Cancer and Metastasis Reviews

, Volume 27, Issue 3, pp 459–470 | Cite as

Cancer stem cells: markers or biomarkers?

Article

Abstract

Introduction

The lineages assumed by stem cells during hematopoiesis can be identified by the pattern of protein markers present on the surface of cells at different stages of differentiation. Specific antibodies directed at these markers have facilitated the isolation of hematopoietic stem cells by flow cytometry.

Discussion

Similarly, stem cells in solid organs also can be identified using cell surface markers. In addition, solid tumors have recently been found to contain small proportions of cells that are capable of proliferation, self-renewal, and differentiation into the various cell types seen in the bulk tumor. Of particular concern, these tumor-initiating cells (termed cancer stem cells when multipotency and self-renewal have been demonstrated) often display characteristics of treatment resistance, particularly to ionizing radiation. Thus, it is important to be able to identify these cells in order to better understand the mechanisms of resistance, and to be able to predict outcome and response to treatment. This depends, of course, on identifying markers that can be used to identify the cells, and for some solid tumors, a specific pattern of cell surface markers is emerging. In breast cancer, for example, the tumor-initiating cells have a characteristic \({\text{Lin}}^ - {\text{CD}}44^ + {\text{CD2}}4^{{ - \mathord{\left/ {\vphantom { - {{\text{lo}}}}} \right. \kern-\nulldelimiterspace} {{\text{lo}}}}} {\text{ESA}}^{\text{ + }} \) antigenic pattern. In cells derived from some high-grade gliomas, expression of CD133 on the cell surface appears to select for a population of tumor-initiating, treatment resistant cells.

Conclusion

Because multiple markers, typically examined on single cells using flow cytometry, are used routinely to identify the subpopulation of tumor-initiating cells, and because the number of these cells is small, the challenge remains to detect them in clinical samples and to determine their ability to predict outcome and/or response to treatment, the hallmarks of established biomarkers.

Keywords

Breast cancer Flow cytometry Colorectal cancer Prostate cancer Pancreatic cancer Review Cancer stem cells Biomarkers Radiation therapy Progenitors 

Notes

Acknowledgements

We thank Jeff Rosen and Betty Notzon for critical review of this manuscript. We also acknowledge contribution of the collaborative work of the Advanced Research Center for Micrometastatic Disease at The University of Texas M.D. Anderson Cancer Center, in particular Massimo Cristofanilli, James Reuben, Anthony Lucci, Savitri Krishnamurthy, Wendy A. Woodward, Li Li, and Hui Gao.

