Advertisement

Cancer Stem Cells in Colorectal Cancer

  • Louis Vermeulen
  • Jan Paul Medema
  • James C.H. Hardwick
  • Gijs R. van den Brink
Chapter

Abstract

Colorectal cancer is the second most common cause of cancer death in the Western world. Due to the high prevalence of colorectal cancer and precancerous lesions, many colonoscopies, and the resulting wide availability of tissue samples, extensive knowledge is available on the stepwise process that leads to colorectal cancer. Most colorectal cancers develop from slowly growing non-invasive adenomas that take many years to grow from a single mutant crypt to an adenoma that can reach several centimeters in size before acquiring invasive characteristics. In this chapter we will discuss some of the early histopathological events in the development of colorectal cancer and try to reconcile these data with the concept of the tumor-initiating or cancer stem cell. We will show that there are many similarities between the mechanism of stem cell expansion during intestinal growth and repair and deregulated clonal expansion of stem cells in an adenoma. We argue that it is important to realize the fact that most known genetic alterations in colorectal cancer development are involved in adenoma formation and are therefore involved in clonal growth and not invasiveness. It would therefore be helpful to distinguish adenoma stem cells from carcinoma stem cells. We will then discuss the available data on the isolation and behavior of colorectal cancer stem cells.

Keywords

Stem Cell Cancer Stem Cell Familial Adenomatous Polyposis Clonal Growth Cancer Stem Cell Population 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Agrawal, D., Chen, T., Irby, R., Quackenbush, J., Chambers, A.F., Szabo, M., Cantor, A., Coppola, D., and Yeatman, T.J. (2003). Osteopontin identified as colon cancer tumor progression marker. C. R. Biol. 326, 1041–1043.PubMedCrossRefGoogle Scholar
  2. Al Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988.PubMedCrossRefGoogle Scholar
  3. Al Hajj, M., Becker, M.W., Wicha, M., Weissman, I., and Clarke, M.F. (2004). Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47.PubMedCrossRefGoogle Scholar
  4. Baker, S.J., Fearon, E.R., Nigro, J.M., Hamilton, S.R., Preisinger, A.C., Jessup, J.M., vanTuinen, P., Ledbetter, D.H., Barker, D.F., Nakamura, Y., White, R., and Vogelstein, B. (1989). Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217–221.PubMedCrossRefGoogle Scholar
  5. Barker, N., van Es, J.H., Kuipers, J., Kujala, P., van den, B.M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P.J., and Clevers, H. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007.Google Scholar
  6. Bhatia, M. (2001). AC133 expression in human stem cells. Leukemia 15, 1685–1688.PubMedGoogle Scholar
  7. Bijlsma, M.F., Spek, C.A., Zivkovic, D., van de, W.S., Rezaee, F., and Peppelenbosch, M.P. (2006). Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 4, e232.PubMedCrossRefGoogle Scholar
  8. Blau, H.M., Brazelton, T.R., and Weimann, J.M. (2001). The evolving concept of a stem cell: entity or function? Cell 105, 829–841.PubMedCrossRefGoogle Scholar
  9. Boman, B.M., Walters, R., Fields, J.Z., Kovatich, A.J., Zhang, T., Isenberg, G.A., Goldstein, S.D., and Palazzo, J.P. (2004). Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population. Am. J. Pathol. 165, 1489–1498.PubMedCrossRefGoogle Scholar
  10. Bonnet, D. and Dick, J.E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737.PubMedCrossRefGoogle Scholar
  11. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F., and Kirchner, T. (2005). Opinion: migrating cancer stem cells – an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749.PubMedCrossRefGoogle Scholar
