CD133 expression is not restricted to stem cells, and both CD133 + and CD133- metastatic colon cancer cells initiate tumors Journal Article
| Authors: | Shmelkov, S. V.; Butler, J. M.; Hooper, A. T.; Hormigo, A.; Kushner, J.; Milde, T.; St Clair, R.; Baljevic, M.; White, I.; Jin, D. K.; Chadburn, A.; Murphy, A. J.; Valenzuela, D. M.; Gale, N. W.; Thurston, G.; Yancopoulos, G. D.; D'Angelica, M.; Kemeny, N.; Lyden, D.; Rafii, S. |
| Article Title: | CD133 expression is not restricted to stem cells, and both CD133 + and CD133- metastatic colon cancer cells initiate tumors |
| Abstract: | Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10 -/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133- subset, which is also capable of tumor initiation in NOD/SCID mice. |
| Keywords: | immunohistochemistry; controlled study; protein expression; human cell; nonhuman; animal cell; mouse; phenotype; animals; mice; animal tissue; gene expression; models, biological; animal experiment; animal model; inflammation; colonic neoplasms; cell differentiation; in vitro study; mice, scid; cell population; inflammatory cell; mice, transgenic; stem cell; gene expression regulation, neoplastic; cell culture; colon cancer; cancer cell; neoplasm metastasis; peptides; reporter gene; epithelial cells; stem cells; models, genetic; cd133 antigen; antigens, cd; hermes antigen; stroma cell; colon adenocarcinoma; glycoproteins; cell adhesion molecule; colon mucosa; promoter regions (genetics); lacz gene |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 118 |
| Issue: | 6 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2008-06-02 |
| Start Page: | 2111 |
| End Page: | 2120 |
| Language: | English |
| DOI: | 10.1172/jci34401 |
| PUBMED: | 18497886 |
| PROVIDER: | scopus |
| PMCID: | PMC2391278 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 252" - "Export Date: 17 November 2011" - "CODEN: JCINA" - "Source: Scopus" |
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