References

  1. 1.
    Bast Jr., R. C., Ravdin, P., Hayes, D. F., et al. (2001). 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. Journal of Clinical Oncology, 19(6), 1865–1878.PubMedGoogle Scholar
  2. 2.
    Hayes, D. F., Bast, R. C., Desch, C. E., et al. (1996). Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. Journal of the National Cancer Institute, 88(20), 1456–1466.PubMedCrossRefGoogle Scholar
  3. 3.
    Schilsky, R. L., & Taube, S. E. (2002). Tumor markers as clinical cancer tests—are we there yet? Seminars in Oncology, 29(3), 211–212.PubMedCrossRefGoogle Scholar
  4. 4.
    Liao, M. J., Zhang, C. C., Zhou, B., et al. (2007). Enrichment of a population of mammary gland cells that form mammospheres and have in vivo repopulating activity. Cancer Research, 67(17), 8131–8138.PubMedCrossRefGoogle Scholar
  5. 5.
    Kaplan, R. N., Psaila, B., & Lyden, D. (2007). Niche-to-niche migration of bone-marrow-derived cells. Trends in Molecular Medicine, 13(2), 72–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Psaila, B., Kaplan, R. N., Port, E. R., et al. (2006). Priming the ‘soil’ for breast cancer metastasis: the pre-metastatic niche. Breast Disease, 26, 65–74.PubMedGoogle Scholar
  7. 7.
    Yang, Z. J., & Wechsler-Reya, R. J. (2007). Hit ‘em where they live: targeting the cancer stem cell niche. Cancer Cell, 11(1), 3–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Smith, G. H. (2006). Mammary stem cells come of age, prospectively. Trends in Molecular Medicine, 12(7), 287–289.PubMedCrossRefGoogle Scholar
  9. 9.
    Weissman, I. L., Anderson, D. J., & Gage, F. (2001). Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annual Review of Cell and Developmental Biology, 17, 387–403.PubMedCrossRefGoogle Scholar
  10. 10.
    Shackleton, M., Vaillant, F., Simpson, K. J., et al. (2006). Generation of a functional mammary gland from a single stem cell. Nature, 439(7072), 84–88.PubMedCrossRefGoogle Scholar
  11. 11.
    Stingl, J., Eirew, P., Ricketson, I., et al. (2006). Purification and unique properties of mammary epithelial stem cells. Nature, 439(7079), 993–997.PubMedGoogle Scholar
  12. 12.
    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., et al. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 3983–3988.PubMedCrossRefGoogle Scholar
  13. 13.
    Alvi, A. J., Clayton, H., Joshi, C., et al. (2003). Functional and molecular characterisation of mammary side population cells. Breast Cancer Research, 5(1), R1–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Goodell, M. A., Brose, K., Paradis, G., et al. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine, 183(4), 1797–1806.PubMedCrossRefGoogle Scholar
  15. 15.
    Welm, B. E., Tepera, S. B., Venezia, T., et al. (2002). Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Developmental Biology, 245(1), 42–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Woodward, W. A., Chen, M. S., Behbod, F., et al. (2007). WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 104(2), 618–623.PubMedCrossRefGoogle Scholar
  17. 17.
    Bao, S., Wu, Q., McLendon, R. E., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(7120), 756–760.PubMedCrossRefGoogle Scholar
  18. 18.
    Phillips, T. M., McBride, W. H., & Pajonk, F. (2006). The response of CD24(-/low)/CD44+breast cancer-initiating cells to radiation. Journal of the National Cancer Institute, 98(24), 1777–1785.PubMedGoogle Scholar
  19. 19.
    Kordon, E. C., & Smith, G. H. (1998). An entire functional mammary gland may comprise the progeny from a single cell. Development (Cambridge, England), 125(10), 1921–1930.Google Scholar
  20. 20.
    Welm, B., Behbod, F., Goodell, M. A., et al. (2003). Isolation and characterization of functional mammary gland stem cells. Cell Proliferation, 36(Suppl 1), 17–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Sleeman, K. E., Kendrick, H., Ashworth, A., et al. (2006). CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Research, 8(1), R7.PubMedCrossRefGoogle Scholar
  22. 22.
    Asselin-Labat, M. L., Shackleton, M., Stingl, J., et al. (2006). Steroid hormone receptor status of mouse mammary stem cells. Journal of the National Cancer Institute, 98(14), 1011–1014.PubMedCrossRefGoogle Scholar
  23. 23.