  12. Brosens, L.A., van Hattem, A., Hylind, L.M., Iacobuzio-Donahue, C., Romans, K.E., Axilbund, J., Cruz-Correa, M., Tersmette, A.C., Offerhaus, G.J., and Giardiello, F.M. (2007). Risk of colorectal cancer in juvenile polyposis. Gut 56, 965–967.PubMedCrossRefGoogle Scholar
  13. Cairns, J. (2006). Cancer and the immortal strand hypothesis. Genetics 174, 1069–1072.PubMedCrossRefGoogle Scholar
  14. Cardoso, J., Boer, J., Morreau, H., and Fodde, R. (2007). Expression and genomic profiling of colorectal cancer. Biochim. Biophys. Acta 1775, 103–137.Google Scholar
  15. Chang, Y.S., di Tomaso, E., McDonald, D.M., Jones, R., Jain, R.K., and Munn, L.L. (2000). Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl Acad. Sci. USA 97, 14608–14613.PubMedCrossRefGoogle Scholar
  16. Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H., Jones, D.L., Visvader, J., Weissman, I.L., and Wahl, G.M. (2006). Cancer stem cells–perspectives on current status and future directions: AACR Workshop on Cancer Stem Cells. Cancer Res. 66, 9339–9344.PubMedCrossRefGoogle Scholar
  17. Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell 127, 469–480.PubMedCrossRefGoogle Scholar
  18. 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., Shelton, A.A., Parmiani, G., Castelli, C., and Clarke, M.F. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163.PubMedCrossRefGoogle Scholar
  19. Dean, M., Fojo, T., and Bates, S. (2005). Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284.PubMedCrossRefGoogle Scholar
  20. Dunker, N., Schmitt, K., Schuster, N., and Krieglstein, K. (2002). The role of transforming growth factor beta-2, beta-3 in mediating apoptosis in the murine intestinal mucosa. Gastroenterology 122, 1364–1375.PubMedCrossRefGoogle Scholar
  21. Engle, S.J., Hoying, J.B., Boivin, G.P., Ormsby, I., Gartside, P.S., and Doetschman, T. (1999). Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res. 59, 3379–3386.PubMedGoogle Scholar
  22. Fearon, E.R. and Vogelstein, B. (1990). A genetic model for colorectal tumorigenesis. Cell 61, 759–767.PubMedCrossRefGoogle Scholar
  23. Fodde, R. and Brabletz, T. (2007). Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 19, 150–158.Google Scholar
  24. Fodde, R., Smits, R., and Clevers, H. (2001). APC, signal transduction and genetic instability in colorectal cancer. Nat. Rev. Cancer 1, 55–67.PubMedCrossRefGoogle Scholar
  25. Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., and Artavanis-Tsakonas, S. (2005). Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968.PubMedCrossRefGoogle Scholar
  26. Giardiello, F.M., Welsh, S.B., Hamilton, S.R., Offerhaus, G.J., Gittelsohn, A.M., Booker, S.V., Krush, A.J., Yardley, J.H., and Luk, G.D. (1987). Increased risk of cancer in the Peutz-Jeghers syndrome. N. Engl. J. Med. 316, 1511–1514.PubMedCrossRefGoogle Scholar
  27. Greaves, L.C., Preston, S.L., Tadrous, P.J., Taylor, R.W., Barron, M.J., Oukrif, D., Leedham, S.J., Deheragoda, M., Sasieni, P., Novelli, M.R., Jankowski, J.A., Turnbull, D.M., Wright, N.A., and McDonald, S.A. (2006). Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc. Natl Acad. Sci. USA 103, 714–719.PubMedCrossRefGoogle Scholar
  28. Gregorieff, A., Pinto, D., Begthel, H., Destree, O., Kielman, M., and Clevers, H. (2005). Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638.PubMedGoogle Scholar
  29. Harada, N., Mizoi, T., Kinouchi, M., Hoshi, K., Ishii, S., Shiiba, K., Sasaki, I., and Matsuno, S. (2001). Introduction of antisense CD44S CDNA down-regulates expression of overall CD44 isoforms and inhibits tumor growth and metastasis in highly metastatic colon carcinoma cells. Int. J. Cancer 91, 67–75.PubMedCrossRefGoogle Scholar
