The implications of cancer stem cells for cancer therapy

International Journal of Molecular Sciences

Volumn 13, Issue 12, 2012, Pages 16636-16657

  Jiang, Wenjing ^a   Peng, Jianhua ^a   Zhang, Yue ^a   Cho, William C S ^b   Jin, Kunlin ^c  

^a WENZHOU MEDICAL UNIVERSITY   (China)

^b QUEEN ELIZABETH HOSPITAL   (Hong Kong)

^c UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER   (United States)

Author keywords

Cancer stem cells; Differentiation; Progenitor; Signaling pathway; Tumorigenesis

Indexed keywords

ALDEHYDE DEHYDROGENASE; BETA CATENIN; BONE MORPHOGENETIC PROTEIN; CD133 ANTIGEN; CD24 ANTIGEN; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FIBROBLAST GROWTH FACTOR; GRANULOCYTE COLONY STIMULATING FACTOR; HERMES ANTIGEN; MAMMALIAN TARGET OF RAPAMYCIN; MULTIDRUG RESISTANCE PROTEIN; NERVE CELL ADHESION MOLECULE L1; NOTCH RECEPTOR; SALINOMYCIN; SONIC HEDGEHOG PROTEIN; STAT3 PROTEIN; WNT PROTEIN;

ANTIGEN EXPRESSION; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER STEM CELL; CANCER SURVIVAL; CELL DIFFERENTIATION; CELL GROWTH; CELL RENEWAL; CELL SUBPOPULATION; CHEMOSENSITIVITY; CYTOLOGY; HUMAN; MALIGNANT NEOPLASTIC DISEASE; METASTASIS POTENTIAL; MOLECULAR MECHANICS; MULTIDRUG RESISTANCE; NONHUMAN; NOTCH SIGNALING PATHWAY; QUALITY OF LIFE; REVIEW; SIGNAL TRANSDUCTION; TARGET CELL; TUMOR CELL; WNT SIGNALING PATHWAY; ANIMAL; DISEASE FREE SURVIVAL; METABOLISM; METASTASIS; MORTALITY; NEOPLASMS; PATHOLOGY; SURVIVAL RATE;

ANIMALS; DISEASE-FREE SURVIVAL; HUMANS; NEOPLASM METASTASIS; NEOPLASMS; NEOPLASTIC STEM CELLS; SURVIVAL RATE;

EID: 84871681506     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms131216636     Document Type: Review

References (153)

1. Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105-111.
2. Baker, D.E.; Harrison, N.J.; Maltby, E.; Smith, K.; Moore, H.D.; Shaw, P.J.; Heath, P.R.; Holden, H.; Andrews, P.W. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat. Biotechnol. 2007, 25, 207-215.
3. Harrison, D.E.; Zhong, R.K. The same exhaustible multilineage precursor produces both myeloid and lymphoid cells as early as 3-4 weeks after marrow transplantation. Proc. Natl. Acad. Sci. USA 1992, 89, 10134-10138.
4. Morrison, S.J.; Shah, N.M.; Anderson, D.J. Regulatory mechanisms in stem cell biology. Cell 1997, 88, 287-298.
5. Iwasaki, H.; Suda, T. Cancer stem cells and their niche. Cancer Sci. 2009, 100, 1166-1172.
6. Clevers, H. The cancer stem cell: Premises, promises and challenges. Nat. Med. 2011, 17, 313-319.
7. Shackleton, M.; Quintana, E.; Fearon, E.R.; Morrison, S.J. Heterogeneity in cancer: Cancer stem cells versus clonal evolution. Cell 2009, 138, 822-829.
8. Shipitsin, M.; Polyak, K. The cancer stem cell hypothesis: In search of definitions, markers, and relevance. Lab. Invest. 2008, 88, 459-463.
9. Yang, Y.M.; Chang, J.W. Current status and issues in cancer stem cell study. Cancer Invest. 2008, 26, 741-755.
10. Li, F.; Tiede, B.; Massague, J.; Kang, Y. Beyond tumorigenesis: Cancer stem cells in metastasis. Cell Res. 2007, 17, 3-14.
11. Hermann, P.C.; Huber, S.L.; Herrler, T.; Aicher, A.; Ellwart, J.W.; Guba, M.; Bruns, C.J.; Heeschen, C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1, 313-323.
12. Pang, R.; Law, W.L.; Chu, A.C.; Poon, J.T.; Lam, C.S.; Chow, A.K.; Ng, L.; Cheung, L.W.; Lan, X.R.; Lan, H.Y.; et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 2010, 6, 603-615.
13. Aguirre-Ghiso, J.A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 2007, 7, 834-846.
14. Besancon, R.; Valsesia-Wittmann, S.; Puisieux, A.; Caron de Fromentel, C.; Maguer-Satta, V. Cancer stem cells: The emerging challenge of drug targeting. Curr. Med. Chem. 2009, 16, 394-416.
15. Kamstrup, M.R.; Gniadecki, R.; Skovgaard, G.L. Putative cancer stem cells in cutaneous malignancies. Exp. Dermatol. 2007, 16, 297-301.
16. Leitch, J.; Klein, G.; Tee, R.; Murdock, C.; Teo, W.S. Neurally mediated syncope and atrial fibrillation. N. Engl. J. Med. 1991, 324, 495-496.
17. Guo, W.; Lasky, J.L., 3rd; Wu, H. Cancer stem cells. Pediatr. Res. 2006, 59, 59R-64R.
18. Pannuti, A.; Foreman, K.; Rizzo, P.; Osipo, C.; Golde, T.; Osborne, B.; Miele, L. Targeting notch to target cancer stem cells. Clin. Cancer Res. 2010, 16, 3141-3152.
19. Patrawala, L.; Calhoun, T.; Schneider-Broussard, R.; Zhou, J.; Claypool, K.; Tang, D.G. Side population is enriched in tumorigenic, stem-like cancer cells, whereas abcg2+ and abcg2-cancer cells are similarly tumorigenic. Cancer Res. 2005, 65, 6207-6219.
20. Cheng, T.; Rodrigues, N.; Shen, H.; Yang, Y.; Dombkowski, D.; Sykes, M.; Scadden, D.T. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000, 287, 1804-1808.
21. Yuan, Y.; Shen, H.; Franklin, D.S.; Scadden, D.T.; Cheng, T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early g1-phase inhibitor, p18ink4c. Nat. Cell Biol. 2004, 6, 436-442.
22. Mackillop, W.J.; Ciampi, A.; Till, J.E.; Buick, R.N. A stem cell model of human tumor growth: Implications for tumor cell clonogenic assays. J. Natl. Cancer Inst. 1983, 70, 9-16.
23. Bonnet, D.; Dick, J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3, 730-737.
24. Blair, A.; Hogge, D.E.; Ailles, L.E.; Lansdorp, P.M.; Sutherland, H.J. Lack of expression of thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 1997, 89, 3104-3112.
25. Lobo, N.A.; Shimono, Y.; Qian, D.; Clarke, M.F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 2007, 23, 675-699.