    Sleeman, K. E., Kendrick, H., Robertson, D., et al. (2007). Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. The Journal of Cell Biology, 176(1), 19–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Dontu, G., Abdallah, W. M., Foley, J. M., et al. (2003). In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes & Development, 17(10), 1253–1270.CrossRefGoogle Scholar
  25. 25.
    Proia, D. A., & Kuperwasser, C. (2006). Reconstruction of human mammary tissues in a mouse model. Nature Protocols, 1(1), 206–214.PubMedCrossRefGoogle Scholar
  26. 26.
    Ponti, D., Costa, A., Zaffaroni, N., et al. (2005). Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Research, 65(13), 5506–5511.PubMedCrossRefGoogle Scholar
  27. 27.
    Woodward, W. A., Lucci, A., & Cristofanilli, M. (2007). A gene signature in breast cancer. The New England Journal of Medicine, 356(18), 1887–1888 author reply, 8).PubMedCrossRefGoogle Scholar
  28. 28.
    Fillmore, C., & Kuperwasser, C. (2007). Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man? Breast Cancer Research, 9(3), 303.PubMedCrossRefGoogle Scholar
  29. 29.
    Liu, R., Wang, X., Chen, G. Y., et al. (2007). The prognostic role of a gene signature from tumorigenic breast-cancer cells. The New England Journal of Medicine, 356(3), 217–226.PubMedCrossRefGoogle Scholar
  30. 30.
    Abraham, B. K., Fritz, P., McClellan, M., et al. (2005). Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clinical Cancer Research, 11(3), 1154–1159.PubMedGoogle Scholar
  31. 31.
    Shipitsin, M., Campbell, L. L., Argani, P., et al. (2007). Molecular definition of breast tumor heterogeneity. Cancer Cell, 11(3), 259–273.PubMedCrossRefGoogle Scholar
  32. 32.
    Balic, M., Lin, H., Young, L., et al. (2006). Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clinical Cancer Research, 12(19), 5615–5621.PubMedCrossRefGoogle Scholar
  33. 33.
    Cristofanilli, M., Budd, G. T., Ellis, M. J., et al. (2004). Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England Journal of Medicine, 351(8), 781–791.PubMedCrossRefGoogle Scholar
  34. 34.
    Langer, I., Guller, U., Koechli, O. R., et al. (2007). Association of the presence of bone marrow micrometastases with the sentinel lymph node status in 410 early stage breast cancer patients: results of the Swiss Multicenter Study. Annals of Surgical Oncology, 14(6), 1896–903.PubMedCrossRefGoogle Scholar
  35. 35.
    Slade, M. J., & Coombes, R. C. (2007). The clinical significance of disseminated tumor cells in breast cancer. Nature Clinical Practice, 4(1), 30–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Thurm, H., Ebel, S., Kentenich, C., et al. (2003). Rare expression of epithelial cell adhesion molecule on residual micrometastatic breast cancer cells after adjuvant chemotherapy. Clinical Cancer Research, 9(7), 2598–2604.PubMedGoogle Scholar
  37. 37.
    Camara, O., Rengsberger, M., Egbe, A., et al. (2007). The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Annals of Oncology, 18(9), 1484–1492.PubMedCrossRefGoogle Scholar
  38. 38.
    Li, C., Heidt, D. G., Dalerba, P., et al. (2007). Identification of pancreatic cancer stem cells. Cancer Research, 67(3), 1030–1037.PubMedCrossRefGoogle Scholar
  39. 39.
    Rodriguez, J. A., Li, M., Yao, Q., et al. (2005). Gene overexpression in pancreatic adenocarcinoma: diagnostic and therapeutic implications. World Journal of Surgery, 29(3), 297–305.PubMedCrossRefGoogle Scholar
  40. 40.
    Wente, M. N., Jain, A., Kono, E., et al. (2005). Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer. Pancreas, 31(2), 119–125.PubMedCrossRefGoogle Scholar
  41. 41.
    Gu, Z., Yamashiro, J., Kono, E., et al. (2005). Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism. Cancer Research, 65(20), 9495–500.PubMedCrossRefGoogle Scholar
  42. 42.
    Cao, D., Ji, H., & Ronnett, B. M. (2005). Expression of mesothelin, fascin, and prostate stem cell antigen in primary ovarian mucinous tumors and their utility in differentiating primary ovarian mucinous tumors from metastatic pancreatic mucinous carcinomas in the ovary. International Journal of Gynecological Pathology, 24(1), 67–72.PubMedGoogle Scholar
  43. 43.
    Olempska, M., Eisenach, P. A., Ammerpohl, O., et al. (2007). Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary and Pancreatic Diseases International, 6(1), 92–97.PubMedGoogle Scholar