  30. Hardwick, J.C., van den Brink, G.R., Bleuming, S.A., Ballester, I., Van Den Brande, J.M., Keller, J.J., Offerhaus, G.J., Van Deventer, S.J., and Peppelenbosch, M.P. (2004). Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology 126, 111–121.PubMedCrossRefGoogle Scholar
  31. He, X.C., Zhang, J., Tong, W.G., Tawfik, O., Ross, J., Scoville, D.H., Tian, Q., Zeng, X., He, X., Wiedemann, L.M., Mishina, Y., and Li, L. (2004). BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat. Genet. 36, 1117–1121.PubMedCrossRefGoogle Scholar
  32. Hemminki, A., Markie, D., Tomlinson, I., Avizienyte, E., Roth, S., Loukola, A., Bignell, G., Warren, W., Aminoff, M., Hoglund, P., Jarvinen, H., Kristo, P., Pelin, K., Ridanpaa, M., Salovaara, R., Toro, T., Bodmer, W., Olschwang, S., Olsen, A.S., Stratton, M.R., de la Chapelle, A., and Aaltonen, L.A. (1998). A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184–187.PubMedCrossRefGoogle Scholar
  33. Hill, R.P. (2006). Identifying cancer stem cells in solid tumors: case not proven. Cancer Res. 66, 1891–1895.PubMedCrossRefGoogle Scholar
  34. Howe, J.R., Roth, S., Ringold, J.C., Summers, R.W., Jarvinen, H.J., Sistonen, P., Tomlinson, I.P., Houlston, R.S., Bevan, S., Mitros, F.A., Stone, E.M., and Aaltonen, L.A. (1998). Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088.PubMedCrossRefGoogle Scholar
  35. Howe, J.R., Bair, J.L., Sayed, M.G., Anderson, M.E., Mitros, F.A., Petersen, G.M., Velculescu, V.E., Traverso, G., and Vogelstein, B. (2001). Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat. Genet. 28, 184–187.PubMedCrossRefGoogle Scholar
  36. Huff, C.A., Matsui, W., Smith, B.D., and Jones, R.J. (2006). The paradox of response and survival in cancer therapeutics. Blood 107, 431–434.PubMedCrossRefGoogle Scholar
  37. Ireland, H., Kemp, R., Houghton, C., Howard, L., Clarke, A.R., Sansom, O.J., and Winton, D.J. (2004). Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology 126, 1236–1246.PubMedCrossRefGoogle Scholar
  38. Jordan, C.T., Guzman, M.L., and Noble, M. (2006). Cancer stem cells. N. Engl. J. Med. 355, 1253–1261.PubMedCrossRefGoogle Scholar
  39. Kiel, M.J., He, S., Ashkenazi, R., Gentry, S.N., Teta, M., Kushner, J.A., Jackson, T.L., and Morrison, S.J. (2007). Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449, 238–242.PubMedCrossRefGoogle Scholar
  40. Korinek, V., Barker, N., Moerer, P., van Donselaar, E., Huls, G., Peters, P.J., and Clevers, H. (1998). Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19, 379–383.PubMedCrossRefGoogle Scholar
  41. Kosinski, C., Li, V.S., Chan, A.S., Zhang, J., Ho, C., Tsui, W.Y., Chan, T.L., Mifflin, R.C., Powell, D.W., Yuen, S.T., Leung, S.Y., and Chen, X. (2007). Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc. Natl Acad. Sci. USA 104, 15418–15423.PubMedCrossRefGoogle Scholar
  42. Krause, D.S., Lazarides, K., von Andrian, U.H., and Van Etten, R.A. (2006). Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat. Med. 12, 1175–1180.PubMedCrossRefGoogle Scholar
  43. Kuhnert, F., Davis, C.R., Wang, H.T., Chu, P., Lee, M., Yuan, J., Nusse, R., and Kuo, C.J. (2004). Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl Acad. Sci. USA 101, 266–271.PubMedCrossRefGoogle Scholar
  44. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M.A., and Dick, J.E. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648.PubMedCrossRefGoogle Scholar
  45. Lee, J., Kotliarova, S., Kotliarov, Y., Li, A., Su, Q., Donin, N.M., Pastorino, S., Purow, B.W., Christopher, N., Zhang, W., Park, J.K., and Fine, H.A. (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, 391–403.PubMedCrossRefGoogle Scholar
  46. Leedham, S.J. and Wright, N.A. (2008). Expansion of a mutated clone: from stem cell to tumour. J. Clin. Pathol. 61, 164–171.PubMedCrossRefGoogle Scholar