26. Prince, M.E.; Sivanandan, R.; Kaczorowski, A.; Wolf, G.T.; Kaplan, M.J.; Dalerba, P.; Weissman, I.L.; Clarke, M.F.; Ailles, L.E. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. USA 2007, 104, 973-978.
27. Ho, M.M.; Ng, A.V.; Lam, S.; Hung, J.Y. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007, 67, 4827-4833.
28. Eramo, A.; Lotti, F.; Sette, G.; Pilozzi, E.; Biffoni, M.; Di Virgilio, A.; Conticello, C.; Ruco, L.; Peschle, C.; De Maria, R. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death. Differ. 2008, 15, 504-514.
29. Yang, Z.F.; Ho, D.W.; Ng, M.N.; Lau, C.K.; Yu, W.C.; Ngai, P.; Chu, P.W.; Lam, C.T.; Poon, R.T.; Fan, S.T. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008, 13, 153-166.
30. Zhang, S.; Balch, C.; Chan, M.W.; Lai, H.C.; Matei, D.; Schilder, J.M.; Yan, P.S.; Huang, T.H.; Nephew, K.P. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008, 68, 4311-4320.
31. O'Brien, C.A.; Pollett, A.; Gallinger, S.; Dick, J.E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445, 106-110.
32. Li, C.; Heidt, D.G.; Dalerba, P.; Burant, C.F.; Zhang, L.; Adsay, V.; Wicha, M.; Clarke, M.F.; Simeone, D.M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67, 1030-1037.
33. Huang, E.H.; Hynes, M.J.; Zhang, T.; Ginestier, C.; Dontu, G.; Appelman, H.; Fields, J.Z.; Wicha, M.S.; Boman, B.M. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (sc) and tracks sc overpopulation during colon tumorigenesis. Cancer Res. 2009, 69, 3382-3389.
34. Ricci-Vitiani, L.; Lombardi, D.G.; Pilozzi, E.; Biffoni, M.; Todaro, M.; Peschle, C.; De Maria, R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445, 111-115.
35. Dalerba, P.; Dylla, S.J.; Park, I.K.; Liu, R.; Wang, X.; Cho, R.W.; Hoey, T.; Gurney, A.; Huang, E.H.; Simeone, D.M.; et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 10158-10163.
36. Schatton, T.; Frank, M.H. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res. 2008, 21, 39-55.
37. Suva, M.L.; Riggi, N.; Stehle, J.C.; Baumer, K.; Tercier, S.; Joseph, J.M.; Suva, D.; Clement, V.; Provero, P.; Cironi, L.; et al. Identification of cancer stem cells in ewing's sarcoma. Cancer Res. 2009, 69, 1776-1781.
38. Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396-401.
39. Gibbs, C.P.; Kukekov, V.G.; Reith, J.D.; Tchigrinova, O.; Suslov, O.N.; Scott, E.W.; Ghivizzani, S.C.; Ignatova, T.N.; Steindler, D.A. Stem-like cells in bone sarcomas: Implications for tumorigenesis. Neoplasia 2005, 7, 967-976.
40. Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 3983-3988.
41. Lang, S.H.; Frame, F.M.; Collins, A.T. Prostate cancer stem cells. J. Pathol. 2009, 217, 299-306.
42. Ginestier, C.; Hur, M.H.; Charafe-Jauffret, E.; Monville, F.; Dutcher, J.; Brown, M.; Jacquemier, J.; Viens, P.; Kleer, C.G.; Liu, S.; et al. Aldh1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007, 1, 555-567.
43. Douville, J.; Beaulieu, R.; Balicki, D. Aldh1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev. 2009, 18, 17-25.
44. Corti, S.; Locatelli, F.; Papadimitriou, D.; Donadoni, C.; Salani, S.; Del Bo, R.; Strazzer, S.; Bresolin, N.; Comi, G.P. Identification of a primitive brain-derived neural stem cell population based on aldehyde dehydrogenase activity. Stem Cells 2006, 24, 975-985.
45. Ma, S.; Chan, K.W.; Lee, T.K.; Tang, K.H.; Wo, J.Y.; Zheng, B.J.; Guan, X.Y. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol. Cancer Res. 2008, 6, 1146-1153.
46. Gunaratne, P.H. Embryonic stem cell micrornas: Defining factors in induced pluripotent (ips) and cancer (csc) stem cells? Curr. Stem Cell Res. Ther. 2009, 4, 168-177.
47. Loh, Y.H.; Agarwal, S.; Park, I.H.; Urbach, A.; Huo, H.; Heffner, G.C.; Kim, K.; Miller, J.D.; Ng, K.; Daley, G.Q. Generation of induced pluripotent stem cells from human blood. Blood 2009, 113, 5476-5479.
