriched population of solid tumor stem cells, wherein;
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(c) determining the response of the solid tumor stem cells to the test compound.
207. The method of claim 206, wherein the animal is an immunocompromised animal.
208. The method of claim 206, wherein the animal is a mammal.
209. The method of claim 208, wherein the mammal is an immunocompromised mammal.
210. The method of claim 208, wherein the mammal is a mouse.
211. The method of claim 210, wherein the mouse is an immunocompromised mouse.
212. The method of claim 211, wherein the immunocompromised mouse is selected from the group consisting of nude mouse, SCID mouse, NOD/SCID mouse, Beige/SCID mouse; and β2 microglobin deficient NOD/SCID mouse. 138
213. The method of claim 206, wherein the solid tumor is a sarcoma or an epithelial cancer.
214. The method of claim 213, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
215. The method of claim 206, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
216. The method of claim 206, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
217. The method of claim 206, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express the cell surface marker CD44.
218. The method of claim 206, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
219. The method of claim 206, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express the cell surface marker B38.1.
220. The method of claim 206, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
221. The method of claim 206, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b. 139
222. A method for screening for a test compound that specifically binds to a solid tumor stem cell, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells, wherein; (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) contacting the enriched population of solid tumor stem cells with a test compound under conditions suitable to allow complex formation; and
(c) detecting complex formation between the test compound and a solid tumor stem cell, wherein the presence of the complex identifies the test compound as specifically binding the tumor stem cell.
223. The method of claim 222, wherein the solid tumor is a sarcoma or an epithelial cancer.
224. The method of claim 223, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
225. The method of claim 222, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
226. The method of claim 222, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
227. The method of claim 222, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
228. The method of claim 222, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA). 140
229. The method of claim 222, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
230. The method of claim 222, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
231. The method of claim 222, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
232. A method for screening for a test compound that specifically binds to a solid tumor stem cell, comprising the steps of:
(a) contacting a population of solid tumor cells with a test compound under conditions suitable to allow complex formation; and
(b) obtaining an enriched population of solid tumor stem cells from the contacted solid tumor cells, wherein;
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(c) detecting complex formation between the test compound and a solid tumor stem cell, wherein the presence of the complex identifies the test compound as specifically binding the tumor stem cell.
233. The method of claim 232, wherein the solid tumor is a sarcoma or an epithelial cancer.
234. The method of claim 233, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
235. The method of claim 232, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell. 141
236. The method of claim 232, wherein the solid tumor cells are in vivo.
237. The method of claim 232, wherein the solid tumor cells are in vitro.
238. The method of claim 232, wherein the solid tumor cells are in raw tumor tissue.
239. The method of claim 232, wherein the solid tumor cells are a cell line.
240. The method of claim 232, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
241. The method of claim 232, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express the cell surface marker CD44.
242. The method of claim 232, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
243. The method of claim 232, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express the cell surface marker B38.1.
244. The method of claim 232, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
245. The method of claim 232, wherein, in the enriched population of solid tumor stem cells of (b), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b. 142
246. A method for diagnosing the presence of solid tumor stem cells, comprising the steps of:
(a) contacting the cells from a solid tumor with a reagent that binds to a positive marker for solid tumor stem cells; and
(b) detecting the contact between the reagent and the cells from the solid tumor, wherein an increased detection of the number of contacted cells as compared with the number of contacted cells in a benign tumor identifies the tumor as containing solid tumor stem cells.
247. The method of claim 246, wherein the detection is by flow-cytometry or immunohistochemistry.
248. The method of claim 247, wherein the solid tumor is a sarcoma or an epithelial cancer.
249. The method of claim 246, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
250. The method of claim 246, wherein the positive marker is a marker selected from the group consisting of CD44, B38.1 and ESA.
251. An in vitro method for the proliferation of a tumor stem cells, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells, wherein; (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(b) proliferating the obtained cells in a culture medium.
252. The method of claim 251, wherein the solid tumor is a sarcoma or an epithelial cancer.
253. The method of claim 252, wherein the epithelial cancer is a breast cancer or an ovarian cancer. 143
254. The method of claim 251, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
255. The method of claim 251, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
256. The method of claim 251 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
257. The method of claim 251 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
258. The method of claim 251, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1.
259. The method of claim 251 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
260. The method of claim 251 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
144
261. An in vivo method for the proliferation of a tumor stem cells, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells, wherein; (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(b) transplanting the isolated cell into a host mammal under conditions that allow the proliferation of solid tumor stem cells in the host mammal.
262. The method of claim 261 , wherein the solid tumor is a sarcoma or an epithelial cancer.
263. The method of claim 262, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
264. The method of claim 261, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
265. The method of claim 261, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
266. The method of claim 261 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
267. The method of claim 261 , wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
268. The method of claim 261, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor. 145
269. The method of claim 261, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
270. The method of claim 261 , further comprising the step of:
(c) isolating the proliferated tumor cells from the host mammal.
271. A method for producing genetically modified tumor stem cells, comprising the steps of:
(a) obtaining an enriched population of solid tumor stem cells, wherein: (i) the tumor cells are derived from a solid tumor;
(ii) the solid tumor stem cells are tumorigenic;
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) genetically modifying the obtained cells.
272. The method of claim 271, wherein the solid tumor is a sarcoma or an epithelial cancer.
273. The method of claim 262, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
274. The method of claim 271 , wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
275. The method of claim 271, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
276. The method of claim 271 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44. 146
277. The method of claim 271 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
278. The method of claim 271 , wherein, in the enriched population of solid rumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
279. The method of claim 271, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
280. The method of claim 271 , wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
281. The method of claim 271 , in which the genetic modification is performed in vitro.
282. The method of claim 271, in which the genetic modification is performed in vivo.
283. The method of claim 271, wherein the genetic modification is the introduction of a plasmid into the solid tumor stem cell.
284. The method of claim 271 , wherein the genetic modification is the introduction of a viral vector into the solid tumor stem cell.
285. The method of claim 271 , in which the virus has been modified to express a protein that recognizes an antigen on the solid tumor stem cell, thus specifically targeting the virus to solid tumor stem cell.
286. The method of claim 271 , further comprising the step of: 147
(c) examining the effect of the genetic modification on tumor formation, tumor growth, tumor cell proliferation, tumor cell survival, tumor stem cell survival, tumor stem cell proliferation, tumor cell cycle status, and tumor stem cell frequency.
287. A method for producing genetically modified tumor stem cells, comprising the steps of:
(a) genetically modifying cells of a population of solid tumor cells; and
(b) obtaining an enriched population of solid tumor stem cells from the genetically modified solid tumor cells, wherein:
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic;
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
288. The method of claim 287, wherein the solid tumor is a sarcoma or an epithelial cancer.
289. The method of claim 288, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
290. The method of claim 287, wherein the obtained enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
291. The method of claim 287, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
292. The method of claim 287, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
293. The method of claim 287, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA). 148
294. The method of claim 287, wherein, in the enriched population of solid tumor stem cells, the solid tumor stem cells express the cell surface marker B38.1.
295. The method of claim 287, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
296. The method of claim 287, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
297. The method of claim 287, in which the genetic modification is performed in vitro.
298. The method of claim 287, in which the genetic modification is performed in vivo.
299. The method of claim 287, wherein the genetic modification is the introduction of a plasmid into the solid tumor cell.
300. The method of claim 287, wherein the genetic modification is the introduction of a viral vector into the solid tumor cell.
301. The method of claim 287, in which the virus has been modified to express a protein that recognizes an antigen on the solid tumor stem cell, thus specifically targeting the virus to solid tumor cell.
302. The method of claim 287, further comprising the step of:
(c) examining the effect of the genetic modification on tumor formation, tumor growth, tumor cell proliferation, tumor cell survival, tumor stem cell survival, tumor stem cell proliferation, tumor cell cycle status, and tumor stem cell frequency. 149
303. An in vivo method for proliferating a population of cancer cells, comprising:
(a) introducing an enriched population of solid tumor stem cells into a host animal; wherein:
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic;
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) proliferating the solid tumor stem cells in the host animal; and
(c) purifying the proliferated solid tumor stem cells from the host animal.
304. The method of claim 303, wherein the animal is an immunocompromised animal.
305. The method of claim 303, wherein the animal is a mammal.
306. The method of claim 305, wherein the mammal is an immunocompromised mammal.
307. The method of claim 305, wherein the mammal is a mouse.
308. The method of claim 307, wherein the mouse is an immunocompromised mouse.
309. The method of claim 308, wherein the immunocompromised mouse is selected from the group consisting of nude mouse, SCID mouse, NOD/SCID mouse, Beige/SCID mouse; and β2 microglobin deficient NOD/SCID mouse.
310. The method of claim 303, wherein the solid tumor is a sarcoma or an epithelial cancer.
311. The method of claim 310, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
312. The method of claim 303, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell. 150
313. The method of claim 303, wherein, in the enriched population of solid tumor stem cells (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
314. The method of claim 303, wherein, in the enriched population of solid tumor stem cells (a), the solid tumor stem cells express the cell surface marker CD44.
315. The method of claim 303, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
316. The method of claim 303, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1.
317. The method of claim 303, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
318. The method of claim 303, wherein the solid tumor stem cell fails to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD 10, CD 14, CD16, CD31, CD45, CD64, and CD140b.
319. The method of claim 303, wherein the cells are introduced subcutaneously or into the mammary fat pad.
320. The method of claim 303, wherein tumors grow in the mammal in greater than 75% of the introductions.
321. The method of claim 303, wherein tumors grow in the mammal in greater than 90% of the introductions.
322. The method of claim 303, wherein the population of cells has been enriched at least 50- fold. 151
323. The method of claim 303, wherein the population of cells has been enriched at least 5- fold.
324. The method of claim 303, wherein the population of cells has been enriched at least 10- fold.
325. The method of claim 303, wherein the mice have been further immunosuppressed by a method selected from the group consisting of administration of NP16, radiation therapy and chemotherapy.
326. The method of claim 303, further comprising:
(d) isolating an enriched population of solid tumor stem cells from the proliferated cells
327. The method of claim 326, wherein the isolation comprises the use of flow-cytometry.
328. A method for growing a solid tumor stem cell from a solid tumor, comprising the steps of:
(a) separating the cells of the solid tumor;
(b) suspending the separated tumor cells in suspension; and
(c) introducing the suspended cell into a host mammal, such that the cells in the introduced suspension forms a tumor in the host mammal.
329. The method of claim 328, wherein the solid tumor is a sarcoma or an epithelial cancer.
330. The method of claim 329, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
331. The method of claim 328, wherein the solid tumor stem cells in the suspension express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1. 152
332. The method of claim 328, wherein the solid tumor stem cells in the suspension express the cell surface marker CD44.
333. The method of claim 328, wherein the solid tumor stem cells in the suspension express the cell surface marker epithelial specific antigen (ESA).
334. The method of claim 328, wherein the solid tumor stem cells in the suspension express the cell surface marker B38.1.
335. The method of claim 328, wherein the solid tumor stem cells in the suspension lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
336. The method of claim 328, wherein the solid tumor stem cells in the suspension fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
337. A tumor bank, comprising cells derived from a single tumor, wherein the tumor has been produced by the steps of:
(a) introducing an enriched population of solid tumor stem cells into a host mammal; wherein:
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells;
(b) proliferating the introduced cells in the host mammal; and
(c) isolating the proliferated cells from the host mammal.
338. The tumor bank of claim 337, wherein the solid tumor is a sarcoma or an epithelial cancer.
339. The tumor bank of claim 338, wherein the epithelial cancer is a breast cancer or an ovarian cancer. 153
340. The tumor bank of claim 337, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
341. The tumor bank of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
342. The tumor bank of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker CD44.
343. The tumor bank of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
344. The tumor bank of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1.
345. The tumor bank of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
346. The tumor bank of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b. 154
347. A chimeric animal, comprising:
(a) the animal; and
(b) an enriched population of solid tumor stem cells, wherein: (i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic;
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and (iv) the cells of the enriched population have been introduced into the animal.
