Cancer Stem Cells and Response to Therapy

  • Tabarestani, Sanaz (Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences) ;
  • Ghafouri-Fard, Soudeh (Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences)
  • Published : 2012.12.31


The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal, either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be due to their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.


  1. Ugolini F, Adelaide J, Charafe-Jauffret E, et al (1999). Differential expression assay of chromosome arm 8p genes identifies Frizzled-related (FRP1/FRZB) and Fibroblast Growth Factor Receptor 1 (FGFR1) as candidate breast cancer genes. Oncogene, 18, 1903-10.
  2. Valent P, Bonnet D, De Maria R, et al (2012). Cancer stem cell definitions and terminology: the devil is in the details. Nature Reviews Cancer, 12, 767-75.
  3. Varnat F, Duquet A, Malerba M, et al (2009). Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med, 1, 338-51.
  4. Virmani AK, Rathi A, Sathyanarayana UG, et al (2001). Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A in breast and lung carcinomas. Clin Cancer Res, 7, 1998-2004.
  5. Wang J, Wakeman TP, Lathia JD, et al (2010). Notch promotes radioresistance of glioma stem cells. Stem Cells, 28, 17-28.
  6. Wang Z, Li Y, Kong D, et al (2009). Acquisition of epithelialmesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res, 69, 2400-7.
  7. Watkins DN, Berman DM, Burkholder SG, et al (2003). Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature, 422, 313-7.
  8. Woodward WA, Chen MS, Behbod F, et al (2007). WNT/betacatenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA, 104, 618-23.
  9. Wulf GG, Wang RY, Kuehnle I, et al (2001). A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia. Blood, 98, 1166-73.
  10. Xie J, Murone M, Luoh SM, et al (1998). Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature, 391, 90-2.
  11. Yamada T, Takaoka AS, Naishiro Y, et al (2000). Transactivation of the multidrug resistance 1 gene by T-cell factor 4/betacatenin complex in early colorectal carcinogenesis. Cancer Res, 60, 4761-6.
  12. Yang ZF, Ho DW, Ng MN, et al (2008). Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell, 13, 153-66.
  13. Yao Z, Mishra L (2009). Cancer stem cells and hepatocellular carcinoma. Cancer Biol Ther, 8, 1691-8.
  14. Yilmaz OH, Valdez R, Theisen BK, et al (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemiainitiating cells. Nature, 441, 475-82.
  15. Zechner D, Fujita Y, Hulsken J, et al (2003). beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol, 258, 406-18.
  16. Puc J, Keniry M, Li HS, et al (2005). Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell, 7, 193-204.
  17. Reiman JM, Knutson KL, Radisky DC, et al (2010). Immune Promotion of Epithelial-mesenchymal Transition and Generation of Breast Cancer Stem Cells. Cancer Res, 70, 3005-8.
  18. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al (2007). Identification and expansion of human colon-cancerinitiating cells. Nature, 445, 111-5.
  19. Riquelme PA, Drapeau E, Doetsch F, et al (2008). Brain microecologies: neural stem cell niches in the adult mammalian brain. Philos Trans R Soc Lond B Biol Sci, 363, 123-37.
  20. Roh MS, Hong SH, Jeong JS, et al (2004). Gene expression profiling of breast cancers with emphasis of beta-catenin regulation. J Korean Med Sci, 19, 275-82.
  21. Rossi DJ, Bryder D, Seita J, et al (2007). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 447, 725-9.
  22. Sato N, Meijer L, Skaltsounis L, et al (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med, 10, 55-63.
  23. Schuller U, Heine V, Mao J, et al (2008). Acquisition of granule neuronprecursor identity is a critical determinant of progenitor cell compecompetence to form Shh-induced medulloblastoma. Cancer Cell, 14, 123-34.
  24. Sell S, Leffert HL (2008). Liver cancer stem cells. J Clin Oncol, 26, 2800-5.
  25. Singh SK, Hawkins C, Clarke ID, et al (2004). Identification of human brain tumour initiating cells. Nature, 432, 396-401.
  26. Stecca B, Mas C, Clement V, et al (2007). Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA, 104, 5895-900.
  27. Takahashi-Yanaga F, Kahn M (2010). Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res, 16, 3153-62.
  28. Takaishi S, Okumura T, Wang TC, et al (2008). Gastric cancer stem cells. J Clin Oncol, 26, 2876-82.
  29. Takebe N, Ivy SP (2010). Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res, 16, 3106-12.
  30. Taylor MD, Liu L, Raffel C, et al (2002). Mutations in SUFU predispose to medulloblastoma. Nat Genet, 31, 306-10.
  31. Thun MJ, Henley SJ, Patrono C, et al (2002). Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst, 94, 252-66.
  32. Todaro M, Alea MP, Di Stefano AB, et al (2007). Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell, 1, 389-402.
  33. Todaro M, Lombardo Y, Francipane MG, et al (2008). Apoptosis resistance in epithelial tumors is mediated by tumor-cellderived interleukin-4. Cell Death Differ, 15, 762-72.