48. Wernig, M.; Meissner, A.; Foreman, R.; Brambrink, T.; Ku, M.; Hochedlinger, K.; Bernstein, B.E.; Jaenisch, R. In vitro reprogramming of fibroblasts into a pluripotent es-cell-like state. Nature 2007, 448, 318-324.
49. Zhang, Y.; Peng, J.; Zhang, H.; Zhu, Y.; Wan, L.; Chen, J.; Chen, X.; Lin, R.; Li, H.; Mao, X.; et al. Notch1 signaling is activated in cells expressing embryonic stem cell proteins in human primary nasopharyngeal carcinoma. J. Otolaryngol. Head Neck Surg. 2010, 39, 157-166.
50. Zhang, H.B.; Ren, C.P.; Yang, X.Y.; Wang, L.; Li, H.; Zhao, M.; Yang, H.; Yao, K.T. Identification of label-retaining cells in nasopharyngeal epithelia and nasopharyngeal carcinoma tissues. Histochem. Cell Biol. 2007, 127, 347-354.
51. Cheng, A.L.; Huang, W.G.; Chen, Z.C.; Peng, F.; Zhang, P.F.; Li, M.Y.; Li, F.; Li, J.L.; Li, C.; Yi, H.; et al. Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin. Cancer Res. 2008, 14, 435-445.
52. Li, Y.; Laterra, J. Cancer stem cells: Distinct entities or dynamically regulated phenotypes? Cancer Res. 2012, 72, 576-580.
53. Passegue, E.; Jamieson, C.H.; Ailles, L.E.; Weissman, I.L. Normal and leukemic hematopoiesis: Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc. Natl. Acad. Sci. USA 2003, 100, 11842-11849.
54. Jamieson, C.H.; Ailles, L.E.; Dylla, S.J.; Muijtjens, M.; Jones, C.; Zehnder, J.L.; Gotlib, J.; Li, K.; Manz, M.G.; Keating, A.; et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis cml. N. Engl. J. Med. 2004, 351, 657-667.
55. Manz, M.G.; Miyamoto, T.; Akashi, K.; Weissman, I.L. Prospective isolation of human clonogenic common myeloid progenitors. Proc. Natl. Acad. Sci. USA 2002, 99, 11872-11877.
56. Proia, T.A.; Keller, P.J.; Gupta, P.B.; Klebba, I.; Jones, A.D.; Sedic, M.; Gilmore, H.; Tung, N.; Naber, S.P.; Schnitt, S.; et al. Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 2011, 8, 149-163.
57. Lowenberg, B.; Touw, I.P. Hematopoietic growth factors and their receptors in acute leukemia. Blood 1993, 81, 281-292.
58. Griffin, J.D.; Lowenberg, B. Clonogenic cells in acute myeloblastic leukemia. Blood 1986, 68, 1185-1195.
59. McCulloch, E.A.; Izaguirre, C.A.; Chang, L.J.; Smith, L.J. Renewal and determination in leukemic blast populations. J. Cell Physiol. Suppl. 1982, 1, 103-111.
60. Graham, S.M.; Jorgensen, H.G.; Allan, E.; Pearson, C.; Alcorn, M.J.; Richmond, L.; Holyoake, T.L. Primitive, quiescent, philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to sti571 in vitro. Blood 2002, 99, 319-325.
61. Copland, M.; Hamilton, A.; Elrick, L.J.; Baird, J.W.; Allan, E.K.; Jordanides, N.; Barow, M.; Mountford, J.C.; Holyoake, T.L. Dasatinib (bms-354825) targets an earlier progenitor population than imatinib in primary cml but does not eliminate the quiescent fraction. Blood 2006, 107, 4532-4539.
62. Jorgensen, H.G.; Allan, E.K.; Jordanides, N.E.; Mountford, J.C.; Holyoake, T.L. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ cml cells. Blood 2007, 109, 4016-4019.
63. Testa, U. Leukemia stem cells. Ann. Hematol. 2011, 90, 245-271.
64. Li, X.; Lewis, M.T.; Huang, J.; Gutierrez, C.; Osborne, C.K.; Wu, M.F.; Hilsenbeck, S.G.; Pavlick, A.; Zhang, X.; Chamness, G.C.; et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl. Cancer Inst. 2008, 100, 672-679.
65. Diehn, M.; Cho, R.W.; Lobo, N.A.; Kalisky, T.; Dorie, M.J.; Kulp, A.N.; Qian, D.; Lam, J.S.; Ailles, L.E.; Wong, M.; et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009, 458, 780-783.
66. Jiang, X.; Zhao, Y.; Chan, W.Y.; Pang, E.; Eaves A.; Eaves, C. Leukemic stem cells of chronic phase cml patients consistently display very high bcr-abl transcript levels and reduced responsiveness to imatinib mesylate in addition to generating a rare subset that produce imatinib mesylate-resistant differentiated progeny. Blood 2004, 104, 711-722.
67. Venugopal, C.; Li, N.; Wang, X.; Manoranjan, B.; Hawkins, C.; Gunnarsson, T.; Hollenberg, R.; Klurfan, P.; Murty, N.; Kwiecien, J.; et al. Bmi1 marks intermediate precursors during differentiation of human brain tumor initiating cells. Stem Cell Res. 2012, 8, 141-153.
68. Scheel, C.; Eaton, E.N.; Li, S.H.; Chaffer, C.L.; Reinhardt, F.; Kah, K.J.; Bell, G.; Guo, W.; Rubin, J.; Richardson, A.L.; et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011, 145, 926-940.
69. Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 2005, 5, 275-284.
70. Bonnet, D. Cancer stem cells: Amls show the way. Biochem. Soc. Trans. 2005, 33, 1531-1533.
71. Wang, Y.; Yang, J.; Zheng, H.; Tomasek, G.J.; Zhang, P.; McKeever, P.E.; Lee, E.Y.; Zhu, Y. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 2009, 15, 514-526.
72. Krivtsov, A.V.; Twomey, D.; Feng, Z.; Stubbs, M.C.; Wang, Y.; Faber, J.; Levine, J.E.; Wang, J.; Hahn, W.C.; Gilliland, D.G.; et al. Transformation from committed progenitor to leukaemia stem cell initiated by mll-af9. Nature 2006, 442, 818-822.
73. Nakano, I.; Kornblum, H.I. Brain tumor stem cells. Pediatr. Res. 2006, 59, 54R-58R.
74. Wagers, A.J.; Weissman, I.L. Plasticity of adult stem cells. Cell 2004, 116, 639-648.
75. Rizvi, A.Z.; Swain, J.R.; Davies, P.S.; Bailey, A.S.; Decker, A.D.; Willenbring, H.; Grompe, M.; Fleming, W.H.; Wong, M.H. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc. Natl. Acad. Sci. USA 2006, 103, 6321-6325.
76. Brabletz, S.; Schmalhofer, O.; Brabletz, T. Gastrointestinal stem cells in development and cancer. J. Pathol. 2009, 217, 307-317.
77. Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133, 704-715.
78. Chiou, S.H.; Wang, M.L.; Chou, Y.T.; Chen, C.J.; Hong, C.F.; Hsieh, W.J.; Chang, H.T.; Chen, Y.S.; Lin, T.W.; Hsu, H.S.; et al. Coexpression of oct4 and nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 2010, 70, 10433-10444.
79. King, C.E.; Cuatrecasas, M.; Castells, A.; Sepulveda, A.R.; Lee, J.S.; Rustgi, A.K. Lin28b promotes colon cancer progression and metastasis. Cancer Res. 2011, 71, 4260-4268.
80. Li, Y.; Li, A.; Glas, M.; Lal, B.; Ying, M.; Sang, Y.; Xia, S.; Trageser, D.; Guerrero-Cazares, H.; Eberhart, C.G.; et al. C-met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc. Natl. Acad. Sci. USA 2011, 108, 9951-9956.
81. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663-676.
82. Yu, J.; Vodyanik, M.A.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J.L.; Tian, S.; Nie, J.; Jonsdottir, G.A.; Ruotti, V.; Stewart, R.; et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318, 1917-1920.
83. Lin, S.L.; Chang, D.C.; Chang-Lin, S.; Lin, C.H.; Wu, D.T.; Chen, D.T.; Ying, S.Y. Mir-302 reprograms human skin cancer cells into a pluripotent es-cell-like state. RNA 2008, 14, 2115-2124.
84. Schepers, A.G.; Snippert, H.J.; Stange, D.E.; van den Born, M.; van Es, J.H.; van de Wetering, M.; Clevers, H. Lineage tracing reveals lgr5+ stem cell activity in mouse intestinal adenomas. Science 2012, 337, 730-735.
85. Chen, J.; Li, Y.; Yu, T.S.; McKay, R.M.; Burns, D.K.; Kernie, S.G.; Parada, L.F. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012, 488, 522-526.
86. Driessens, G.; Beck, B.; Caauwe, A.; Simons, B.D.; Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 2012, 488, 527-530.
87. Artavanis-Tsakonas, S.; Rand, M.D.; Lake, R.J. Notch signaling: Cell fate control and signal integration in development. Science 1999, 284, 770-776.
88. Vilimas, T.; Mascarenhas, J.; Palomero, T.; Mandal, M.; Buonamici, S.; Meng, F.; Thompson, B.; Spaulding, C.; Macaroun, S.; Alegre, M.L.; et al. Targeting the nf-kappab signaling pathway in notch1-induced t-cell leukemia. Nat. Med. 2007, 13, 70-77.
89. McCleary-Wheeler, A.L.; McWilliams, R.; Fernandez-Zapico, M.E. Aberrant signaling pathways in pancreatic cancer: A two compartment view. Mol. Carcinog. 2012, 51, 25-39.
90. Hu, Y.Y.; Zheng, M.H.; Zhang, R.; Liang, Y.M.; Han, H. Notch signaling pathway and cancer metastasis. Adv. Exp. Med. Biol. 2012, 727, 186-198.
91. Hovinga, K.E.; Shimizu, F.; Wang, R.; Panagiotakos, G.; Van Der Heijden, M.; Moayedpardazi, H.; Correia, A.S.; Soulet, D.; Major, T.; Menon, J.; et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 2010, 28, 1019-1029.
92. Androutsellis-Theotokis, A.; Leker, R.R.; Soldner, F.; Hoeppner, D.J.; Ravin, R.; Poser, S.W.; Rueger, M.A.; Bae, S.K.; Kittappa, R.; McKay, R.D. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006, 442, 823-826.
93. Fan, X.; Khaki, L.; Zhu, T.S.; Soules, M.E.; Talsma, C.E.; Gul, N.; Koh, C.; Zhang, J.; Li, Y.M.; Maciaczyk, J.; et al. Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2010, 28, 5-16.
94. Stockhausen, M.T.; Kristoffersen, K.; Poulsen, H.S. The functional role of notch signaling in human gliomas. Neuro. Oncol. 2010, 12, 199-211.
95. Wang, J.; Wakeman, T.P.; Lathia, J.D.; Hjelmeland, A.B.; Wang, X.F.; White, R.R.; Rich, J.N.; Sullenger, B.A. Notch promotes radioresistance of glioma stem cells. Stem Cells 2010, 28, 17-28.
96. Huelsken, J.; Behrens, J. The wnt signalling pathway. J. Cell Sci. 2002, 115, 3977-3978.
97. Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell 2006, 127, 469-480.
98. Tetsu, O.; McCormick, F. Beta-catenin regulates expression of cyclin d1 in colon carcinoma cells. Nature 1999, 398, 422-426.
99. He, T.C.; Sparks, A.B.; Rago, C.; Hermeking, H.; Zawel, L.; da Costa, L.T.; Morin, P.J.; Vogelstein, B.; Kinzler, K.W. Identification of c-myc as a target of the apc pathway. Science 1998, 281, 1509-1512.
100. van de Wetering, M.; Sancho, E.; Verweij, C.; de Lau, W.; Oving, I.; Hurlstone, A.; van der Horn, K.; Batlle, E.; Coudreuse, D.; Haramis, A.P.; et al. The beta-catenin/tcf-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002, 111, 241-250.
101. Rich, J.N. Cancer stem cells in radiation resistance. Cancer Res. 2007, 67, 8980-8984.
102. Polakis, P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol. 2012, 4, a0080052.
103. Ayyanan, A.; Civenni, G.; Ciarloni, L.; Morel, C.; Mueller, N.; Lefort, K.; Mandinova, A.; Raffoul, W.; Fiche, M.; Dotto, G.P.; et al. Increased wnt signaling triggers oncogenic conversion of human breast epithelial cells by a notch-dependent mechanism. Proc. Natl. Acad. Sci. USA 2006, 103, 3799-3804.
104. Shiras, A.; Chettiar, S.T.; Shepal, V.; Rajendran, G.; Prasad, G.R.; Shastry, P. Spontaneous transformation of human adult nontumorigenic stem cells to cancer stem cells is driven by genomic instability in a human model of glioblastoma. Stem Cells 2007, 25, 1478-1489.
105. Zhang, T.; Otevrel, T.; Gao, Z.; Ehrlich, S.M.; Fields, J.Z.; Boman, B.M. Evidence that apc regulates survivin expression: A possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res. 2001, 61, 8664-8667.
106. Kim, P.J.; Plescia, J.; Clevers, H.; Fearon, E.R.; Altieri, D.C. Survivin and molecular pathogenesis of colorectal cancer. Lancet 2003, 362, 205-209.
107. Bienz, M.; Clevers, H. Linking colorectal cancer to wnt signaling. Cell 2000, 103, 311-320.
108. Polakis, P. Wnt signaling and cancer. Genes Dev. 2000, 14, 1837-1851.
109. Zhao, C.; Blum, J.; Chen, A.; Kwon, H.Y.; Jung, S.H.; Cook, J.M.; Lagoo, A.; Reya, T. Loss of beta-catenin impairs the renewal of normal and cml stem cells in vivo. Cancer Cell 2007, 12, 528-541.
110. Vermeulen, L.; de Sousa, E.M.F.; van der Heijden, M.; Cameron, K.; de Jong, J.H.; Borovski, T.; Tuynman, J.B.; Todaro, M.; Merz, C.; Rodermond, H.; et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 2010, 12, 468-476.
111. Chen, M.S.; Woodward, W.A.; Behbod, F.; Peddibhotla, S.; Alfaro, M.P.; Buchholz, T.A.; Rosen, J.M. Wnt/beta-catenin mediates radiation resistance of sca1+ progenitors in an immortalized mammary gland cell line. J. Cell Sci. 2007, 120, 468-477.
112. Woodward, W.A.; Chen, M.S.; Behbod, F.; Alfaro, M.P.; Buchholz, T.A.; Rosen, J.M. Wnt/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc. Natl. Acad. Sci. USA 2007, 104, 618-623.
113. Yuan, T.L.; Cantley, L.C. PI3K pathway alterations in cancer: Variations on a theme. Oncogene 2008, 27, 5497-5510.
114. Zhou, J.; Wulfkuhle, J.; Zhang, H.; Gu, P.; Yang, Y.; Deng, J.; Margolick, J.B.; Liotta, L.A.; Petricoin, E., 3rd; Zhang, Y. Activation of the pten/mtor/stat3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc. Natl. Acad. Sci. USA 2007, 104, 16158-16163.
115. Hambardzumyan, D.; Becher, O.J.; Rosenblum, M.K.; Pandolfi, P.P.; Manova-Todorova, K.; Holland, E.C. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008, 22, 436-448.
116. Dvorak, P.; Dvorakova, D.; Hampl, A. Fibroblast growth factor signaling in embryonic and cancer stem cells. FEBS Lett. 2006, 580, 2869-2874.
117. Dirks, P.B. Brain tumor stem cells: Bringing order to the chaos of brain cancer. J. Clin. Oncol. 2008, 26, 2916-2924.
118. Song, Z.; Yue, W.; Wei, B.; Wang, N.; Li, T.; Guan, L.; Shi, S.; Zeng, Q.; Pei, X.; Chen, L. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One 2011, 6, e17687. doi:10.1371/journal.pone.0017687.
119. Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruiz i Altaba, A. Hedgehog-gli1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 2007, 17, 165-172.
120. Korkaya, H.; Paulson, A.; Iovino, F.; Wicha, M.S. Her2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008, 27, 6120-6130.
121. Nagata, Y.; Lan, K.H.; Zhou, X.; Tan, M.; Esteva, F.J.; Sahin, A.A.; Klos, K.S.; Li, P.; Monia, B.P.; Nguyen, N.T.; et al. Pten activation contributes to tumor inhibition by trastuzumab, and loss of pten predicts trastuzumab resistance in patients. Cancer Cell 2004, 6, 117-127.
122. Lee, J.; Kotliarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N.M.; Pastorino, S.; Purow, B.W.; Christopher, N.; Zhang, W.; et al. Tumor stem cells derived from glioblastomas cultured in bfgf and egf more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006, 9, 391-403.
123. Bao, S.; Wu, Q.; Li, Z.; Sathornsumetee, S.; Wang, H.; McLendon, R.E.; Hjelmeland, A.B.; Rich, J.N. Targeting cancer stem cells through l1cam suppresses glioma growth. Cancer Res. 2008, 68, 6043-6048.
124. Cao, Y.; Lathia, J.D.; Eyler, C.E.; Wu, Q.; Li, Z.; Wang, H.; McLendon, R.E.; Hjelmeland, A.B.; Rich, J.N. Erythropoietin receptor signaling through stat3 is required for glioma stem cell maintenance. Genes Cancer 2010, 1, 50-61.
125. Sherry, M.M.; Reeves, A.; Wu, J.K.; Cochran, B.H. Stat3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 2009, 27, 2383-2392.
126. Lage, H. An overview of cancer multidrug resistance: A still unsolved problem. Cell Mol. Life Sci. 2008, 65, 3145-3167.
127. Rangwala, F.; Omenetti, A.; Diehl, A.M. Cancer stem cells: Repair gone awry? J. Oncol. 2011, 2011, doi:10.1155/2011/465343.
128. Kvinlaug, B.T.; Huntly, B.J. Targeting cancer stem cells. Expert Opin. Ther. Targets 2007, 11, 915-927.
129. Calabrese, C.; Poppleton, H.; Kocak, M.; Hogg, T.L.; Fuller, C.; Hamner, B.; Oh, E.Y.; Gaber, M.W.; Finklestein, D.; Allen, M.; et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007, 11, 69-82.
130. Azzi, S.; Bruno, S.; Giron-Michel, J.; Clay, D.; Devocelle, A.; Croce, M.; Ferrini, S.; Chouaib, S.; Vazquez, A.; Charpentier, B.; et al. Differentiation therapy: Targeting human renal cancer stem cells with interleukin 15. J. Natl. Cancer Inst. 2011, 103, 1884-1898.