348. The chimeric animal of claim 337, wherein the solid tumor of (b) is a sarcoma or an epithelial cancer.
349. The chimeric animal of claim 338, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
350. The chimeric animal of claim 337, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
351. The chimeric animal of claim 337, wherein, in the enriched population of solid tumor stem cells (b), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
352. The chimeric animal of claim 337, wherein, in the enriched population of solid tumor stem cells (b), the solid tumor stem cells express the cell surface marker CD44.
353. The chimeric animal of claim 337, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
354. The chimeric animal of claim 337, wherein, in the enriched population of solid tumor stem cells (b), the solid tumor stem cells express the cell surface marker B38.1. 155
355. The chimeric animal of claim 337, wherein, in the enriched population of solid tumor stem cells (b), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid rumor.
356. The chimeric animal of claim 337, wherein, in the enriched population of solid tumor stem cells (b), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
357. The chimeric animal of claim 337, wherein the introduction is by injection.
358. The chimeric animal of claim 337, wherein the animal is an immunocompromised ( animal.
359. The chimeric animal of claim 337, wherein the animal is a mammal.
360. The chimeric animal of claim 349, wherein the mammal is an immunocompromised mammal.
361. The chimeric animal of claim 349, wherein the mammal is a mouse.
362. The chimeric animal of claim 351, wherein the mouse is an immunocompromised mouse.
363. The chimeric animal of claim 352, wherein the immunocompromised mouse is selected from the group consisting of nude mouse, SCID mouse, NOD/SCID mouse, Beige/SCID mouse; and β2 microglobin deficient NOD/SCID mouse. 156
364. An in vivo method for modeling a tumor treatment regime, comprising the steps of:
(a) introducing an enriched population of solid tumor stem cells into an immunocompromised mouse under conditions that allow the solid tumor stem cells to proliferate to form a tumor; wherein:
(i) the tumor cells are derived from a solid tumor; (ii) the solid tumor stem cells are tumorigenic; and
(iii) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells; and
(b) testing the effects of treatment regimens on the solid tumor cells in the immunocompromised mouse by monitoring the effect of the treatment regimen.
365. The method of claim 354, wherein the solid tumor is a sarcoma or an epithelial cancer.
366. The method of claim 355, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
367. The method of claim 354, wherein the enriched population of solid tumor stem cells is an isolated solid tumor stem cell.
368. The method of claim 354, wherein, in the enriched population of solid tumor stem cells (a), the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
369. The method of claim 354, wherein, in the enriched population of solid tumor stem cells (a), the solid tumor stem cells express the cell surface marker CD44.
370. The method of claim 354, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
371. The method of claim 354, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express the cell surface marker B38.1. 157
372. The method of claim 354, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
373. The method of claim 354, wherein, in the enriched population of solid tumor stem cells of (a), the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
374. A method for reducing the size of a solid tumor, comprising the step of: contacting the cells of the solid tumor with a therapeutically effective amount of an agent directed against a Notch 4 polypeptide.
375. The method of claim 364, wherein the therapeutically effective amount is an amount sufficient to cause cell death of or inhibit the proliferation of solid tumor stem cells in the solid tumor.
376. The method of claim 364, wherein the agent is an antibody, peptide or small molecule directed against a Notch 4 polypeptide. ,
377. The method of claim 366, wherein the antibody, peptide or small molecule is directed against the extracellular domain of Notch 4.
378. A method for reducing the size of a solid tumor, comprising: contacting the cells of the solid tumor with a therapeutically effective amount of an agent that modulates the activity of a Notch 4 ligand.
379. The method of claim 37, wherein the Notch 4 ligand is selected from the group consisting of Delta 1, Delta 2, Delta-like ligand 4 (D114), Jagged 1 and Jagged 2.
380. The method of claim 37, wherein the agent is a Notch ligand agonist.
381. The method of claim 37, wherein the agent is a Notch ligand antagonist. 158
382. A method for reducing the size of a solid tumor, comprising: contacting the cells of the solid tumor with a therapeutically effective amount of an agent that modulates the activity of Maniac Fringe.
383. The method of claim 38, wherein the agent is a Maniac Fringe agonist.
384. The method of claim 38, wherein the agent is a Maniac Fringe antagonist.
385. A method for killing or inhibiting the proliferation of solid tumor stem cells, comprising the step of: contacting the cells of a solid tumor with an agent or combination of agents selectively targeted to the solid tumor stem cells of the solid tumor, wherein the agent or combination of agents kills or inhibits the proliferation of solid tumor stem cells.
386. The method of claim 385, further comprising the step of: identifying the death of or the prevention of the growth of solid tumor stem cells in the solid tumor following contact by the agent or combination of agents.
387. The method of claim 385, wherein the killing is by the activation of cell death in the solid tumor stem cells.
388. The method of claim 387, wherein the cell death is apoptosis.
389. The method of claim 385, wherein the agent or combination of agents inhibits Notch-4 signaling.
390. The method of claim 385, wherein the agent is an antibody, peptide or small molecule directed against a Notch 4 polypeptide.
391. The method of claim 385, wherein the antibody, peptide or small molecule is directed against the extracellular domain of Notch 4. 159
392. The method of claim 385, wherein the agent or combination of agents modulates the activity of a Notch 4 ligand.
393. The method of claim 392, wherein the Notch 4 ligand is selected from the group consisting of Delta 1, Delta 2, Delta-like ligand 4 (D114), Jagged 1 and Jagged 2.
394. The method of claim 385, wherein the agent or combination of agents modulates the activity of Maniac Fringe.
395. The method of claim 385, wherein the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
396. The method of claim 385, wherein the solid tumor stem cells express the cell surface marker CD44.
397. The method of claim 385, wherein the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
398. The method of claim 385, wherein the solid tumor stem cells express the cell surface marker B38.1.
399. The method of claim 385, wherein the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells of the solid tumor.
400. The method of claim 385, wherein the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
401. The method of claim 385, wherein the solid tumor is an epithelial cancer or a sarcoma. 160
402. The method of claim 401, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
403. A method for reducing the size of a solid tumor, comprising the step of: contacting the cells of the solid tumor in vivo with an agent or combination of agents selectively targeted to the solid rumor stem cells of the solid tumor, wherein the agent or combination of agents kills or inhibits the proliferation of solid tumor stem cells.
404. The method of claim 400, further comprising the step of: identifying the death of or the prevention of the growth of solid tumor stem cells in the solid tumor following contact by the agent or combination of agents.
405. The method of claim 403, wherein the killing is by the activation of cell death in the solid tumor stem cells.
406. The method of claim 405, wherein the cell death is apoptosis.
407. The method of claim 403, wherein the agent or combination of agents inhibits Notch-4 signaling.
408. The method of claim 403, wherein the agent is an antibody, peptide or small molecule directed against a Notch 4 polypeptide.
409. The method of claim 408, wherein the antibody, peptide or small molecule is directed against the extracellular domain of Notch 4.
410. The method of claim 403, wherem the agent or combination of agents modulates the activity of a Notch ligand.
411. The method of claim 403, wherein the Notch 4 ligand is selected from the group consisting of Delta 1, Delta 2, Delta-like ligand 4 (D114), Jagged 1 and Jagged 2. 161
412. The method of claim 403, wherein the agent or combination of agents modulates the activity of Maniac Fringe.
413. The method of claim 403, wherein the solid tumor stem cells express at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
414. The method of claim 403, wherein the solid tumor stem cells express the cell surface marker CD44.
415. The method of claim 403, wherein the solid tumor stem cells express the cell surface marker epithelial specific antigen (ESA).
416. The method of claim 403, wherein the solid tumor stem cells express the cell surface marker B38.1.
417. The method of claim 403, wherein the solid tumor stem cells fail to express at least one LINEAGE marker selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
418. The method of claim 403, wherein the solid tumor stem cells express lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells of the solid tumor.
419. The method of claim 403, wherein the solid tumor is an epithelial cancer or a sarcoma.
420. The method of claim 419, wherein the epithelial cancer is a breast cancer or an ovarian cancer.
421. A method for selectively targeting a solid tumor stem cell, comprising the steps of:
(a) identifying a marker present on a solid tumor stem cell;
(b) obtaining a biomolecule or set of biomolecules that selectively binds to the marker present on the solid tumor stem cell. 162
422. The method of claim 421 , wherein the biomolecule genetically modifies the targeted solid tumor stem cell.
423. The method of claim 422, wherein the genetic modification results in solid tumor stem cell death.
424. The method of claim 421, wherein the biomolecule or set of biomolecules comprises a bi-specific conjugate.
425. The method of claim 421, wherein the biomolecule or set of biomolecules comprises an adenoviral vector.
426. The method of claim 425, wherein the adenoviral vector is selectively targeted to a solid tumor stem cell.
427. A biomolecule or set of biomolecules that is selectively targeted to solid tumor stem cell.
428. The method of claim 427, wherein the biomolecule genetically modifies the targeted solid tumor stem cell.
429. The method of claim 428, wherein the genetic modification results in solid tumor stem cell death.
430. The method of claim 427, wherein the biomolecule or set of biomolecules comprises a bi-specific conjugate.
431. The method of claim 427, wherein the biomolecule or set of biomolecules comprises an adenoviral vector.
432. The method of claim 431 , wherein the adenoviral vector is selectively targeted to a solid tumor stem cell. 163
433. A method for forming a tumor in an animal, comprising: introducing a cell dose of purified solid tumor stem cells into the animal, wherein:
(a) the solid tumor stem cell is derived from a solid tumor;
(b) the solid tumor stem cell population is enriched at least 2-fold relative to unfractionated tumor cells.
434. The method of claim 433, wherein the animal is an immunocompromised animal.
435. The method of claim 433, wherein the animal is a mammal.
436. The method of claim 435, wherein the mammal is an immunocompromised mammal.
437. The method of claim 435, wherein the mammal is a mouse.
438. The method of claim 437, wherem the mouse is an immunocompromised mouse.
439. The method of claim 438, wherein the immunocompromised mouse is selected from the group consisting of nude mouse, SCID mouse, NOD/SCID mouse, Beige/SCID mouse; and β2 microglobin deficient NOD/SCID mouse.
440. The method of claim 433, wherein the number of cells in the cell dose is between about 100 cells and about 5xl05 cells.
441. The method of claim 433, wherein the number of cells in the cell dose is about between about 100 cells and 500 cells.
442. The method of claim 433, wherein the number of cells in the cell dose is between about 100 cells and 200 cells.
443. The method of claim 433, wherein the number of cells in the cell dose is about 100 cells. 164
444. The method of claim 433, wherein the solid tumor stem cell expresses at least one marker selected from the group consisting of CD44, epithelial specific antigen (ESA), and B38.1.
445. The method of claim 433, wherein the solid tumor stem cell expresses the cell surface marker CD44.
446. The method of claim 433, wherein the solid tumor stem cell expresses the cell surface marker epithelial specific antigen (ESA).
447. The method of claim 433, wherein the solid tumor stem cell expresses the cell surface marker B38.1.
448. The method of claim 433, wherein the solid tumor stem cell expresses lower levels of the marker CD24 than the mean expression of CD24 by non-tumorigenic cancer cells derived from the solid tumor.
449. The method of claim 433, wherein the solid tumor stem cell does not express detectable levels of one or more LINEAGE markers, wherein a LINEAGE marker is selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b.