  47. Li, X., Madison, B.B., Zacharias, W., Kolterud, A., States, D., and Gumucio, D.L. (2007). Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk. Physiol. Genom. 29, 290–301.CrossRefGoogle Scholar
  48. Liaw, D., Marsh, D.J., Li, J., Dahia, P.L., Wang, S.I., Zheng, Z., Bose, S., Call, K.M., Tsou, H.C., Peacocke, M., Eng, C., and Parsons, R. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67.PubMedCrossRefGoogle Scholar
  49. Mathers, C. and Boschi-Pinto, C. (2006). Global burden of cancer in the year 2000: version 1 estimates. Report, World Health Organization, Geneva.Google Scholar
  50. Maw, M.A., Corbeil, D., Koch, J., Hellwig, A., Wilson-Wheeler, J.C., Bridges, R.J., Kumaramanickavel, G., John, S., Nancarrow, D., Roper, K., Weigmann, A., Huttner, W.B., and Denton, M.J. (2000). A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum. Mol. Genet. 9, 27–34.PubMedCrossRefGoogle Scholar
  51. Mizrak, D., Brittan, M., and Alison, M.R. (2008). CD133: molecule of the moment. J. Pathol. 214, 3–9.PubMedCrossRefGoogle Scholar
  52. Muncan, V., Sansom, O.J., Tertoolen, L., Phesse, T.J., Begthel, H., Sancho, E., Cole, A.M., Gregorieff, A., de Alboran, I., Clevers, H., and Clarke, A.R. (2006). Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol. Cell Biol. 26, 8418–8426.PubMedCrossRefGoogle Scholar
  53. Nakamura, S. and Kino, I. (1984). Morphogenesis of minute adenomas in familial polyposis coli. J. Natl Cancer Inst. 73, 41–49.PubMedGoogle Scholar
  54. Novelli, M.R., Williamson, J.A., Tomlinson, I.P., Elia, G., Hodgson, S.V., Talbot, I.C., Bodmer, W.F., and Wright, N.A. (1996). Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. Science 272, 1187–1190.PubMedCrossRefGoogle Scholar
  55. O'Brien, C.A., Pollett, A., Gallinger, S., and Dick, J.E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110.PubMedCrossRefGoogle Scholar
  56. Oshima, H., Oshima, M., Kobayashi, M., Tsutsumi, M., and Taketo, M.M. (1997). Morphological and molecular processes of polyp formation in Apc(delta716) knockout mice. Cancer Res. 57, 1644–1649.PubMedGoogle Scholar
  57. Pierce, G.B., Nakane, P.K., Martinez-Hernandez, A., and Ward, J.M. (1977). Ultrastructural comparison of differentiation of stem cells of murine adenocarcinomas of colon and breast with their normal counterparts. J. Natl Cancer Inst. 58, 1329–1345.PubMedGoogle Scholar
  58. Potten, C.S., Booth, C., and Pritchard, D.M. (1997). The intestinal epithelial stem cell: the mucosal governor. Int. J. Exp. Pathol. 78, 219–243.PubMedCrossRefGoogle Scholar
  59. Potten, C.S., Booth, C., Tudor, G.L., Booth, D., Brady, G., Hurley, P., Ashton, G., Clarke, R., Sakakibara, S., and Okano, H. (2003). Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation 71, 28–41.PubMedCrossRefGoogle Scholar
  60. Regula, J., Rupinski, M., Kraszewska, E., Polkowski, M., Pachlewski, J., Orlowska, J., Nowacki, M.P., and Butruk, E. (2006). Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia. N. Engl. J. Med. 355, 1863–1872.PubMedCrossRefGoogle Scholar
  61. Ricci-Vitiani, L., Lombardi, D.G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., and De Maria, R. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115.PubMedCrossRefGoogle Scholar
  62. Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D., and Dirks, P.B. (2004). Identification of human brain tumour initiating cells. Nature 432, 396–401.PubMedCrossRefGoogle Scholar
  63. Sjoblom, T., Jones, S., Wood, L.D., Parsons, D.W., Lin, J., Barber, T.D., Mandelker, D., Leary, R.J., Ptak, J., Silliman, N., Szabo, S., Buckhaults, P., Farrell, C., Meeh, P., Markowitz, S.D., Willis, J., Dawson, D., Willson, J.K., Gazdar, A.F., Hartigan, J., Wu, L., Liu, C., Parmigiani, G., Park, B.H., Bachman, K.E., Papadopoulos, N., Vogelstein, B., Kinzler, K.W., and Velculescu, V.E. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274.PubMedCrossRefGoogle Scholar