  34. Magnifico A, Albano L, Campaner S, et al (2009). Tumorinitiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res, 15, 2010-21.
  35. Mani SA, Guo W, Liao MJ, et al (2008). The epithelialmesenchymal transition generates cells with properties of stem cells. Cell, 133, 704-15.
  36. Maugeri-Sacca M, Vigneri P, De Maria R, et al (2011). Cancer stem cells and chemosensitivity. Clin Cancer Res, 17, 4942-7.
  37. Maynard S, Swistowska AM, Lee JW, et al (2008). Human embryonic stem cells have enhanced repair of multiple forms of DNA damage. Stem Cells, 26, 2266-74.
  38. Merchant AA, Matsui W (2010). Targeting hedgehog--a cancer stem cell pathway. Clin Cancer Res, 16, 3130-40.
  39. Moeller BJ, Dreher MR, Rabbani ZN, et al (2005). Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell, 8, 99-110.
  40. Moitra K, Lou H, Dean M, et al (2011). Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther, 89, 491-502.
  41. Nagahata T, Shimada T, Harada A, et al (2003). Amplification, up-regulation and over-expression of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers. Cancer Sci, 94, 515-8.
  42. Nelson WJ, Nusse R (2004). Convergence of Wnt, beta-catenin, and cadherin pathways. Sci, 303, 1483-7.
  43. Nguyen L (2012). Cancer stem cells: an evolving concept. Nature Rev Cancer, 12, 133-43.
  44. O'Brien CA, Kreso A, Jamieson CH, et al (2010). Cancer stem cells and self-renewal. Clin Cancer Res, 16, 3113-20.
  45. Pannuti A, Foreman K, Rizzo P, et al (2010). Targeting Notch to target cancer stem cells. Clin Cancer Res, 16, 3141-52.
  46. Pearce DJ, Taussig D, Simpson C, et al (2005). Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells, 23, 752-60.
  47. Phillips TM, McBride WH, Pajonk F, et al (2006). The response of CD24(-/low)/$CD^{44+}$ breast cancer-initiating cells to radiation. J Natl Cancer Inst, 98, 1777-85.
  48. Pietsch T, Waha A, Koch A, et al (1997). Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res, 57, 2085-8.
  49. Prince ME, Ailles LE (2008). Cancer stem cells in head and neck squamous cell cancer. J Clin Oncol, 26, 2871-5.
  50. Prince ME, Sivanandan R, Kaczorowski A, et al (2007). Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA, 104, 973-8.
  51. Huff CA, Matsui W (2008). Multiple myeloma cancer stem cells. J Clin Oncol, 26, 2895-900.
  52. Iliopoulos D, Hirsch HA, Wang G, et al (2011). Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA, 108, 1397-402.
  53. Ingham PW (2008). Hedgehog signalling. Curr Biol, 18, 238-41.
  54. Jamieson CH, Weissman IL, Passegue E, et al (2004). Chronic versus acute myelogenous leukemia: a question of selfrenewal. Cancer Cell, 6, 531-3.
  55. Johnson RL, Rothman AL, Xie J, et al (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Sci, 272, 1668-71.
  56. Jones S, Zhang X, Parsons DW, et al (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Sci, 321, 1801-6.
  57. Kakarala M, Wicha MS (2007). Cancer stem cells: implications for cancer treatment and prevention. Cancer J, 13, 271-5.
  58. Kakarala M, Wicha MS (2008). Implications of the cancer stemcell hypothesis for breast cancer prevention and therapy. J Clin Oncol, 26, 2813-20.
  59. Kao GD, Jiang Z, Fernandes AM, et al (2007). Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem, 282, 21206-12.
  60. Karhadkar SS, Bova GS, Abdallah N, et al (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 431, 707-12.
  61. Kopan R, Ilagan MX (2009). The canonical Notch signaling pathway: unfolding the activation mechanism. Cell, 137, 216-33.
  62. Krause M, Yaromina A, Eicheler W, et al (2011). Cancer stem cells: targets and potential biomarkers for radiotherapy. Clin Cancer Res, 17, 7224-9.
  63. LaBarge MA (2010). The Difficulty of Targeting Cancer Stem Cell Niches. Clin Cancer Res, 16, 3121-9.
  64. Li C, Heidt DG, Dalerba P, et al (2007). Identification of pancreatic cancer stem cells. Cancer Res, 67, 1030-7.
  65. Li X, Lewis MT, Huang J, et al (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst, 100, 672-9.
  66. Li Y, Laterra J (2012). Cancer stem cells: distinct entities or dynamically regulated phenotypes? Cancer Res, 72, 576-80.