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AU7813401A AU7813401A (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
EP10179961.7A EP2359863B1 (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
AU2001278134A AU2001278134B2 (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
EP01956101.8A EP1343871B1 (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
ES01956101.8T ES2553796T3 (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
JP2002517738A JP5352037B2 (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
US10/343,692 US7115360B2 (en) 2000-08-03 2001-08-02 Isolation and use of solid tumor stem cells
US11/529,869 US7850961B2 (en) 2000-08-03 2006-09-29 Methods for targeting solid tumor stem cells in a solid tumor using a notch4 receptor antagonist
US11/607,780 US7754206B2 (en) 2000-08-03 2006-12-01 Method for treating cancer using a Notch4 ligand antagonist
US11/651,214 US20090004205A1 (en) 2000-08-03 2007-01-09 Prospective identification and characterization of breast cancer stem cells
US11/788,489 US20080194022A1 (en) 2000-08-03 2007-04-20 Isolation and use of solid tumor stem cells
US11/776,935 US8044259B2 (en) 2000-08-03 2007-07-12 Determining the capability of a test compound to affect solid tumor stem cells
US12/758,540 US20110033481A1 (en) 2000-08-03 2010-04-12 Prospective identification and characterization of breast cancer stem cells
US12/979,991 US8357491B2 (en) 2000-08-03 2010-12-28 Isolation and use of solid tumor stem cells
US13/241,701 US8420885B2 (en) 2000-08-03 2011-09-23 Determining the capability of a test compound to affect solid tumor stem cells
US13/563,884 US20120295350A1 (en) 2000-08-03 2012-08-01 Prospective Identification and Characterization of Breast Cancer Stem Cells
US13/714,921 US20140011274A1 (en) 2000-08-03 2012-12-14 Isolation and use of solid tumor stem cells
US13/795,381 US9089556B2 (en) 2000-08-03 2013-03-12 Method for treating cancer using an antibody that inhibits notch4 signaling

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9228020B2 (en) 2006-09-29 2016-01-05 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
US9492538B2 (en) 2000-08-03 2016-11-15 The Regents Of The University Of Michigan Isolation and use of solid tumor stem cells
US9599620B2 (en) 2012-10-31 2017-03-21 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a DLL4 antagonist

Families Citing this family (186)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7361336B1 (en) * 1997-09-18 2008-04-22 Ivan Bergstein Methods of cancer therapy targeted against a cancer stem line
US8044259B2 (en) 2000-08-03 2011-10-25 The Regents Of The University Of Michigan Determining the capability of a test compound to affect solid tumor stem cells
CA2469204A1 (en) * 2001-12-07 2003-06-19 Regents Of The University Of Michigan Prospective identification and characterization of breast cancer stem cells
US20030226159A1 (en) * 2002-04-16 2003-12-04 Bachoo Robert M. Cancer models
AU2003277153A1 (en) 2002-09-27 2004-04-19 The General Hospital Corporation Microfluidic device for cell separation and uses thereof
US20060084599A1 (en) * 2003-03-05 2006-04-20 Maine Medical Center Compositions, methods and kits relating to notch signaling
WO2004090110A2 (en) * 2003-03-31 2004-10-21 Bresagen Inc. Compositions and methods for the control, differentiation and/or manipulation of pluripotent cells through a gamma-secretase signaling pathway
US20040265281A1 (en) * 2003-04-07 2004-12-30 Denis Rodgerson System capable of treating and defining various diseases using stem cells
GB0310191D0 (en) * 2003-05-02 2003-06-04 Cytovation As Method of generating and isolating tumour cells
US20060019256A1 (en) * 2003-06-09 2006-01-26 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
US7413734B2 (en) 2003-06-27 2008-08-19 Ethicon, Incorporated Treatment of retinitis pigmentosa with human umbilical cord cells
US8491883B2 (en) 2003-06-27 2013-07-23 Advanced Technologies And Regenerative Medicine, Llc Treatment of amyotrophic lateral sclerosis using umbilical derived cells
US8518390B2 (en) 2003-06-27 2013-08-27 Advanced Technologies And Regenerative Medicine, Llc Treatment of stroke and other acute neural degenerative disorders via intranasal administration of umbilical cord-derived cells
US7875273B2 (en) 2004-12-23 2011-01-25 Ethicon, Incorporated Treatment of Parkinson's disease and related disorders using postpartum derived cells
US8790637B2 (en) 2003-06-27 2014-07-29 DePuy Synthes Products, LLC Repair and regeneration of ocular tissue using postpartum-derived cells
US9592258B2 (en) 2003-06-27 2017-03-14 DePuy Synthes Products, Inc. Treatment of neurological injury by administration of human umbilical cord tissue-derived cells
US7875272B2 (en) 2003-06-27 2011-01-25 Ethicon, Incorporated Treatment of stroke and other acute neuraldegenerative disorders using postpartum derived cells
US9572840B2 (en) 2003-06-27 2017-02-21 DePuy Synthes Products, Inc. Regeneration and repair of neural tissue using postpartum-derived cells
US20050193432A1 (en) * 2003-11-18 2005-09-01 Whitehead Institute For Biomedical Research Xenograft model of functional normal and malignant human breast tissues in rodents and methods thereof
CN1950518A (en) 2004-02-03 2007-04-18 密执安州立大学董事会 Compositions and methods for characterizing, regulating, diagnosing, and treating cancer
US20050232927A1 (en) * 2004-02-03 2005-10-20 The Regents Of The University Of Michigan Compositions and methods for characterizing, regulating, diagnosing, and treating cancer
US20060121624A1 (en) * 2004-03-03 2006-06-08 Huang Lotien R Methods and systems for fluid delivery
EP1765503A2 (en) * 2004-03-03 2007-03-28 The General Hospital Corporation System for delivering a diluted solution
US8252591B2 (en) 2004-05-07 2012-08-28 Whitehead Institute For Biomedical Research Hormone responsive tissue culture system and uses thereof
CA2566549C (en) * 2004-05-12 2014-01-14 The Walter And Eliza Hall Institute Of Medical Research A method for isolating mammary stem cells
WO2005113753A2 (en) * 2004-05-14 2005-12-01 New York University Prostatic stem cells, isolation and uses
BRPI0512256A (en) * 2004-06-17 2008-02-19 Massachusetts Inst Technology method for characterizing the stage of development or pathology of a tissue sample; method of identifying a cell of interest or multi-nuclear syncytia of interest; method for diagnosis of pre-neoplasia or neoplasia; methods of identifying one or more antitumor agents and method of preparing a mammalian tissue sample suitable for the identification of cells
US7989001B2 (en) * 2004-09-13 2011-08-02 Untae Kim Method of separating tumor cells with and without lymphotropic metastatic potential in a human carcinoma
ITRM20040438A1 (en) * 2004-09-15 2004-12-15 Univ Palermo METHOD FOR PURIFICATION AND AMPLIFICATION OF CANCER STEM CELLS.
GB0421838D0 (en) * 2004-09-30 2004-11-03 Congenia S R L Cancer markers
US20080107648A1 (en) * 2005-12-16 2008-05-08 Regeneron Pharmaceuticals, Inc. Therapeutic methods for inhibiting tumor growth with DII4 antagonists
US8048418B2 (en) 2004-10-29 2011-11-01 Regeneron Pharmaceuticals, Inc. Therapeutic methods for inhibiting tumor growth with combination of Dll4 antagonists and VEGF antagonists
WO2006047878A1 (en) * 2004-11-03 2006-05-11 British Columbia Cancer Agency Branch Cancer therapeutics and methods for their use
WO2006051405A2 (en) * 2004-11-12 2006-05-18 Cambridge University Technical Services Ltd. Methods and means related to cancer stem cells
CA2589041C (en) 2004-12-23 2019-08-20 Ethicon, Incorporated Postpartum cells derived from umbilical cord tissue, and methods of making and using the same
US20070026418A1 (en) * 2005-07-29 2007-02-01 Martin Fuchs Devices and methods for enrichment and alteration of circulating tumor cells and other particles
US20060252073A1 (en) * 2005-04-18 2006-11-09 Regents Of The University Of Michigan Compositions and methods for the treatment of cancer
TWI399383B (en) 2005-05-16 2013-06-21 Abbott Biotech Ltd Use of tnfα inhibitor for treatment of erosive polyarthritis
EP1726208A3 (en) * 2005-05-24 2007-02-28 Centro de Investigacion Biomolecular Aplicada S.L. Murine stem cells and applications thereof
EP1915618A4 (en) * 2005-06-02 2009-09-30 Fluidigm Corp Analysis using microfluidic partitioning devices
AU2006259583A1 (en) * 2005-06-13 2006-12-28 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
WO2006135886A2 (en) * 2005-06-13 2006-12-21 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
WO2007005611A2 (en) 2005-06-30 2007-01-11 Whitehead Institute Progenitor cells and uses thereof
US20070044168A1 (en) * 2005-07-12 2007-02-22 Northwestern University Transplantable tumor model
US20070059680A1 (en) * 2005-09-15 2007-03-15 Ravi Kapur System for cell enrichment
US8921102B2 (en) 2005-07-29 2014-12-30 Gpb Scientific, Llc Devices and methods for enrichment and alteration of circulating tumor cells and other particles
US20070059719A1 (en) * 2005-09-15 2007-03-15 Michael Grisham Business methods for prenatal Diagnosis
US20070059716A1 (en) * 2005-09-15 2007-03-15 Ulysses Balis Methods for detecting fetal abnormality
DE102005052384B4 (en) * 2005-10-31 2009-09-24 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Method for the detection, labeling and treatment of epithelial lung tumor cells and means for carrying out the method
AU2006308847C1 (en) * 2005-10-31 2012-05-10 Oncomed Pharmaceuticals, Inc. Compositions and methods for treating and diagnosing cancer
JP2009513708A (en) 2005-10-31 2009-04-02 オンコメッド ファーマシューティカルズ インコーポレイテッド Compositions and methods for diagnosis and treatment of cancer
US7723477B2 (en) 2005-10-31 2010-05-25 Oncomed Pharmaceuticals, Inc. Compositions and methods for inhibiting Wnt-dependent solid tumor cell growth
US20070220621A1 (en) * 2005-10-31 2007-09-20 Clarke Michael F Genetic characterization and prognostic significance of cancer stem cells in cancer
WO2007067795A2 (en) * 2005-12-09 2007-06-14 Massachusetts Institute Of Technology Methods for identifying and targeting tumor stem cells based on nuclear morphology
PL1971681T3 (en) 2005-12-16 2018-01-31 Depuy Synthes Products Inc Compositions and methods for inhibiting adverse immune response in histocompatibility-mismatched transplantation
AU2006327073B2 (en) * 2005-12-19 2012-08-30 Ethicon, Inc. In vitro expansion of postpartum derived cells in roller bottles
US9125906B2 (en) 2005-12-28 2015-09-08 DePuy Synthes Products, Inc. Treatment of peripheral vascular disease using umbilical cord tissue-derived cells
WO2008121102A2 (en) * 2006-02-21 2008-10-09 The Regents Of The University Of Michigan Hedgehog signaling pathway antagonist cancer treatment
US20070243192A1 (en) * 2006-02-21 2007-10-18 Regents Of The University Of Michigan Growth hormone receptor antagonist cancer treatment
KR20090013752A (en) * 2006-03-16 2009-02-05 헬스 리서치 인코포레이티드 Inhibition of breast carcinoma stem cell growth and metastasis
WO2008063213A2 (en) 2006-04-10 2008-05-29 Abbott Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
WO2007134274A2 (en) * 2006-05-12 2007-11-22 Attenuon, Llc Antibodies to urokinase- type plasminogen activator receptor(upar)bind cancer stem cells: use in diagnosis and therapy
US7919092B2 (en) 2006-06-13 2011-04-05 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