  44. 44.
    Esposito, I., Kleeff, J., Bischoff, S. C., et al. (2002). The stem cell factor-c-kit system and mast cells in human pancreatic cancer. Laboratory Investigation 82(11), 1481–1492.Google Scholar
  45. 45.
    Cunha, G. R., Hayward, S. W., Wang, Y. Z. (2002). Role of stroma in carcinogenesis of the prostate. Differentiation, 70(9–10), 473–485.Google Scholar
  46. 46.
    Isaacs, J. T., & Coffey, D. S. (1989). Etiology and disease process of benign prostatic hyperplasia. The Prostate, 2, 33–50.CrossRefGoogle Scholar
  47. 47.
    Azuma, M., Hirao, A., Takubo, K., et al. (2005). A quantitative matrigel assay for assessing repopulating capacity of prostate stem cells. Biochemical and Biophysical Research Communications, 338(2), 1164–1170.PubMedCrossRefGoogle Scholar
  48. 48.
    Hayward, S. W., Haughney, P. C., Rosen, M. A., et al. (1998). Interactions between adult human prostatic epithelium and rat urogenital sinus mesenchyme in a tissue recombination model. Differentiation, 63(3), 131–140.Google Scholar
  49. 49.
    Tsujimura, A., Koikawa, Y., Salm, S., et al. (2002). Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. The Journal of Cell Biology, 157(7), 1257–1265.PubMedCrossRefGoogle Scholar
  50. 50.
    Bhatia, B., Tang, S., Yang, P., et al. (2005). Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells. Oncogene, 24(22), 3583–3595.PubMedCrossRefGoogle Scholar
  51. 51.
    Hudson, D. L., O’Hare, M., Watt, F. M., et al. (2000). Proliferative heterogeneity in the human prostate: evidence for epithelial stem cells. Laboratory Investigation, 80(8), 1243–1250.Google Scholar
  52. 52.
    Burger, P. E., Xiong, X., Coetzee, S., et al. (2005). Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proceedings of the National Academy of Sciences of the United States of America, 102(20), 7180–7185.PubMedCrossRefGoogle Scholar
  53. 53.
    Xin, L., Lawson, D. A., & Witte, O. N. (2005). The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 102(19), 6942–6947.PubMedCrossRefGoogle Scholar
  54. 54.
    Reiter, R. E., Gu, Z., Watabe, T., et al. (1998). Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 95(4), 1735–1740.PubMedCrossRefGoogle Scholar
  55. 55.
    Amara, N., Palapattu, G. S., Schrage, M., et al. (2001). Prostate stem cell antigen is overexpressed in human transitional cell carcinoma. Cancer Research, 61(12), 4660–4665.PubMedGoogle Scholar
  56. 56.
    Han, K. R., Seligson, D. B., Liu, X., et al. (2004). Prostate stem cell antigen expression is associated with Gleason score, seminal vesicle invasion and capsular invasion in prostate cancer. The Journal of Urology, 171(3), 1117–1121.PubMedCrossRefGoogle Scholar
  57. 57.
    Saffran, D. C., Raitano, A. B., Hubert, R. S., et al. (2001). Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2658–2663.PubMedCrossRefGoogle Scholar
  58. 58.
    Patrawala, L., Calhoun, T., Schneider-Broussard, R., et al. (2006). Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene, 25(12), 1696–1708.PubMedCrossRefGoogle Scholar
  59. 59.
    Collins, A. T., Berry, P. A., Hyde, C., et al. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65(23), 10946–10951.PubMedCrossRefGoogle Scholar
  60. 60.
    Richardson, G. D., Robson, C. N., Lang, S. H., et al. (2004). CD133, a novel marker for human prostatic epithelial stem cells. Journal of Cell Science, 117(Pt 16), 3539–3545.PubMedCrossRefGoogle Scholar
  61. 61.
    Collins, A. T., Habib, F. K., Maitland, N. J., et al. (2001). Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. Journal of Cell Science, 114(Pt 21), 3865–3872.PubMedGoogle Scholar
  62. 62.
    Liu, A. Y., True, L. D., LaTray, L., et al. (1997). Cell-cell interaction in prostate gene regulation and cytodifferentiation. Proceedings of the National Academy of Sciences of the United States of America, 94(20), 10705–10.PubMedCrossRefGoogle Scholar
  63. 63.
    Prince, M. E., 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. Proceedings of the National Academy of Sciences of the United States of America, 104(3), 973–978.PubMedCrossRefGoogle Scholar
  64. 64.
