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CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors
Sergey V. Shmelkov, … , David Lyden, Shahin Rafii
Sergey V. Shmelkov, … , David Lyden, Shahin Rafii
Published May 22, 2008
Citation Information: J Clin Invest. 2008;118(6):2111-2120. https://doi.org/10.1172/JCI34401.
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Research Article

CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors

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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.

Authors

Sergey V. Shmelkov, Jason M. Butler, Andrea T. Hooper, Adilia Hormigo, Jared Kushner, Till Milde, Ryan St. Clair, Muhamed Baljevic, Ian White, David K. Jin, Amy Chadburn, Andrew J. Murphy, David M. Valenzuela, Nicholas W. Gale, Gavin Thurston, George D. Yancopoulos, Michael D’Angelica, Nancy Kemeny, David Lyden, Shahin Rafii

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Figure 3

CD133 is widely expressed in murine colonic epithelial lining.

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CD133 is widely expressed in murine colonic epithelial lining.
(A–C) X-g...
(A–C) X-gal staining shows the distribution of β-galactosidase activity in the colon of CD133lacZ/+ mice (A), and in sagittal (B) and transverse (C) sections of the Lieberkuhn’s crypt. (D–F) Corresponding immunostaining with anti-CD133 antibody confirms the X-gal staining and demonstrates that CD133 protein is localized to the apical surface of mouse colon epithelium (indicated with the arrows). (G) X-Gal staining of a wild-type mouse colon. (H) Magnification of rectangle in E showing the brush border localization of CD133 protein. The inset shows a negative control staining, where arrows point to brush borders on both sides of the lumen. Original magnification, ×200 (inset). (I) Coimmunofluorescence with anti-CD31 antibody (green) and anti-CD133 antibody (red) shows the apical localization of CD133 protein in mouse colon (indicated with arrows). Scale bar: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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