WO2007147074A2 (en) * 2006-06-14 2007-12-21 Living Microsystems, Inc. Use of highly parallel snp genotyping for fetal diagnosis
US8137912B2 (en) * 2006-06-14 2012-03-20 The General Hospital Corporation Methods for the diagnosis of fetal abnormalities
EP2589668A1 (en) * 2006-06-14 2013-05-08 Verinata Health, Inc Rare cell analysis using sample splitting and DNA tags
US20080050739A1 (en) 2006-06-14 2008-02-28 Roland Stoughton Diagnosis of fetal abnormalities using polymorphisms including short tandem repeats
US20080124721A1 (en) * 2006-06-14 2008-05-29 Martin Fuchs Analysis of rare cell-enriched samples
WO2007147165A2 (en) * 2006-06-16 2007-12-21 Bresagen, Inc. Human cancer stem cell culture compositions comprising erbb2 variants and methods of use thereof
AU2007277508A1 (en) * 2006-07-28 2008-01-31 Chundsell Medicals Ab Embryonic stem cell markers for cancer diagnosis and prognosis
US20110244501A1 (en) * 2006-08-02 2011-10-06 Biogen Idec Ma Inc. Cancer stem cells
WO2008030538A2 (en) * 2006-09-07 2008-03-13 Stemline Therapeutics, Inc. Cancer stem cell-targeted cancer therapy
WO2008030616A2 (en) * 2006-09-07 2008-03-13 Stemline Therapeutics, Inc. Monitoring cancer stem cells
WO2008036419A2 (en) * 2006-09-22 2008-03-27 The Regents Of The University Of Michigan Aldehyde dehydrogenase 1(aldh1) as a cancer stem cell marker
CA2700573C (en) * 2006-09-26 2016-11-22 Cedars-Sinai Medical Center Cancer stem cell antigen vaccines and methods
US8871211B2 (en) * 2006-09-28 2014-10-28 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
ITMI20062100A1 (en) * 2006-10-31 2008-05-01 Fondazione I R C C S Istituto Neurologico METHOD FOR THE STIMULATION OF DENDRITIC CELLS AND CELL PRODUCT SO OBTAINED FOR AUTOLOGOUS IMMUNOTHERAPY OF HUMAN SOLID TUMORS
US8765390B2 (en) * 2006-12-08 2014-07-01 The Board Of Trustees Of The Leland Stanford Junior University Identification and isolation of squamous carcinoma stem cells
EP2610267A1 (en) 2006-12-18 2013-07-03 Genentech, Inc. Antagonist anti-Notch3 antibodies and their use in the prevention and treatment of Notch3-related diseases
NZ578181A (en) * 2006-12-20 2012-02-24 Novarx Universal tumor cell vaccine for anti cancer therapeutic and prophylactic utilization
US8309354B2 (en) * 2007-01-22 2012-11-13 Macrogenics West, Inc. Human cancer stem cells
WO2008091641A2 (en) 2007-01-24 2008-07-31 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
WO2008092002A2 (en) 2007-01-24 2008-07-31 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing pancreatic cancer
CA2676292C (en) * 2007-02-01 2017-09-19 Dana-Farber Cancer Institute, Inc. Cell co-culture systems and uses thereof
WO2008100563A2 (en) * 2007-02-14 2008-08-21 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
WO2008143795A1 (en) * 2007-05-11 2008-11-27 Champions Biotechnology, Inc. Human mesenchymal chrondrosarcoma xenograft model and its use in chemosensitivity testing
WO2008140751A1 (en) * 2007-05-11 2008-11-20 Champions Biotechnology, Inc. Human leiosarcoma and non small cell lung cancer lung xenograft models
JP5190861B2 (en) * 2007-05-11 2013-04-24 オリンパス株式会社 Biological tissue decomposition method
EP2155249A4 (en) * 2007-05-15 2011-11-16 Oncomed Pharm Inc Compositions and methods for diagnosing and treating cancer
JP5171945B2 (en) * 2007-06-13 2013-03-27 マサチューセッツ インスティテュート オブ テクノロジー Methods and agents for inhibiting tumor growth
KR101113167B1 (en) * 2007-06-14 2012-03-07 미쯔이 죠센 가부시키가이샤 Flow cytometer having cell-fractionation function and method of fractionating living cells
PT2173379E (en) 2007-07-02 2015-11-24 Oncomed Pharm Inc Compositions and methods for treating and diagnosing cancer
EP2676678A1 (en) * 2007-07-17 2013-12-25 The General Hospital Corporation Methods to identify and enrich populations of ovarian cancer stem cells and somatic stem cells and uses thereof
US20110244502A1 (en) 2007-08-10 2011-10-06 Whitehead Institute For Biomedical Research Hormone responsive tissue culture system and uses thereof
EP2037265A1 (en) * 2007-09-17 2009-03-18 Adnagen AG Solid phase cell isolation and/or enrichment method
EP2188630A4 (en) * 2007-10-02 2010-11-03 Univ Rochester Methods and compositions related to synergistic responses to oncogenic mutations
BRPI0818183A2 (en) 2007-10-05 2019-07-16 Ethicon Inc Renal tissue repair and regeneration using cells derived from human umbilical cord tissue
US8236538B2 (en) 2007-12-20 2012-08-07 Advanced Technologies And Regenerative Medicine, Llc Methods for sterilizing materials containing biologically active agents
US20110124032A1 (en) * 2008-02-01 2011-05-26 Maximilian Diehn Methods and Compositions for Treating Carcinoma Stem Cells
US8008032B2 (en) * 2008-02-25 2011-08-30 Cellective Dx Corporation Tagged ligands for enrichment of rare analytes from a mixed sample
WO2009111644A2 (en) * 2008-03-05 2009-09-11 The Regents Of The University Of Michigan Compositions and methods for diagnosing and treating pancreatic cancer
US9132189B2 (en) 2008-07-08 2015-09-15 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
JP5560270B2 (en) 2008-07-08 2014-07-23 オンコメッド ファーマシューティカルズ インコーポレイテッド NOTCH binding agents and antagonists and methods of use thereof
EP2318040A4 (en) * 2008-07-24 2013-05-01 Univ Central Florida Res Found Therapy targeting cancer stem cells
DK2328923T3 (en) 2008-09-02 2016-03-21 Cedars Sinai Medical Center CD133 epitopes
AU2009294415B2 (en) * 2008-09-19 2015-09-24 Medimmune Llc Antibodies directed to DLL4 and uses thereof
SI2334812T1 (en) 2008-09-20 2017-05-31 The Board of Trustees of the Leland Stanford Junior University Office of the General Counsel Building 170 Noninvasive diagnosis of fetal aneuploidy by sequencing
BRPI0919473A2 (en) 2008-09-26 2017-08-29 Oncomed Pharm Inc FRIZZLED BINDING AGENTS AND THEIR USES
US20100093552A1 (en) 2008-10-09 2010-04-15 Asit Panja Use and identification of biomarkers for gastrointestinal diseases
EP2340303B1 (en) * 2008-10-24 2016-10-12 Childrens Hospital Los Angeles Amniotic fluid cells and uses thereof
SI2356462T1 (en) 2008-11-11 2017-05-31 The Regents Of The University Of Michigan Anti-cxcr1 compositions and methods
EP2379088B1 (en) 2008-12-19 2018-02-28 DePuy Synthes Products, Inc. Treatment of lung and pulmonary diseases and disorders
US10179900B2 (en) * 2008-12-19 2019-01-15 DePuy Synthes Products, Inc. Conditioned media and methods of making a conditioned media
WO2010097793A2 (en) * 2009-02-26 2010-09-02 Tel Hashomer Medical Research Infrastructure And Services Ltd. Isolated populations of renal stem cells and methods of isolating and using same
US8170320B2 (en) 2009-03-03 2012-05-01 Hologic, Inc. Mammography/tomosynthesis systems and methods automatically deriving breast characteristics from breast x-ray images and automatically adjusting image processing parameters accordingly
US8762069B2 (en) * 2009-03-11 2014-06-24 Institute for Medical Biomathematics Therapeutic implications of dickkopf affecting cancer stem cell fate
JP5908394B2 (en) 2009-03-26 2016-04-26 デピュイ・シンセス・プロダクツ・インコーポレイテッド Human umbilical cord tissue cells as a therapy for Alzheimer's disease
PT2427485T (en) * 2009-05-07 2017-03-13 Immunocellular Therapeutics Ltd Cd133 epitopes
DK2488204T3 (en) 2009-10-16 2016-06-06 Oncomed Pharm Inc Therapeutic combination and use of DLL4 antagonist antibodies and blood pressure lowering agents
EP2496690A4 (en) * 2009-11-05 2013-07-24 Sloan Kettering Inst Cancer Catenae: serosal cancer stem cells
WO2011063237A2 (en) 2009-11-19 2011-05-26 Oncomed Pharmaceuticals, Inc. Jagged-binding agents and uses thereof
CA2782299A1 (en) * 2009-12-01 2011-06-09 Oncomed Pharmaceuticals, Inc. Methods for treating cancers comprising k-ras mutations
JP5808054B2 (en) * 2009-12-25 2015-11-10 中外製薬株式会社 Anticancer drug target search and screening method using non-human animal model transplanted with NOG established cancer cell line
TWI535445B (en) 2010-01-12 2016-06-01 安可美德藥物股份有限公司 Wnt antagonists and methods of treatment and screening
CN102958534B (en) 2010-01-13 2014-11-05 昂考梅德药品有限公司 Notch1 binding agents and methods of use thereof
US20110312503A1 (en) 2010-01-23 2011-12-22 Artemis Health, Inc. Methods of fetal abnormality detection
CA2788575C (en) 2010-01-28 2015-04-21 Shuichi Takayama Hanging drop devices, systems and/or methods
CA2794674A1 (en) 2010-04-01 2011-10-06 Oncomed Pharmaceuticals, Inc. Frizzled-binding agents and uses thereof
CA2806127C (en) 2010-07-23 2021-12-21 Advanced Cell Technology, Inc. Methods for detection of rare subpopulations of cells and highly purified compositions of cells
US9778264B2 (en) 2010-09-03 2017-10-03 Abbvie Stemcentrx Llc Identification and enrichment of cell subpopulations
CN103313726B (en) * 2010-09-03 2016-08-17 施特姆森特克斯股份有限公司 The qualification of cell subsets and enrichment
US8551479B2 (en) 2010-09-10 2013-10-08 Oncomed Pharmaceuticals, Inc. Methods for treating melanoma
AU2011308567B2 (en) 2010-10-01 2015-09-03 Fundacion Centro Nacional De Investigaciones Oncologicas, Carlos Iii Manipulation of stem cell function by p53 isoforms
SG196836A1 (en) 2010-10-06 2014-02-13 Pharmalogicals Res Pte Ltd Cancer stem cell population and method for production thereof
US9677042B2 (en) 2010-10-08 2017-06-13 Terumo Bct, Inc. Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
JP2013540276A (en) 2010-10-25 2013-10-31 マサチューセッツ インスティテュート オブ テクノロジー Metakaryotic stem cells that heal wounds and methods of use thereof
US8912156B1 (en) 2011-02-04 2014-12-16 Whitehead Institute For Biomedical Research Markers for and methods of targeting tumor stem cells
US9791449B2 (en) 2011-06-03 2017-10-17 The General Hospital Corporation Ovarian cancer stem cells and methods of isolation and uses thereof
CN106167526A (en) 2011-07-15 2016-11-30 昂考梅德药品有限公司 RSPO bonding agent and its application
US10018630B2 (en) 2011-09-07 2018-07-10 Chugai Seiyaku Kabushiki Kaisha Cancer stem cell isolation
PL3485903T3 (en) 2011-09-23 2023-06-12 Mereo Biopharma 5, Inc. Vegf/dll4 binding agents and uses thereof
CA2849011A1 (en) 2011-10-05 2013-04-11 Genentech, Inc. Methods of treating liver conditions using notch2 antagonists
US9327023B2 (en) 2011-10-25 2016-05-03 The Regents Of The University Of Michigan HER2 targeting agent treatment in non-HER2-amplified cancers having HER2 expressing cancer stem cells
US20140302511A1 (en) 2011-10-28 2014-10-09 Pharmalogicals Research Pte. Ltd. Cancer stem cell-specific molecule
WO2013096686A1 (en) 2011-12-23 2013-06-27 Advanced Technologies And Regenerative Medicine, Llc Detection of human umbilical cord tissue-derived cells
US10247731B2 (en) * 2012-02-22 2019-04-02 Verik Bio, Inc. System for immunotherapy targeting tumor propagation and progression
US20140147861A1 (en) * 2012-05-04 2014-05-29 The Regents of the University of Califomia Markers to identify primary cells from tumor biopsies
CA2874343C (en) 2012-05-21 2021-11-09 Fluidigm Corporation Single-particle analysis of particle populations
AU2013289990B2 (en) 2012-07-13 2018-06-14 Oncomed Pharmaceuticals, Inc. RSPO3 binding agents and uses thereof
EP2882441B1 (en) * 2012-08-09 2020-04-29 Celgene Corporation Treatment of immune-related and inflammatory diseases
US20150038511A1 (en) 2012-08-09 2015-02-05 Celgene Corporation Treatment of immune-related and inflammatory diseases
MX357675B (en) 2012-08-13 2018-07-18 Genentech Inc Anti-jagged anitbodies and methods of use.