  64. Southam, C.M. and Brunschwig, A. (1960). Quantitative studies of autotransplantation of human cancer. Cancer 14, 971–978.CrossRefGoogle Scholar
  65. Todaro, M., Perez Alea, M., Di Stefano, A.B., Cammareri, P., Vermeulen, L., Iovino, F., Tripodo, C., Russo, A., Gulotta, G., Medema, J.P., and Stassi, G. (2007a). Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402.PubMedCrossRefGoogle Scholar
  66. Todaro, M., Perez, A.M., Scopelliti, A., Medema, J.P., and Stassi, G. (2007b). IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle 7, 309–313.Google Scholar
  67. 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., Tjon-Pon-Fong, M., Moerer, P., van den Born, M., Soete, G., Pals, S., Eilers, M., Medema, R., and Clevers, H. (2002). The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250.PubMedCrossRefGoogle Scholar
  68. van den Brink, G.R. (2007). Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol. Rev. 87, 1343–1375.PubMedCrossRefGoogle Scholar
  69. van den Brink, G.R. and Offerhaus, G.J. (2007). The morphogenetic code and colon cancer development. Cancer Cell 11, 109–117.PubMedCrossRefGoogle Scholar
  70. Van der Flier, L.G., Sabates-Bellver, J., Oving, I., Haegebarth, A., De Palo, M., Anti, M., van Gijn, M.E., Suijkerbuijk, S., Van de Wetering, M., Marra, G., and Clevers, H. (2007). The intestinal Wnt/TCF signature. Gastroenterology 132, 628–632.PubMedCrossRefGoogle Scholar
  71. van Es, J.H., Jay, P., Gregorieff, A., van Gijn, M.E., Jonkheer, S., Hatzis, P., Thiele, A., van den Born, M., Begthel, H., Brabletz, T., Taketo, M.M., and Clevers, H. (2005a). Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat. Cell Biol. 7, 381–386.PubMedCrossRefGoogle Scholar
  72. van Es, J.H., van Gijn, M.E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D.J., Radtke, F., and Clevers, H. (2005b). Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963.PubMedCrossRefGoogle Scholar
  73. Vermeulen, L., Sprick, M.R., Kemper, K., Stassi, G., and Medema, J.P. (2008). Cancer stem cells – old concepts, new insights. Cell Death Differ, 947–958.Google Scholar
  74. Wasan, H.S., Park, H.S., Liu, K.C., Mandir, N.K., Winnett, A., Sasieni, P., Bodmer, W.F., Goodlad, R.A., and Wright, N.A. (1998). APC in the regulation of intestinal crypt fission. J. Pathol. 185, 246–255.PubMedCrossRefGoogle Scholar
  75. Weinberg, R.A. (2007). The Biology of Cancer. New York: Garland Science, pp. 413–416.Google Scholar
  76. Winton, D.J., Blount, M.A., and Ponder, B.A. (1988). A clonal marker induced by mutation in mouse intestinal epithelium. Nature 333, 463–466.PubMedCrossRefGoogle Scholar
  77. Wood, L.D., Parsons, D.W., Jones, S., Lin, J., Sjoblom, T., Leary, R.J., Shen, D., Boca, S.M., Barber, T., Ptak, J., Silliman, N., Szabo, S., Dezso, Z., Ustyanksky, V., Nikolskaya, T., Nikolsky, Y., Karchin, R., Wilson, P.A., Kaminker, J.S., Zhang, Z., Croshaw, R., Willis, J., Dawson, D., Shipitsin, M., Willson, J.K., Sukumar, S., Polyak, K., Park, B.H., Pethiyagoda, C.L., Pant, P.V., Ballinger, D.G., Sparks, A.B., Hartigan, J., Smith, D.R., Suh, E., Papadopoulos, N., Buckhaults, P., Markowitz, S.D., Parmigiani, G., Kinzler, K.W., Velculescu, V.E., and Vogelstein, B. (2007). The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Louis Vermeulen
    • 1
  • Jan Paul Medema
    • 1
  • James C.H. Hardwick
    • 2
  • Gijs R. van den Brink
    • 3
  1. 1.Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical CenterThe Netherlands
  2. 2.Department of Gastroenterology & HepatologyLeiden University Medical CenterLeidenThe Netherlands
  3. 3.Department of Gastroenterology & HepatologyLeiden University Medical CenterThe Netherlands

Personalised recommendations