  67. Liu G, Yuan X, Zeng Z, et al (2006). Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer, 5, 67.
  68. Liu S, Dontu G, Mantle ID, et al (2006). Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res, 66, 6063-71.
  69. Magni M, Shammah S, Schiro R, et al (1996). Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood, 87, 1097-103.
  70. Gallmeier E, Hermann PC, Mueller MT, et al (2011). Inhibition of ataxia telangiectasia- and Rad3-related function abrogates the in vitro and in vivo tumorigenicity of human colon cancer cells through depletion of the CD133(+) tumor-initiating cell fraction. Stem Cells, 29, 418-29.
  71. Gao MQ, Choi YP, Kang S, et al (2010). CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene, 29, 2672-80.
  72. Ghafouri-Fard S, Modarressi MH (2009). Cancer-testis antigens: potential targets for cancer immunotherapy. Arch Iran Med, 12, 395-404.
  73. Ghafouri-Fard S (2012). Are cancer-testis antigens cancer stem cell markers? J Sing Cel Genom Proteomics, 1, 1.
  74. Ghafouri-Fard S, Modarressi MH (2012). Expression of cancer-testis genes in brain tumors: implications for cancer immunotherapy. Immunotherapy, 4, 59-75.
  75. Ghafouri-Fard S, Ghafouri-Fard S (2012). Immunotherapy in nonmelanoma skin cancer. Immunotherapy, 4, 499-510.
  76. Ginestier C, Hur MH, Charafe-Jauffret E, et al (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1, 555-67.
  77. Grana TM, Rusyn EV, Zhou H, et al (2002). Ras mediates radioresistance through both phosphatidylinositol 3-kinasedependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinaseindependent signaling pathways. Cancer Res, 62, 4142-50.
  78. Gurney A, Axelrod F, Bond CJ, et al (2012). Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA, 109, 11717-22.
  79. Hari L, Brault V, Kleber M, et al (2002). Lineage-specific requirements of beta-catenin in neural crest development. J Cell Biol, 159, 867-80.
  80. Harrison H, Farnie G, Brennan KR, et al (2010). Breast cancer stem cells: something out of notching? Cancer Res, 70, 8973-6.
  81. Harrison H, Farnie G, Howell SJ, et al (2010). Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res, 70, 709-18.
  82. Hart LS, El-Deiry WS (2008). Invincible, but not invisible: imaging approaches toward in vivo detection of cancer stem cells. J Clin Oncol, 26, 2901-10.
  83. Hecht A, Vleminckx K, Stemmler MP, et al (2000). The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J, 19, 1839-50.
  84. Hermann PC, Huber SL, Herrler T, et al (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1, 313-23.
  85. Hirschmann-Jax C, Foster AE, Wulf GG, et al (2004). A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA, 101, 14228-33.
  86. Boman BM, Huang E (2008). Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol, 26, 2828-38.
  87. Boman BM, Wicha MS (2008). Cancer stem cells: a step toward the cure. J Clin Oncol, 26, 2795-9.
  88. Bonnet D, Dick JE (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 3, 730-7.
  89. Boon EM, Keller JJ, Wormhoudt TA, et al (2004). Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br J Cancer, 90, 224-9.
  90. Bracker TU, Giebel B, Spanholtz J, et al (2006). Stringent regulation of DNA repair during human hematopoietic differentiation: a gene expression and functional analysis. Stem Cells, 24, 722-30.
  91. Chen MS, Woodward WA, Behbod F, et al (2007). Wnt/betacatenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J Cell Sci, 120, 468-77.
  92. Chen Y, Fischer WH, Gill GN, et al (1997). Regulation of the ERBB-2 promoter by RBPJkappa and NOTCH. J Biol Chem, 272, 14110-4.
  93. Clement V, Sanchez P, de Tribolet N, et al (2007). HEDGEHOGGLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol, 17, 165-72.
  94. Collins AT, Berry PA, Hyde C, et al (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res, 65, 10946-51.
  95. Dihlmann S, Siermann A, von Knebel Doeberitz M, et al (2001). The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene, 20, 645-53.
  96. Dirks PB (2008). Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol, 26, 2916-24.
  97. Domanska UM, Kruizinga RC, Nagengast WB, et al (2012). A review on CXCR4/CXCL12 axis in oncology: No place to hide. Eur J Cancer, Epub ahead of print.
  98. Eramo A, Lotti F, Sette G, et al (2008). Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ, 15, 504-14.
  99. Eyler CE, Foo WC, LaFiura KM, et al (2008). Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells, 26, 3027-36.
  100. Eyler CE, Rich JN (2008). Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol, 26, 2839-45.
  101. Fan X, Khaki L, Zhu TS, et al (2010). NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells, 28, 5-16.
  102. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 100, 3983-8.
  103. Bao S, Wu Q, McLendon RE, et al (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444, 756-60.
  104. Bao S, Wu Q, Sathornsumetee S, et al (2006). Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res, 66, 7843-8.
  105. Blazek ER, Foutch JL, Maki G, et al (2007). Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys, 67, 1-5.

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