JP2015526087A (en) * 2012-08-15 2015-09-10 ネオステム オンコロジー リミテッド ライビリティ カンパニー Rapid preparation of high purity cancer stem cells and high purity cancer stem cell populations
US20160017293A1 (en) * 2012-08-15 2016-01-21 Neostem Oncology, Llc Individualized high purity hepatocellular carcinoma stem cells, methods and use of the same
US11183269B2 (en) 2012-10-09 2021-11-23 Five3 Genomics, Llc Systems and methods for tumor clonality analysis
CN104854839B (en) * 2012-10-19 2018-10-12 交互数字专利控股公司 More hypothesis rate adaptations of HTTP steaming transfer
JP2015536933A (en) 2012-10-23 2015-12-24 オンコメッド ファーマシューティカルズ インコーポレイテッド Methods of treating neuroendocrine tumors using Wnt pathway binding agents
CN105073195A (en) 2013-02-04 2015-11-18 昂科梅德制药有限公司 Methods and monitoring of treatment with a Wnt pathway inhibitor
US20140234351A1 (en) 2013-02-14 2014-08-21 Immunocellular Therapeutics, Ltd. Cancer vaccines and vaccination methods
AU2014249344A1 (en) * 2013-03-11 2015-09-10 Neostem Oncology, Llc Method of induction and purification of a cell population responsible for vasculary mimicry and use of the same
AU2014248713A1 (en) * 2013-03-12 2015-09-10 Neostem Oncology, Llc Individualized high-purity glioblastoma multiforme stem cells and methods for stimulating immune response
US9168300B2 (en) 2013-03-14 2015-10-27 Oncomed Pharmaceuticals, Inc. MET-binding agents and uses thereof
WO2014151866A1 (en) 2013-03-15 2014-09-25 Genentech, Inc. Compositions and methods for diagnosis and treatment of hepatic cancers
EP3049155A1 (en) * 2013-09-27 2016-08-03 Vaccinogen International Partners, LP Autologous tumor vaccines and methods
WO2015073918A1 (en) 2013-11-16 2015-05-21 Terumo Bct, Inc. Expanding cells in a bioreactor
EP3097418B1 (en) * 2014-01-20 2021-04-28 National Centre For Cell Science A tumor deconstruction platform for the analysis of intra-tumor heterogeneity
KR102030891B1 (en) 2014-02-12 2019-10-11 제넨테크, 인크. Anti-jagged1 antibodies and methods of use
EP3613841B1 (en) 2014-03-25 2022-04-20 Terumo BCT, Inc. Passive replacement of media
EP3145513B1 (en) 2014-05-19 2023-11-15 Celgene Corporation 3-(4-((4-(morpholinomethyl-benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione for the treatment of systemic lupus erythematosus
US10883994B2 (en) 2014-06-25 2021-01-05 Tel Hashomer Medical Research Infrastructure And Services Ltd. Identification of cancer stem cells markers and use of same for diagnosis and treatment
WO2016044295A1 (en) 2014-09-16 2016-03-24 Oncomed Pharmaceuticals, Inc. Treatment of fibrotic diseases
JP6830059B2 (en) 2014-09-26 2021-02-17 テルモ ビーシーティー、インコーポレーテッド Scheduled cell feeding
EP3212233B1 (en) 2014-10-31 2020-06-24 Oncomed Pharmaceuticals, Inc. Combination therapy for treatment of disease
RU2720280C2 (en) 2015-04-16 2020-04-28 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Human notch4 antibody
WO2017004592A1 (en) 2015-07-02 2017-01-05 Terumo Bct, Inc. Cell growth with mechanical stimuli
AU2016326609B2 (en) 2015-09-23 2023-03-09 Mereo Biopharma 5, Inc. Methods and compositions for treatment of cancer
US11685883B2 (en) 2016-06-07 2023-06-27 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
US11104874B2 (en) 2016-06-07 2021-08-31 Terumo Bct, Inc. Coating a bioreactor
EP3566053A4 (en) * 2017-01-04 2020-11-25 National Taiwan University Biomarkers for lung cancer stem cells
US11629332B2 (en) 2017-03-31 2023-04-18 Terumo Bct, Inc. Cell expansion
US11624046B2 (en) 2017-03-31 2023-04-11 Terumo Bct, Inc. Cell expansion
JP2021534785A (en) 2018-08-28 2021-12-16 フレッド ハッチンソン キャンサー リサーチ センター Methods and Compositions for Adoptive T Cell Therapy Using Induced Notch Signaling
CN110487998B (en) * 2019-08-13 2023-01-31 迈克医疗电子有限公司 Parameter optimization method and device for magnetic separation system, analysis instrument and storage medium
KR20220116475A (en) * 2019-12-12 2022-08-23 아킬레스 테라퓨틱스 유케이 리미티드 Methods for obtaining nucleic acids for sequencing
RU2735982C2 (en) * 2020-06-02 2020-11-11 Федеральное государственное бюджетное учреждение Method for prediction of radiosensitivity of malignant growths of upper respiratory tract
WO2023225352A2 (en) * 2022-05-20 2023-11-23 Helex Inc. Methods for assessment of effects of gene editing

Family Cites Families (306)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) * 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US4089003A (en) * 1977-02-07 1978-05-09 Motorola, Inc. Multifrequency microstrip antenna
US4109496A (en) * 1977-12-20 1978-08-29 Norris Industries Trapped key mechanism
US4323546A (en) * 1978-05-22 1982-04-06 Nuc Med Inc. Method and composition for cancer detection in humans
US4411990A (en) 1979-06-13 1983-10-25 University Patents, Inc. Primary bioassay of human tumor stem cells
US4873191A (en) * 1981-06-12 1989-10-10 Ohio University Genetic transformation of zygotes
US4584268A (en) 1981-10-13 1986-04-22 Ceriani Roberto Luis Method and compositions for carcinoma diagnosis
US4612282A (en) * 1981-12-15 1986-09-16 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Monoclonal antibodies reactive with human breast cancer
US4670393A (en) * 1982-03-22 1987-06-02 Genentech, Inc. DNA vectors encoding a novel human growth hormone-variant protein
NZ207394A (en) 1983-03-08 1987-03-06 Commw Serum Lab Commission Detecting or determining sequence of amino acids
US4816567A (en) * 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4753894A (en) 1984-02-08 1988-06-28 Cetus Corporation Monoclonal anti-human breast cancer antibodies
US4960716A (en) 1984-05-01 1990-10-02 Ciba Corning Diagnostics Corp. Monoclonal antibodies specific for 330 KD breast tumor antigen and assay using said monoclonal antibodies
US5019497A (en) * 1984-11-09 1991-05-28 Lennart Olsson Human squamous lung carcinoma cell specific antigens and antibodies
US5034506A (en) * 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US4751177A (en) 1985-06-13 1988-06-14 Amgen Methods and kits for performing nucleic acid hybridization assays
EP0228075B1 (en) 1986-01-03 1991-04-03 Molecular Diagnostics, Inc. Eucaryotic genomic dna dot-blot hybridization method
US5225539A (en) * 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4877745A (en) 1986-11-17 1989-10-31 Abbott Laboratories Apparatus and process for reagent fluid dispensing and printing
GB2198290B (en) * 1986-11-29 1990-05-09 Stc Plc Dual band circularly polarised antenna with hemispherical coverage
US5116742A (en) 1986-12-03 1992-05-26 University Patents, Inc. RNA ribozyme restriction endoribonucleases and methods
US6270961B1 (en) 1987-04-01 2001-08-07 Hyseq, Inc. Methods and apparatus for DNA sequencing and DNA identification
US5202231A (en) 1987-04-01 1993-04-13 Drmanac Radoje T Method of sequencing of genomes by hybridization of oligonucleotide probes
US4904582A (en) 1987-06-11 1990-02-27 Synthetic Genetics Novel amphiphilic nucleic acid conjugates
US5080891A (en) * 1987-08-03 1992-01-14 Ddi Pharmaceuticals, Inc. Conjugates of superoxide dismutase coupled to high molecular weight polyalkylene glycols
US5087570A (en) 1988-05-10 1992-02-11 Weissman Irving L Homogeneous mammalian hematopoietic stem cell composition
US4981785A (en) * 1988-06-06 1991-01-01 Ventrex Laboratories, Inc. Apparatus and method for performing immunoassays
US4968103A (en) * 1988-07-22 1990-11-06 Photofinish Cosmetics Inc. Method of making a brush
WO1990001564A1 (en) 1988-08-09 1990-02-22 Microprobe Corporation Methods for multiple target analyses through nucleic acid hybridization
US5223409A (en) * 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5994617A (en) 1988-09-19 1999-11-30 Hsc Research Development Corporation Engraftment of immune-deficient mice with human cells
CA1335181C (en) 1988-10-11 1995-04-11 R. Alan Hardwick System for selective cell separation from cell concentrate
GB8823869D0 (en) * 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
US5534617A (en) * 1988-10-28 1996-07-09 Genentech, Inc. Human growth hormone variants having greater affinity for human growth hormone receptor at site 1
US5688666A (en) * 1988-10-28 1997-11-18 Genentech, Inc. Growth hormone variants with altered binding properties
DE68919715T2 (en) 1988-12-28 1995-04-06 Stefan Miltenyi METHOD AND MATERIALS FOR HIGHLY GRADUATED MAGNETIC SPLITTING OF BIOLOGICAL MATERIALS.
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
GB8901778D0 (en) 1989-01-27 1989-03-15 Univ Court Of The University O Manipulatory technique
US5219726A (en) 1989-06-02 1993-06-15 The Salk Institute For Biological Studies Physical mapping of complex genomes
US5143854A (en) 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
US5744101A (en) 1989-06-07 1998-04-28 Affymax Technologies N.V. Photolabile nucleoside protecting groups
US5527681A (en) 1989-06-07 1996-06-18 Affymax Technologies N.V. Immobilized molecular synthesis of systematically substituted compounds
US5545522A (en) 1989-09-22 1996-08-13 Van Gelder; Russell N. Process for amplifying a target polynucleotide sequence using a single primer-promoter complex
US6583115B1 (en) 1989-10-12 2003-06-24 Ohio University/Edison Biotechnology Institute Methods for treating acromegaly and giantism with growth hormone antagonists
JP2802518B2 (en) * 1989-10-13 1998-09-24 戸田工業株式会社 Magnetic recording media
US6673986B1 (en) 1990-01-12 2004-01-06 Abgenix, Inc. Generation of xenogeneic antibodies
EP1690935A3 (en) 1990-01-12 2008-07-30 Abgenix, Inc. Generation of xenogeneic antibodies
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5061620A (en) 1990-03-30 1991-10-29 Systemix, Inc. Human hematopoietic stem cell
US5614396A (en) * 1990-06-14 1997-03-25 Baylor College Of Medicine Methods for the genetic modification of endogenous genes in animal cells by homologous recombination
US5489677A (en) * 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
US5602240A (en) * 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5633425A (en) * 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) * 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5625126A (en) * 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5545806A (en) * 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
ES2246502T3 (en) * 1990-08-29 2006-02-16 Genpharm International, Inc. TRANSGENIC NON-HUMAN ANIMALS ABLE TO PRODUCE HETEROLOGICAL ANTIBODIES.