    Kawano, T., Yanoma, S., Nakamura, Y., et al. (2005). Soluble CD44 standard, CD44 variant 5 and CD44 variant 6 and their relation to staging in head and neck cancer. Acta Oto-laryngologica, 125(4), 392–397.PubMedCrossRefGoogle Scholar
  65. 65.
    Kawano, T., Yanoma, S., Nakamura, Y., et al. (2005). Evaluation of soluble adhesion molecules CD44 (CD44st, CD44v5, CD44v6), ICAM-1, and VCAM-1 as tumor markers in head and neck cancer. American Journal of Otolaryngology, 26(5), 308–313.PubMedCrossRefGoogle Scholar
  66. 66.
    Franzmann, E. J., Reategui, E. P., Pedroso, F., et al. (2007). Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiology, Biomarkers & Prevention, 16(7), 1348–1355.CrossRefGoogle Scholar
  67. 67.
    Reategui, E. P., de Mayolo, A. A., Das, P. M., et al. (2006). Characterization of CD44v3-containing isoforms in head and neck cancer. Cancer Biology & Therapy, 5(9), 1163–1168.Google Scholar
  68. 68.
    Tijink, B. M., Buter, J., de Bree, R., et al. (2006). A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clinical Cancer Research, 12(20 Pt 1), 6064–6072.PubMedCrossRefGoogle Scholar
  69. 69.
    Wang, S. J., & Bourguignon, L. Y. (2006). Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Archives of Otolaryngology, Head & Neck Surgery, 132(7), 771–778.CrossRefGoogle Scholar
  70. 70.
    His, W. (1889). Die neuroblasten und deren enstehung im embryonalen mark. Abh Kgl Sachs Ges Wissensch Math Phys Kl, 15, 311–372.Google Scholar
  71. 71.
    Doe, C. Q., Fuerstenberg, S., & Peng, C. Y. (1998). Neural stem cells: from fly to vertebrates. Journal of Neurobiology, 36(2), 111–127.PubMedCrossRefGoogle Scholar
  72. 72.
    Burd, G. D., & Nottebohm, F. (1985). Ultrastructural characterization of synaptic terminals formed on newly generated neurons in a song control nucleus of the adult canary forebrain. Journal of Comparative Neurology, 240(2), 143–152.PubMedCrossRefGoogle Scholar
  73. 73.
    Goldman, S. A., & Nottebohm, F. (1983). Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proceedings of the National Academy of Sciences of the United States of America, 80(8), 2390–2394.PubMedCrossRefGoogle Scholar
  74. 74.
    Cameron, H. A., Woolley, C. S., McEwen, B. S., et al. (1993). Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience, 56(2), 337–344.PubMedCrossRefGoogle Scholar
  75. 75.
    Gage, F. H., Kempermann, G., Palmer, T. D., et al. (1998). Multipotent progenitor cells in the adult dentate gyrus. Journal of Neurobiology, 36(2), 249–266.PubMedCrossRefGoogle Scholar
  76. 76.
    Kaplan, M. S., & Bell, D. H. (1984). Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. Journal of Neuroscience, 4(6), 1429–1441.PubMedGoogle Scholar
  77. 77.
    Gritti, A., Parati, E. A., Cova, L., et al. (1996). Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. Journal of Neuroscience, 16(3), 1091–1100.PubMedGoogle Scholar
  78. 78.
    Sanai, H., Tramontin, A. D., Quinones-Hinojosa, A., et al. (2004). Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature, 427(6976), 740–744.PubMedCrossRefGoogle Scholar
  79. 79.
    Lois, C., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (1996). Chain migration of neuronal precursors. Science, 271(5251), 978–981.PubMedCrossRefGoogle Scholar
  80. 80.
    Doetsch, F., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (1997). Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. Journal of Neuroscience, 17(13), 5046–5061.PubMedGoogle Scholar
  81. 81.
    Sanai, N., Alvarez-Buylla, A., & Berger, M. S. (2005). Mechanisms of disease: Neural stem cells and the origin of gliomas. The New England Journal of Medicine, 353(8), 811–822.PubMedCrossRefGoogle Scholar
  82. 82.
    Holland, E. C., Hively, W. P., Gallo, V., et al. (1998). Modeling mutations in the G1 arrest pathway in human gliomas: Overexpression of CDK4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes. Genes and Development, 12(23), 3644–3649.PubMedCrossRefGoogle Scholar
  83. 83.
    Zhu, Y., Guignard, F., Zhao, D., et al. (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell, 8(2), 119–130.PubMedCrossRefGoogle Scholar
  84. 84.
    Holland, E. C., Celestino, J., Dai, C., et al. (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genetics, 25(1), 55–57.PubMedCrossRefGoogle Scholar
  85. 85.
