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Identification and expansion of human colon-cancer-initiating cells


Colon carcinoma is the second most common cause of death from cancer1. The isolation and characterization of tumorigenic colon cancer cells may help to devise novel diagnostic and therapeutic procedures. Although there is increasing evidence that a rare population of undifferentiated cells is responsible for tumour formation and maintenance2,3,4, this has not been explored for colorectal cancer. Here, we show that tumorigenic cells in colon cancer are included in the high-density CD133+ population, which accounts for about 2.5% of the tumour cells. Subcutaneous injection of colon cancer CD133+ cells readily reproduced the original tumour in immunodeficient mice, whereas CD133- cells did not form tumours. Such tumours were serially transplanted for several generations, in each of which we observed progressively faster tumour growth without significant phenotypic alterations. Unlike CD133- cells, CD133+ colon cancer cells grew exponentially for more than one year in vitro as undifferentiated tumour spheres in serum-free medium, maintaining the ability to engraft and reproduce the same morphological and antigenic pattern of the original tumour. We conclude that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.

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Figure 1: A rare CD133 + population of tumorigenic cells is present in colon cancer.
Figure 2: The tumorigenic potential of CD133 + colon cancer cells is lost upon differentiation.
Figure 3: Long-term tumorigenic potential of colon cancer CD133 + cells.


  1. Jemal, A. et al. Cancer statistics, 2006. CA Cancer J. Clinic. 56, 106–130 (2006)

    Article  Google Scholar 

  2. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997)

    Article  CAS  Google Scholar 

  3. Pardal, R., Clarke, M. F. & Morrison, S. J. Applying the principles of stem-cell biology to cancer. Nature Rev. Cancer 3, 895–902 (2003)

    Article  CAS  Google Scholar 

  4. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004)

    Article  ADS  CAS  Google Scholar 

  5. Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720–14725 (2000)

    Article  ADS  CAS  Google Scholar 

  6. Yin, A. H. et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90, 5002–5012 (1997)

    CAS  PubMed  Google Scholar 

  7. Salven, P., Mustjoki, S., Alitalo, R., Alitalo, K. & Rafii, S. VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood 101, 168–172 (2003)

    Article  CAS  Google Scholar 

  8. Moll, R. Cytokeratins as markers of differentiation in the diagnosis of epithelial tumors. Subcell. Biochem. 31, 205–262 (1998)

    CAS  PubMed  Google Scholar 

  9. Davidson, B. et al. Detection of malignant epithelial cells in effusions using flow cytometric immunophenotyping: an analysis of 92 cases. Am. J. Clin. Pathol. 118, 85–92 (2002)

    Article  Google Scholar 

  10. Sheahan, K. et al. Differential reactivities of carcinoembryonic antigen (CEA) and CEA-related monoclonal and polyclonal antibodies in common epithelial malignancies. Am. J. Clin. Pathol. 94, 157–164 (1990)

    Article  CAS  Google Scholar 

  11. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992)

    Article  ADS  CAS  Google Scholar 

  12. Rodrigues, N. R. et al. p53 mutations in colorectal cancer. Proc. Natl Acad. Sci. USA 87, 7555–7559 (1990)

    Article  ADS  CAS  Google Scholar 

  13. Jessup, J. M. et al. Growth potential of human colorectal carcinomas in nude mice: association with the preoperative serum concentration of carcinoembryonic antigen in patients. Cancer Res. 48, 1689–1692 (1988)

    CAS  PubMed  Google Scholar 

  14. 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 100, 3983–3988 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Vescovi, A. L. et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp. Neurol. 156, 71–83 (1999)

    Article  CAS  Google Scholar 

  16. Dontu, G. et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17, 1253–1270 (2003)

    Article  CAS  Google Scholar 

  17. Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003)

    CAS  PubMed  Google Scholar 

  18. Chu, P., Wu, E. & Weiss, L. M. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod. Pathol. 13, 962–972 (2000)

    Article  CAS  Google Scholar 

  19. Ee, H. C., Erler, T., Bhathal, P. S., Young, G. P. & James, R. J. Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am. J. Pathol. 147, 586–592 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Witek, M. E. et al. The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas. Clin. Cancer Res. 11, 8549–8556 (2005)

    Article  CAS  Google Scholar 

  21. Wang, J. C. & Dick, J. E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15, 494–501 (2005)

    Article  CAS  Google Scholar 

  22. Clevers, H. Stem cells, asymmetric division and cancer. Nature Genet. 37, 1027–1028 (2005)

    Article  CAS  Google Scholar 

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We thank A. Zeuner for discussions. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro and the Italian Health Ministry to R.D.M. Author Contributions Experimental work and data analysis were done by L.R.-V., D.G.L., E.P., M.B. and M.T.; project planning and supervision was done by R.D.M.

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Correspondence to Ruggero De Maria.

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Ricci-Vitiani, L., Lombardi, D., Pilozzi, E. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).

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