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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
CD133 in cancer stem cells revisited
Submitter: Christopher Heeschen | christopher.heeschen@med.uni-muenchen.de
Authors: Stephan Huber, Patrick C. Hermann
Ludwig-Maximilian-University, Munich, Germany
Published June 16, 2008
Shmelkov et al. report that CD133 might not be a suitable marker for colon cancer stem cells (CSC).1 First, in transgenic mice expressing LacZ under the CD133 promoter, LacZ was broadly expressed in normal and malignant colonic epithelium. Consistently, we also see strong surface expression of CD133 in murine (malignant) pancreatic epithelial cells. Most strikingly, however, the authors report extensive CD133 staining in human epithelium and metastatic colon cancer cells using immunohistochemistry. Contradictory to previous results, CD133(-) cells also formed xenografts. Of course, the nature of these cells remains illusive since all EpCAM positive cancer cells reportedly expressed CD133. This is surprising as for primary human pancreatic cancer, we reproducibly find CD133 expression restricted to a discrete population of tumor-initiating cells ranging from 0.5-5% that is mostly negative for epithelial markers.2 These results suggest that murine models have limited analogy to human (pancreatic) cancer tissue. Indeed, the significance of the presented genetic studies in mice remains unclear as our investigations indicate similar CD133 mRNA-transcription in pancreatic CD133(+) and CD133(-) cells, respectively, implicating that the CD133 promoter activity is not restricted to cells with CD133 surface expression. Moreover, isolation of CSC from solid tumors requires the use of proteolytic enzymes that may destroy or modulate some surface antigens. While Shmelkov et al. show flow cytometry plots with a 2 log shift for the CD133(+) population in metastatic colon cancer,1 we and other groups find only low levels of CD133 expression in different tumor entities. Of course, our current knowledge about surface markers for normal tissue stem cells is limited and even more so for CSC. Tumor cells accumulate multiple mutations during transformation so that surface markers used in normal tissue may not reflect their biological relevance in cancer specimens. CD133 as a single marker certainly has limitations due to incomplete CSC specificity reflected by the relatively high number of cells that need to be implanted. Therefore, while we agree that CD133 is not a suitable marker for murine CSC, we are more reluctant to share their conclusion that CD133 is generally expressed in human cancers. At least in pancreatic cancer, we find CD133(+)cells bearing exclusive tumorigenicity, particularly when combined with other markers (e.g.CXCR4, CD44). 1. Shmelkov SV et al. CD133 expression is not restricted to stem cells, and both CD133 and CD133 metastatic colon cancer cells initiate tumors. J Clin Invest. Epub 2008 May 22. 2. Hermann PC et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313-323.
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ISSN: 0021-9738 (print), 1558-8238 (online)