ATE164395T1 (en) * 1990-12-03 1998-04-15 Genentech Inc METHOD FOR ENRICHMENT OF PROTEIN VARIANTS WITH MODIFIED BINDING PROPERTIES
CA2097708A1 (en) 1990-12-06 1992-06-07 Stephen P. A. Fodor Very large scale immobilized polymer synthesis
DE69132905T2 (en) 1990-12-06 2002-08-01 Affymetrix Inc N D Ges D Staat Detection of nucleic acid sequences
DE4039677A1 (en) 1990-12-12 1992-06-17 Boehringer Mannheim Gmbh UNIVERSAL BINDING FILM
US5856441A (en) * 1991-05-03 1999-01-05 Yale University Serrate fragments and derivatives
IE20030749A1 (en) * 1991-05-03 2003-11-12 Indiana University Foundation Human notch and delta binding domains in torporythmic proteins, and methods based thereon
IL101728A (en) 1991-05-03 2007-08-19 Univ Yale Human notch and delta, binding domains in toporythmic proteins, and methods based thereon
ATE196548T1 (en) 1991-05-10 2000-10-15 Genentech Inc SELECTING AGONISTS AND ANTAGONISTS OF LIGANDS
US6429186B1 (en) 1991-05-10 2002-08-06 Genentech, Inc. Ligand antagonists for treatment of breast cancer
US5539082A (en) * 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5719262A (en) * 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5714331A (en) * 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
WO1994004679A1 (en) * 1991-06-14 1994-03-03 Genentech, Inc. Method for making humanized antibodies
US5851832A (en) 1991-07-08 1998-12-22 Neurospheres, Ltd. In vitro growth and proliferation of multipotent neural stem cells and their progeny
US5750376A (en) 1991-07-08 1998-05-12 Neurospheres Holdings Ltd. In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny
ES2136092T3 (en) * 1991-09-23 1999-11-16 Medical Res Council PROCEDURES FOR THE PRODUCTION OF HUMANIZED ANTIBODIES.
DE69230873T3 (en) 1991-09-24 2006-04-06 Keygene N.V. Selective restriction fragment amplification: general procedure for DNA fingerprinting
US5753229A (en) * 1991-09-25 1998-05-19 Mordoh; Jose Monoclonal antibodies reactive with tumor proliferating cells
US5605662A (en) 1993-11-01 1997-02-25 Nanogen, Inc. Active programmable electronic devices for molecular biological analysis and diagnostics
JP3509859B2 (en) * 1991-11-07 2004-03-22 ナノトロニクス,インコーポレイテッド Hybridization of chromophore and fluorophore conjugated polynucleotides to create donor-donor energy transfer systems
US6353150B1 (en) 1991-11-22 2002-03-05 Hsc Research And Development Limited Partnership Chimeric mammals with human hematopoietic cells
US5384261A (en) 1991-11-22 1995-01-24 Affymax Technologies N.V. Very large scale immobilized polymer synthesis using mechanically directed flow paths
US5869282A (en) * 1991-12-11 1999-02-09 Imperial Cancer Research Technology, Ltd. Nucleotide and protein sequences of the serrate gene and methods based thereon
US6004924A (en) * 1991-12-11 1999-12-21 Imperial Cancer Research Technology, Ltd. Protein sequences of serrate gene products
EP0552108B1 (en) * 1992-01-17 1999-11-10 Lakowicz, Joseph R. Energy transfer phase-modulation fluoro-immunoassay
US5376313A (en) * 1992-03-27 1994-12-27 Abbott Laboratories Injection molding a plastic assay cuvette having low birefringence
US5786158A (en) 1992-04-30 1998-07-28 Yale University Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
US20050112121A1 (en) 1992-04-30 2005-05-26 Yale University Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
US5840484A (en) 1992-07-17 1998-11-24 Incyte Pharmaceuticals, Inc. Comparative gene transcript analysis
US5654183A (en) 1992-07-27 1997-08-05 California Institute Of Technology Genetically engineered mammalian neural crest stem cells
US5849553A (en) 1992-07-27 1998-12-15 California Institute Of Technology Mammalian multipotent neural stem cells
NZ256154A (en) 1992-07-27 1997-02-24 California Inst Of Techn Production of mammalian multipotent neural stem cells, antibodies
US5693482A (en) 1992-07-27 1997-12-02 California Institute Of Technology Neural chest stem cell assay
US5589376A (en) 1992-07-27 1996-12-31 California Institute Of Technology Mammalian neural crest stem cells
DE69333366T2 (en) 1992-10-30 2004-09-16 The General Hospital Corp., Boston A NEW CELL CYCLE CONTROL PROTEIN
GB9223084D0 (en) * 1992-11-04 1992-12-16 Imp Cancer Res Tech Compounds to target cells
JP3106021B2 (en) * 1992-11-30 2000-11-06 キヤノン株式会社 Pattern data compression method and apparatus and output method and apparatus
JP3189279B2 (en) * 1993-02-19 2001-07-16 日本新薬株式会社 Pharmaceutical composition containing nucleic acid copolymer
US5639606A (en) * 1993-04-06 1997-06-17 The University Of Rochester Method for quantitative measurement of gene expression using multiplex competitive reverse transcriptase-polymerase chain reaction
US5876978A (en) * 1993-04-06 1999-03-02 Medical College Of Ohio Method for quantitative measurement of gene expression using multiplex competitive reverse transcriptase-polymerase chain reaction
US5643765A (en) * 1993-04-06 1997-07-01 University Of Rochester Method for quantitative measurement of gene expression using multiplex competitive reverse transcriptase-polymerase chain reaction
US5744306A (en) 1993-04-19 1998-04-28 Emory University Methods for nucleic acid detection, sequencing, and cloning using exonuclease
US5674694A (en) 1993-09-21 1997-10-07 Biologic & Immunologic Science Laboratories, Inc. Clonogenic assay for detecting micro levels of tumor cells in hematopoietic samples
US5681860A (en) 1993-09-21 1997-10-28 The Trustees Of Columbia University In The City Of New York Method of increasing expression of HLA, cell surface and TAA antigens of cells using 3-(N-acetylamino)-5-(N-decyl-N-methylamino)-benzyl alcohol
AU8126694A (en) 1993-10-26 1995-05-22 Affymax Technologies N.V. Arrays of nucleic acid probes on biological chips
US5538848A (en) * 1994-11-16 1996-07-23 Applied Biosystems Division, Perkin-Elmer Corp. Method for detecting nucleic acid amplification using self-quenching fluorescence probe
US5599677A (en) * 1993-12-29 1997-02-04 Abbott Laboratories Immunoassays for prostate specific antigen
US5654419A (en) 1994-02-01 1997-08-05 The Regents Of The University Of California Fluorescent labels and their use in separations
US5631734A (en) 1994-02-10 1997-05-20 Affymetrix, Inc. Method and apparatus for detection of fluorescently labeled materials
US5578832A (en) 1994-09-02 1996-11-26 Affymetrix, Inc. Method and apparatus for imaging a sample on a device
US6015880A (en) 1994-03-16 2000-01-18 California Institute Of Technology Method and substrate for performing multiple sequential reactions on a matrix
US5571639A (en) 1994-05-24 1996-11-05 Affymax Technologies N.V. Computer-aided engineering system for design of sequence arrays and lithographic masks
ATE336587T1 (en) * 1994-06-10 2006-09-15 Genvec Inc ADENOVIRUS VECTOR SYSTEMS AND CELL LINES
US5807522A (en) 1994-06-17 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods for fabricating microarrays of biological samples
US6156305A (en) 1994-07-08 2000-12-05 Baxter International Inc. Implanted tumor cells for the prevention and treatment of cancer
US5710000A (en) 1994-09-16 1998-01-20 Affymetrix, Inc. Capturing sequences adjacent to Type-IIs restriction sites for genomic library mapping
US5650317A (en) 1994-09-16 1997-07-22 Michigan State University Human breast epithelial cell type with stem cell and luminal epithelial cell characteristics
US5567326A (en) 1994-09-19 1996-10-22 Promega Corporation Multisample magnetic separation device
US5556752A (en) 1994-10-24 1996-09-17 Affymetrix, Inc. Surface-bound, unimolecular, double-stranded DNA
WO1996013597A2 (en) * 1994-10-28 1996-05-09 The Trustees Of The University Of Pennsylvania Improved adenovirus and methods of use thereof
US6218166B1 (en) 1994-12-09 2001-04-17 John Wayne Cancer Institute Adjuvant incorporation into antigen carrying cells: compositions and methods
US5736396A (en) 1995-01-24 1998-04-07 Case Western Reserve University Lineage-directed induction of human mesenchymal stem cell differentiation
US5872154A (en) * 1995-02-24 1999-02-16 The Trustees Of The University Of Pennsylvania Method of reducing an immune response to a recombinant adenovirus
US5599695A (en) 1995-02-27 1997-02-04 Affymetrix, Inc. Printing molecular library arrays using deprotection agents solely in the vapor phase
US5731168A (en) * 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US6090822A (en) * 1995-03-03 2000-07-18 Margolin; Solomon B. Treatment of cytokine growth factor caused disorders
US5707618A (en) * 1995-03-24 1998-01-13 Genzyme Corporation Adenovirus vectors for gene therapy
US6091001A (en) 1995-03-29 2000-07-18 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US6130364A (en) 1995-03-29 2000-10-10 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US5633161A (en) * 1995-03-29 1997-05-27 Millennium Pharmaceuticals, Inc. Murine gene fomy030 coding for tumor progression inhibitor
US5641870A (en) * 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
US5821108A (en) 1995-04-07 1998-10-13 The Board Of Trustees Of The Leland Stanford Junior University Enrichment for a thymocyte subset having progenitor cell activity using c-kit as a selection marker
AU705616B2 (en) 1995-04-21 1999-05-27 Cell Genesys, Inc. Generation of large genomic DNA deletions
US5753439A (en) 1995-05-19 1998-05-19 Trustees Of Boston University Nucleic acid detection methods
US5610620A (en) * 1995-05-19 1997-03-11 Comant Industries, Inc. Combination antenna
US6019978A (en) * 1995-06-05 2000-02-01 The Wistar Institute Of Anatomy And Biology Replication-defective adenovirus human type 5 recombinant as a vaccine carrier
US5545531A (en) 1995-06-07 1996-08-13 Affymax Technologies N.V. Methods for making a device for concurrently processing multiple biological chip assays
ATE445705T1 (en) * 1995-06-15 2009-10-15 Crucell Holland Bv PACKAGING SYSTEMS FOR HUMAN RECOMBINANT ADENOVIRUSES FOR GENE THERAPY
US6117985A (en) * 1995-06-16 2000-09-12 Stemcell Technologies Inc. Antibody compositions for preparing enriched cell preparations
ES2334953T3 (en) 1995-06-28 2010-03-17 Imperial Cancer Research Technology Limited SEQUENCES OF NUCLEOTIDES AND PROTEINS OF DELTA GENES OF VERTEBRATES AND METHODS BASED ON THE SAME.
US5733729A (en) 1995-09-14 1998-03-31 Affymetrix, Inc. Computer-aided probability base calling for arrays of nucleic acid probes on chips
ES2190388T3 (en) * 1995-09-21 2006-04-01 Genentech, Inc. VARIANTS OF HUMAN GROWTH HORMONE.
US5780300A (en) 1995-09-29 1998-07-14 Yale University Manipulation of non-terminally differentiated cells using the notch pathway
US5986170A (en) * 1995-11-13 1999-11-16 Corixa Corporation Murine model for human carcinoma
CA2237589A1 (en) 1995-11-16 1997-05-22 Michael W. Dahm Method of quantifying tumour cells in a body fluid and a suitable test kit
JP4283891B2 (en) 1995-11-17 2009-06-24 旭化成株式会社 Differentiation-inhibiting polypeptide
US5598677A (en) * 1995-12-19 1997-02-04 Rehm, Iii; Frederick G. Insulated covering for building sheathing
WO1997023782A1 (en) 1995-12-22 1997-07-03 Abbott Laboratories Fluorescence polarization immunoassay diagnostic method
US5720722A (en) * 1996-01-11 1998-02-24 Medela, Incorporated Connector for use in single and double breast pumping and breast pump using same
US5994316A (en) 1996-02-21 1999-11-30 The Immune Response Corporation Method of preparing polynucleotide-carrier complexes for delivery to cells
US5714352A (en) 1996-03-20 1998-02-03 Xenotech Incorporated Directed switch-mediated DNA recombination
DE69713336T2 (en) 1996-03-30 2002-12-05 Science Park Raf S P A Process for the production of activated labeled tumor-specific T cells and their use in the treatment of tumors
US5753506A (en) 1996-05-23 1998-05-19 Cns Stem Cell Technology, Inc. Isolation propagation and directed differentiation of stem cells from embryonic and adult central nervous system of mammals
US6716974B1 (en) 1996-05-31 2004-04-06 Maine Medical Center Research Institute Therapeutic and diagnostic methods and compositions based on jagged/notch proteins and nucleic acids
JP2000512134A (en) 1996-05-31 2000-09-19 ザ ナショナル アメリカン レッド クロス Methods and compositions for therapeutic and diagnostics based on Jagged / Notch proteins and nucleic acids
US5928638A (en) 1996-06-17 1999-07-27 Systemix, Inc. Methods for gene transfer
US5885529A (en) * 1996-06-28 1999-03-23 Dpc Cirrus, Inc. Automated immunoassay analyzer
FR2751986B1 (en) 1996-08-01 1998-12-31 Inst Nat Sante Rech Med GENE INVOLVED IN CADASIL, DIAGNOSTIC METHOD AND THERAPEUTIC APPLICATION
EP0963432A4 (en) * 1996-08-29 2002-11-20 Univ California Kuz, a novel family of metalloproteases
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
KR20000049096A (en) 1996-10-11 2000-07-25 린다 에스. 스티븐슨 Cancer immunotherapy using tumor cells combined with mixed lymphocytes
US5994132A (en) * 1996-10-23 1999-11-30 University Of Michigan Adenovirus vectors
US5859535A (en) * 1997-02-12 1999-01-12 The United States Of America As Represented By The Secretary Of The Navy System for determining size and location of defects in material by use of microwave radiation
SE508356C2 (en) * 1997-02-24 1998-09-28 Ericsson Telefon Ab L M Antenna Installations
US6165709A (en) 1997-02-28 2000-12-26 Fred Hutchinson Cancer Research Center Methods for drug target screening
DE69837839T2 (en) * 1997-03-07 2007-12-13 Clare Chemical Research LLC, Denver Fluorometric detection with visible light
US6080912A (en) * 1997-03-20 2000-06-27 Wisconsin Alumni Research Foundation Methods for creating transgenic animals
US20020137890A1 (en) 1997-03-31 2002-09-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US20030180784A1 (en) 1997-04-04 2003-09-25 Millennium Pharmaceuticals, Inc. Novel human Delta3 compositions and therapeutic and diagnostic uses therefor
US20060122373A1 (en) 1997-04-04 2006-06-08 Millennium Pharmaceuticals, Inc. Delta3, FTHMA-070, Tango85, Tango77, SPOIL,NEOKINE, Tango129 and integrin alpha subunit protein and nucleic acid molecules and uses thereof
US6121045A (en) * 1997-04-04 2000-09-19 Millennium Biotherapeutics, Inc. Human Delta3 nucleic acid molecules
DE69836131T3 (en) 1997-04-04 2017-06-14 Millennium Pharmaceuticals, Inc. NEW HUMAN DELTA3 COMPOSITION AND ITS THERAPEUTIC AND DIAGNOSTIC USES
DE19715484A1 (en) 1997-04-14 1998-10-15 Boehringer Mannheim Gmbh Procedure for applying reagent spots
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US5830730A (en) * 1997-05-08 1998-11-03 The Regents Of The University Of California Enhanced adenovirus-assisted transfection composition and method
US5894869A (en) * 1997-05-12 1999-04-20 Crosman Corporation CO2 cartridge pressurization device
CA2288218C (en) 1997-05-14 2013-03-12 Asahi Kasei Kogyo Kabushiki Kaisha Novel differentiation-inhibitor
US6379925B1 (en) 1997-06-18 2002-04-30 The Trustees Of Columbia University In The City Of New York Angiogenic modulation by notch signal transduction
AU8162898A (en) 1997-06-18 1999-01-04 Trustees Of Columbia University In The City Of New York, The Angiogenic modulation by notch signal transduction
US6136952A (en) * 1997-06-25 2000-10-24 University Of Washington Human jagged polypeptide, encoding nucleic acids and methods of use
CA2290736A1 (en) 1997-07-11 1999-01-21 Introgene B.V. Interleukin-3 gene therapy for cancer
US6004528A (en) 1997-09-18 1999-12-21 Bergstein; Ivan Methods of cancer diagnosis and therapy targeted against the cancer stemline
US7361336B1 (en) * 1997-09-18 2008-04-22 Ivan Bergstein Methods of cancer therapy targeted against a cancer stem line
DE69804653T2 (en) 1997-10-31 2002-11-28 Pe Corp Ny Foster City METHOD AND DEVICE FOR PRODUCING MATRIXES OF SAMPLES
US6197523B1 (en) * 1997-11-24 2001-03-06 Robert A. Levine Method for the detection, identification, enumeration and confirmation of circulating cancer and/or hematologic progenitor cells in whole blood
US6506559B1 (en) 1997-12-23 2003-01-14 Carnegie Institute Of Washington Genetic inhibition by double-stranded RNA
US6183968B1 (en) 1998-03-27 2001-02-06 Incyte Pharmaceuticals, Inc. Composition for the detection of genes encoding receptors and proteins associated with cell proliferation
US5981225A (en) * 1998-04-16 1999-11-09 Baylor College Of Medicine Gene transfer vector, recombinant adenovirus particles containing the same, method for producing the same and method of use of the same
US5965352A (en) 1998-05-08 1999-10-12 Rosetta Inpharmatics, Inc. Methods for identifying pathways of drug action
US6218122B1 (en) 1998-06-19 2001-04-17 Rosetta Inpharmatics, Inc. Methods of monitoring disease states and therapies using gene expression profiles
US6818213B1 (en) * 1998-07-13 2004-11-16 Board Of Regents, The University Of Texas System Cancer treatment compositions comprising therapeutic conjugates that bind to aminophospholipids
AU4870599A (en) 1998-07-27 2000-02-21 Amgen, Inc. Delta-related polypeptides
WO2000009675A1 (en) 1998-08-14 2000-02-24 Aventis Pharmaceuticals Products Inc. Adenovirus formulations for gene therapy
CA2341061A1 (en) 1998-08-27 2000-03-09 Aventis Pharma S.A. Targeted adenovirus vectors for delivery of heterologous genes
GB9819681D0 (en) 1998-09-09 1998-11-04 Smithkline Beecham Plc Novel compounds
US6146830A (en) 1998-09-23 2000-11-14 Rosetta Inpharmatics, Inc. Method for determining the presence of a number of primary targets of a drug
CA2343963A1 (en) * 1998-10-02 2000-04-13 The Government Of The United States Of America As Represented By The Secretary, Dept. Of Health And Human Services, The National Institutes Of Health Apotosis inducing agents and methods
DE69939327D1 (en) 1998-11-02 2008-09-25 Curis Inc FUNCTIONAL ANTAGONISTS OF HEDGEHOG ACTIVITY
WO2000028090A2 (en) 1998-11-12 2000-05-18 Nyxis, Inc. Diagnostic assay for cancer
US6291516B1 (en) 1999-01-13 2001-09-18 Curis, Inc. Regulators of the hedgehog pathway, compositions and uses related thereto
US6610484B1 (en) 1999-01-26 2003-08-26 Cytyc Health Corporation Identifying material from a breast duct
US6215894B1 (en) 1999-02-26 2001-04-10 General Scanning, Incorporated Automatic imaging and analysis of microarray biochips
EP1119368A2 (en) 1999-03-03 2001-08-01 Biogen, Inc. Methods of modulating lipid metabolism and storage
US20030003572A1 (en) 1999-03-05 2003-01-02 David J. Anderson Isolation and enrichment of neural stem cells from uncultured tissue based on cell-surface marker expression
US20030119029A1 (en) 1999-04-30 2003-06-26 Regents Of The University Of Michigan Compositions and methods relating to novel benzodiazepine compounds and targets thereof
WO2000073337A1 (en) 1999-06-01 2000-12-07 Biogen, Inc. Polymer conjugates of hedgehog proteins and uses
US6703221B1 (en) 1999-08-19 2004-03-09 Chiron Corporation Notch receptor ligands and uses thereof
EP1690872A3 (en) 1999-12-01 2006-08-23 Genentech, Inc. Composition and methods for the diagnosis of tumours
US6380362B1 (en) 1999-12-23 2002-04-30 Genesis Research & Development Corporation Ltd. Polynucleotides, polypeptides expressed by the polynucleotides and methods for their use
AU2000226035A1 (en) 2000-01-10 2001-07-24 Cd Warehouse, Inc. Method and apparatus for arranging for sales using centralized ordering and decentralized shipping
US20040048249A1 (en) 2000-01-21 2004-03-11 Tang Y. Tom Novel nucleic acids and secreted polypeptides
JP2003520266A (en) 2000-01-24 2003-07-02 メルク シャープ エンド ドーム リミテッド γ-secretase inhibitor
GB0005251D0 (en) 2000-03-03 2000-04-26 Merck Sharp & Dohme Therapeutic compounds
US7115653B2 (en) 2000-03-30 2006-10-03 Curis, Inc. Small organic molecule regulators of cell proliferation
US20050070578A1 (en) 2000-03-30 2005-03-31 Baxter Anthony David Small organic molecule regulators of cell proliferation
GB0008710D0 (en) 2000-04-07 2000-05-31 Merck Sharp & Dohme Therapeutic compounds
US7498304B2 (en) 2000-06-16 2009-03-03 Curis, Inc. Angiogenesis-modulating compositions and uses
AU2001268513A1 (en) 2000-06-17 2002-01-02 Third Wave Technologies, Inc. Nucleic acid accessible hybridization sites
CA2414015A1 (en) 2000-06-21 2001-12-27 Incyte Genomics, Inc. Human receptors
US6632620B1 (en) * 2000-06-22 2003-10-14 Andrew N. Makarovskiy Compositions for identification and isolation of stem cells
DE10031380A1 (en) 2000-06-28 2002-01-10 Merck Patent Gmbh Process for the transfer of alkylidene groups to organic compounds
GB0016681D0 (en) 2000-07-06 2000-08-23 Merck Sharp & Dohme Therapeutic compounds
WO2002008765A2 (en) 2000-07-26 2002-01-31 Stanford University Basal cell markers in breast cancer and uses thereof
US6984522B2 (en) 2000-08-03 2006-01-10 Regents Of The University Of Michigan Isolation and use of solid tumor stem cells
WO2002018544A2 (en) 2000-08-31 2002-03-07 Loyola University Chicago Method and reagents for treatment of skin disorders by modulating the notch pathway
US6689744B2 (en) 2000-09-22 2004-02-10 Genentech, Inc. Notch receptor agonists and uses
US20020061289A1 (en) * 2000-10-04 2002-05-23 Boman Bruce M. Stem cell-based methods for preventing and treating tumor
US7708998B2 (en) 2000-10-13 2010-05-04 Curis, Inc. Methods of inhibiting unwanted cell proliferation using hedgehog antagonists
US7413873B2 (en) 2001-01-30 2008-08-19 The Regents Of The University Of California Method of detection and treatment of colon cancer
US20020169300A1 (en) 2001-01-30 2002-11-14 Waterman Marian L. Method of detection and treatment of colon cancer by analysis of beta-catenin-sensitive isoforms of lymphoid enhancer factor-1
US20030064384A1 (en) 2001-04-02 2003-04-03 Mien-Chie Hung Beta-catenin is a strong and independent prognostic factor for cancer
US7713526B2 (en) 2001-05-01 2010-05-11 The Regents Of The University Of California Wnt and frizzled receptors as targets for immunotherapy in head and neck squamous cell carcinomas
US20030044409A1 (en) 2001-05-01 2003-03-06 Carson Dennis A. Immunologic compositions and methods for studying and treating cancers expressing frizzled antigens
WO2002088081A2 (en) 2001-05-01 2002-11-07 The Regents Of The University Of California Wnt and frizzled receptors as targets for immunotherapy in head and neck squamous cell carcinomas
WO2002102978A2 (en) 2001-06-15 2002-12-27 Genentech, Inc. Human growth hormone antagonists
US7171311B2 (en) 2001-06-18 2007-01-30 Rosetta Inpharmatics Llc Methods of assigning treatment to breast cancer patients
US20040023244A1 (en) 2001-06-21 2004-02-05 Griffin Jennifer A Receptors
EP1406998B1 (en) * 2001-06-22 2007-08-22 StemCells, Inc. Liver engrafting cells, assays, and uses thereof
WO2003000893A2 (en) 2001-06-26 2003-01-03 Decode Genetics Ehf. Nucleic acids encoding g protein-coupled receptors
EP1411938B1 (en) 2001-07-02 2005-07-06 Tas, Sinan Use of cyclopamine for the manufacture of a medicament for the treatemnt of psoriasis
CA2452151C (en) 2001-07-02 2012-01-03 Sinan Tas Use of cyclopamine, an inducer of the differentiation and apoptosis of the basal cell carcinoma (bcc) cells, in the treatment of bcc's and other tumors that use the hedgehog/smoothened pathway for proliferation of apoptosis
AU2002317105A1 (en) 2001-07-05 2003-01-21 University Of British Columbia Methods for identifying therapeutic agents for treating diseases involving wnt polypeptides and wnt receptors
JP2004537314A (en) 2001-07-25 2004-12-16 ロランティス リミテッド Methods for detecting Notch signaling modulators
CA2455100C (en) 2001-07-27 2013-05-28 Curis, Inc. Mediators of hedgehog signaling pathways,compositions and uses related thereto
US7122675B2 (en) 2001-08-03 2006-10-17 Schering Corporation Gamma secretase inhibitors
EP1492765B1 (en) 2001-08-03 2011-07-06 Schering Corporation Novel gamma secretase inhibitors
WO2003042246A2 (en) 2001-11-14 2003-05-22 Lorantis Limited Inhibitors of the notch signalling pathway for use in the treatment of cancer
US20050137130A1 (en) 2001-11-14 2005-06-23 Bodmer Mark W. Medical treatment
AU2002352967A1 (en) 2001-11-29 2003-06-10 The Trustees Of Princeton University Increased emission efficiency in organic light-emitting devices on high-index substrates
CA2469204A1 (en) 2001-12-07 2003-06-19 Regents Of The University Of Michigan Prospective identification and characterization of breast cancer stem cells
EP1465984A1 (en) 2002-01-17 2004-10-13 Kobenhavns Universitet A suprabasal breast cell line with stem cell properties
GB0201674D0 (en) 2002-01-25 2002-03-13 Lorantis Ltd Medical treatment
US20050089896A1 (en) 2003-02-18 2005-04-28 Roy Frans V. Method to control tumor progression and invasiveness
US20030185829A1 (en) 2002-03-12 2003-10-02 Erich Koller Jagged 2 inhibitors for inducing apoptosis
EP3115470B1 (en) 2002-03-13 2018-07-18 Genomic Health, Inc. Gene expression profiling in biopsied tumor tissues
JP2005529876A (en) 2002-04-22 2005-10-06 ジョンズ ホプキンス ユニバーシティー スクール オブ メディシン Modulators of the Hedgehog signaling pathway, compositions related thereto and uses
EP2365004B1 (en) 2002-06-21 2016-01-06 Johns Hopkins University School of Medicine Membrane associated tumor endothelium markers
GB0218879D0 (en) 2002-08-14 2002-09-25 Lorantis Ltd Medical treatment
US7803370B2 (en) 2002-08-30 2010-09-28 Oncotherapy Science, Inc. Method for treating synovial sarcoma
AU2003267563A1 (en) 2002-09-10 2004-04-30 Lorantis Limited Pharmaceutical composition and medical treatments comprising notch ligand proteins
GB0221952D0 (en) 2002-09-20 2002-10-30 Novartis Forschungsstiftung Wnt mediated ErbB1 signalling,compositions and uses related thereto
CA2501235A1 (en) 2002-10-04 2004-04-22 The Regents Of The University Of California Methods for treating cancer by inhibiting wnt signaling
CA2503390A1 (en) 2002-11-01 2004-05-21 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
US20040231909A1 (en) 2003-01-15 2004-11-25 Tai-Yang Luh Motorized vehicle having forward and backward differential structure
WO2004073657A2 (en) 2003-02-19 2004-09-02 Protein Design Labs, Inc. Methods of diagnosis of cancer and other diseases, composition and methods of screening for modulators of cancer and other diseases
JP2007525167A (en) 2003-04-01 2007-09-06 ジェンザイム・コーポレーション Breast endothelial cell expression pattern
WO2004097030A2 (en) 2003-04-28 2004-11-11 Bristol-Myers Squibb Company Prognostic breast cancer biomarkers
WO2004099379A2 (en) 2003-05-02 2004-11-18 Health Research, Inc. Use of jag2 expression in diagnosis of plasma cell disorders
US20060019256A1 (en) 2003-06-09 2006-01-26 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
GB0321805D0 (en) 2003-09-18 2003-10-15 Univ Wales Medicine Human tumour growth patterns
US6894522B2 (en) * 2003-10-06 2005-05-17 International Business Machines Corporation Specific site backside underlaying and micromasking method for electrical characterization of semiconductor devices
US20050232927A1 (en) 2004-02-03 2005-10-20 The Regents Of The University Of Michigan Compositions and methods for characterizing, regulating, diagnosing, and treating cancer
US20050221476A1 (en) 2004-03-18 2005-10-06 Arindom Sen Chemical dissociation of cell aggregates
CA2566549C (en) 2004-05-12 2014-01-14 The Walter And Eliza Hall Institute Of Medical Research A method for isolating mammary stem cells
US20060040883A1 (en) 2004-05-14 2006-02-23 The Regents Of The University Of California Methods for treating cancer using anti-Wnt2 monoclonal antibodies and siRNA
KR101487481B1 (en) 2004-08-27 2015-01-28 인피니티 디스커버리, 인코포레이티드 Cyclopamine analogues and methods of use thereof
WO2006027693A2 (en) 2004-09-09 2006-03-16 Exonhit Therapeutics Sa Tumor specific genes and variant rnas and uses thereof as targets for cancer therapy and diagnosis
GB0421838D0 (en) 2004-09-30 2004-11-03 Congenia S R L Cancer markers
US8048418B2 (en) 2004-10-29 2011-11-01 Regeneron Pharmaceuticals, Inc. Therapeutic methods for inhibiting tumor growth with combination of Dll4 antagonists and VEGF antagonists
US20060134121A1 (en) 2004-10-29 2006-06-22 Gavin Thurston DII4 antagonists, assays, and therapeutic methods thereof
US20080107648A1 (en) * 2005-12-16 2008-05-08 Regeneron Pharmaceuticals, Inc. Therapeutic methods for inhibiting tumor growth with DII4 antagonists
WO2006052128A1 (en) 2004-11-10 2006-05-18 Hubrecht Laboratorium Treatment of an intestinal adenoma and/or adenocarcinoma by inhibition of notch pathway activation
AU2006259583A1 (en) 2005-06-13 2006-12-28 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
WO2006135886A2 (en) 2005-06-13 2006-12-21 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
AU2006308847C1 (en) 2005-10-31 2012-05-10 Oncomed Pharmaceuticals, Inc. Compositions and methods for treating and diagnosing cancer
US20070220621A1 (en) 2005-10-31 2007-09-20 Clarke Michael F Genetic characterization and prognostic significance of cancer stem cells in cancer
US7714014B2 (en) 2005-12-09 2010-05-11 The Regents Of The University Of California Targeting GLI proteins in human cancer by small molecules
US20070243192A1 (en) 2006-02-21 2007-10-18 Regents Of The University Of Michigan Growth hormone receptor antagonist cancer treatment
WO2008121102A2 (en) 2006-02-21 2008-10-09 The Regents Of The University Of Michigan Hedgehog signaling pathway antagonist cancer treatment
WO2008057144A2 (en) 2006-05-15 2008-05-15 The Brigham And Women's Hospital, Inc. Functional negative regulatory domain sequences from human notch1 and 2 and isolated lnr domains from human notch1
BRPI0710411A2 (en) * 2006-06-06 2012-04-10 Genentch Inc Empresa Americana METHODS FOR TREATING A TUMOR, FOR TREATING A PATHOLOGICAL CONDITION ASSOCIATED WITH ANGIOGENESIS, TO STIMULATING ENDOTHELIAL CELL PROLIFERATION, TO REDUCE OR INHIBIT ENDOTHELIAL CELL DIFFERENTIATION, TO REDUCE OR INHIBIT TO DEVELOP, DETERMINING, DETECTING EFFECTIVENESS OF AN ANTI-ANGIOGENIC AGENT, USES OF A DLL4 ANTAGONIST AND USE OF A DLL4 AGONISTER
WO2008036419A2 (en) 2006-09-22 2008-03-27 The Regents Of The University Of Michigan Aldehyde dehydrogenase 1(aldh1) as a cancer stem cell marker
US7700113B2 (en) 2006-10-19 2010-04-20 Maine Medical Research Institute, A Division Of Maine Medical Center Inhibiting breast cancer cell growth by administering an intracellular domain of NOTCH2
KR20150023953A (en) 2006-10-19 2015-03-05 제넨테크, 인크. Anti-Notch3 agonist antibodies and their use in the treatment of Notch3-related diseases
ITRM20060583A1 (en) 2006-10-27 2008-04-28 Francesco Bistoni USE OF THE TIMAMA ALFA 1 FOR THE PREPARATION OF A MEDICATION FOR THE PREVENTION AND CARE OF ALLERGIES
WO2008070042A2 (en) 2006-12-04 2008-06-12 Medimmune, Inc. High potency recombinant antibodies, methods for producing them and use in cancer therapy
RU2448979C2 (en) 2006-12-14 2012-04-27 Ридженерон Фармасьютикалз, Инк. Human antibodies to delta-like human ligand-4
EP2610267A1 (en) 2006-12-18 2013-07-03 Genentech, Inc. Antagonist anti-Notch3 antibodies and their use in the prevention and treatment of Notch3-related diseases
WO2008092002A2 (en) 2007-01-24 2008-07-31 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing pancreatic cancer
JP2010517944A (en) 2007-01-26 2010-05-27 バイオインヴェント インターナショナル アーベー DLL4 signaling inhibitor and use thereof
US20100062012A1 (en) 2007-03-05 2010-03-11 Ioannides Constantin G Negative Genetic Regulation of Cancer Cell Renewal in Synergy with Notch- or Numb-Specific Immunotherapy
GB0709333D0 (en) 2007-05-15 2007-06-20 Smart Targeting Ltd Binding protein
PE20090321A1 (en) * 2007-06-04 2009-04-20 Genentech Inc ANTI-NOTCH1 NRR ANTIBODIES, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITION
CN101808648B (en) 2007-07-25 2013-04-03 博洛尼亚大学阿尔玛母校研究室 Pharmaceutical composition and pharmaceutical kit for the treatment of hepatocellular carcinoma
RU2532830C2 (en) 2007-08-23 2014-11-10 Дзе Трастиз Оф Коламбия Юниверсити Ин Дзе Сити Оф Нью Йорк Compositions of humanised notch fused proteins and methods of treating
US8377886B2 (en) 2007-09-14 2013-02-19 Albert Einstein College Of Medicine Of Yeshiva University Use of gamma secretase inhibitors and notch pathway inhibitors for treatment and prevention of renal disease
WO2009075565A1 (en) 2007-12-12 2009-06-18 Erasmus University Medical Center Rotterdam Methods for controlling vasculogenesis
JP5560270B2 (en) * 2008-07-08 2014-07-23 オンコメッド ファーマシューティカルズ インコーポレイテッド NOTCH binding agents and antagonists and methods of use thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492538B2 (en) 2000-08-03 2016-11-15 The Regents Of The University Of Michigan Isolation and use of solid tumor stem cells
US9228020B2 (en) 2006-09-29 2016-01-05 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
US9376497B2 (en) 2006-09-29 2016-06-28 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
US9599620B2 (en) 2012-10-31 2017-03-21 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a DLL4 antagonist

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