131. Pham, P.V.; Phan, N.L.; Nguyen, N.T.; Truong, N.H.; Duong, T.T.; Le, D.V.; Truong, K.D.; Phan, N.K. Differentiation of breast cancer stem cells by knockdown of CD44: Promising differentiation therapy. J. Transl. Med. 2011, 9, doi:10.1186/1479-5876-9-209.
132. Cole, M.F.; Johnstone, S.E.; Newman, J.J.; Kagey, M.H.; Young, R.A. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev. 2008, 22, 746-755.
133. Wei, G.; Ku, S.; Ma, G.K.; Saito, S.; Tang, A.A.; Zhang, J.; Mao, J.H.; Appella, E.; Balmain, A.; Huang, E.J. Hipk2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proc. Natl. Acad. Sci. USA 2007, 104, 13040-13045.
134. Singh, A.; Settleman, J. Emt, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 2010, 29, 4741-4751.
135. Alison, M.R.; Lim, S.M.; Nicholson, L.J. Cancer stem cells: Problems for therapy? J. Pathol. 2011, 223, 147-161.
136. Pece, S.; Tosoni, D.; Confalonieri, S.; Mazzarol, G.; Vecchi, M.; Ronzoni, S.; Bernard, L.; Viale, G.; Pelicci, P.G.; Di Fiore, P.P. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 2010, 140, 62-73.
137. Iliopoulos, D.; Hirsch, H.A.; Wang, G.; Struhl, K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via il6 secretion. Proc. Natl. Acad. Sci. USA 2011, 108, 1397-1402.
138. Cho, W.C. Targeting signaling pathways in cancer therapy. Expert Opin. Ther. Targets 2012, 16, 1-3.
139. Zimmerman, A.L.; Wu, S. MicroRNAs, cancer and cancer stem cells. Cancer Lett. 2011, 300, 10-19.
140. Yu, Z.R.; Pestell, R.G. MicroRNAs and cancer stem cells. In MicroRNAs in Cancer Translational Research; Cho, W.C.S., Ed.; Springer: Dordrecht, The Netherlands, 2011, pp. 373-388.
141. Riccioni, R.; Dupuis, M.L.; Bernabei, M.; Petrucci, E.; Pasquini, L.; Mariani, G.; Cianfriglia, M.; Testa, U. The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol. Dis. 2010, 45, 86-92.
142. Piccirillo, S.G.; Reynolds, B.A.; Zanetti, N.; Lamorte, G.; Binda, E.; Broggi, G.; Brem, H.; Olivi, A.; Dimeco, F.; Vescovi, A.L. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006, 444, 761-765.
143. Saito, Y.; Uchida, N.; Tanaka, S.; Suzuki, N.; Tomizawa-Murasawa, M.; Sone, A.; Najima, Y.; Takagi, S.; Aoki, Y.; Wake, A.; et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of aml. Nat. Biotechnol. 2010, 28, 275-280.
144. Kang, M.K.; Hur, B.I.; Ko, M.H.; Kim, C.H.; Cha, S.H.; Kang, S.K. Potential identity of multi-potential cancer stem-like subpopulation after radiation of cultured brain glioma. BMC Neurosci.2008, 9, doi:10.1186/1471-2202-9-15.
145. Dingli, D.; Michor, F. Successful therapy must eradicate cancer stem cells. Stem Cells 2006, 24, 2603-2610.
146. Fuchs, E. The tortoise and the hair: Slow-cycling cells in the stem cell race. Cell 2009, 137, 811-819.
147. Essers, M.A.; Trumpp, A., Targeting leukemic stem cells by breaking their dormancy. Mol Oncol 2010, 4, 443-450.
148. Tan, B.; Piwnica-Worms, D.; Ratner, L. Multidrug resistance transporters and modulation. Curr. Opin. Oncol. 2000, 12, 450-458.
149. Raguz, S.; Yague, E. Resistance to chemotherapy: New treatments and novel insights into an old problem. Br. J. Cancer 2008, 99, 387-391.
150. Wang, J.; Guo, L.P.; Chen, L.Z.; Zeng, Y.X.; Lu, S.H. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res. 2007, 67, 3716-3724.
151. Liang, Y.; Zhong, Z.; Huang, Y.; Deng, W.; Cao, J.; Tsao, G.; Liu, Q.; Pei, D.; Kang, T.; Zeng, Y.X. Stem-like cancer cells are inducible by increasing genomic instability in cancer cells. J. Biol. Chem. 2010, 285, 4931-4940.
152. Eyler, C.E.; Rich, J.N. Survival of the fittest: Cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 2008, 26, 2839-2845.
153. Baumann, M.; Krause, M.; Hill, R. Exploring the role of cancer stem cells in radioresistance. Nat. Rev. Cancer 2008, 8, 545-554.