    Reynolds, B. A., & Rietze, R. L. (2005). Neural stem cells and neurospheres–re-evaluating the relationship. Nature Methods, 2(5), 333–336.PubMedCrossRefGoogle Scholar
  86. 86.
    Reynolds, B. A., & Weiss, S. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 255(5052), 1707–1710.PubMedCrossRefGoogle Scholar
  87. 87.
    Singh, S. K., Hawkins, C., Clarke, I. D., et al. (2004). Identification of human brain tumour initiating cells. Nature, 432(7015), 396–401.PubMedCrossRefGoogle Scholar
  88. 88.
    Galli, R., Binda, E., Orfanelli, U., et al. (2004). Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Research, 64(19), 7011–7021.PubMedCrossRefGoogle Scholar
  89. 89.
    Singh, S. K., Clarke, I. D., Terasaki, M., et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Research, 63(18), 5821–5828.PubMedGoogle Scholar
  90. 90.
    Lee, J., Kotliarova, S., Kotliarov, Y., et al. (2006). 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, 9(5), 391–403.PubMedCrossRefGoogle Scholar
  91. 91.
    Hemmati, H. D., Nakano, I., Lazareff, J. A., et al. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 100(25), 15178–15183.PubMedCrossRefGoogle Scholar
  92. 92.
    Taylor, M. D., Poppleton, H., Fuller, C., et al. (2005). Radial glia cells are candidate stem cells of ependymoma. Cancer Cell, 8(4), 323–335.PubMedCrossRefGoogle Scholar
  93. 93.
    Freije, W. A., Castro-Vargas, F. E., Fang, Z., et al. (2004). Gene expression profiling of gliomas strongly predicts survival. Cancer Research, 64(18), 6503–6510.PubMedCrossRefGoogle Scholar
  94. 94.
    Haas-Kogan, D. A., Prados, M. D., Lamborn, K. R., et al. (2005). Biomarkers to predict response to epidermal growth factor receptor inhibitors. Cell Cycle 4(10), 1369–1372.Google Scholar
  95. 95.
    Nigro, J. M., Misra, A., Zhang, L., et al. (2005). Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Research, 65(5), 1678–1686.PubMedCrossRefGoogle Scholar
  96. 96.
    Phillips, H. S., Kharbanda, S., Chen, R., et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell, 9(3), 157–173.PubMedCrossRefGoogle Scholar
  97. 97.
    Bao, S., Wu, Q., Sathornsumetee, S., et al. (2006). Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Research, 66(16), 7843–7848.PubMedCrossRefGoogle Scholar
  98. 98.
    O’Brien, C. A., Pollett, A., Gallinger, S., et al. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445(7123), 106–110.PubMedCrossRefGoogle Scholar
  99. 99.
    Ricci-Vitiani, L., Lombardi, D. G., Pilozzi, E., et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature, 445(7123), 111–115.PubMedCrossRefGoogle Scholar
  100. 100.
    Dalerba, P., Dylla, S. J., Park, I. K., et al. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(24), 10158–10163.PubMedCrossRefGoogle Scholar
  101. 101.
    Bar, E. E., Chaudhry, A., Lin, A., et al. (2007). Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells, 25, 2524–2533.Google Scholar
  102. 102.
    Chen, M. S., Woodward, W. A., Behbod, F., et al. (2007). Wnt/beta-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. Journal of Cell Science, 120(Pt 3), 468–477.PubMedCrossRefGoogle Scholar
  103. 103.
    Bonner, J. A., Harari, P. M., Giralt, J., et al. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England Journal of Medicine, 354(6), 567–578.PubMedCrossRefGoogle Scholar
  104. 104.
    Group, B. W. D. (2001). Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics, 69(3), 89–94.CrossRefGoogle Scholar
  105. 105.
    Schmitt, M., Harbeck, N., Daidone, M. G., et al. (2004). Identification, validation, and clinical implementation of tumor-associated biomarkers to improve therapy concepts, survival, and quality of life of cancer patients: Tasks of the Receptor and Biomarker Group of the European Organization for Research and Treatment of Cancer. International Journal of Oncology, 25(5), 1397–1406.PubMedGoogle Scholar
  106. 106.
    Schmitt, M., Mengele, K., Schueren, E., et al. (2007). European Organisation for Research and Treatment of Cancer (EORTC) Pathobiology Group standard operating procedure for the preparation of human tumour tissue extracts suited for the quantitative analysis of tissue-associated biomarkers. European Journal of Cancer, 43(5), 835–844.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Radiation OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations