Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells[reference 1]. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5+ cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.See also: Tracking down bowel cancer stem cells by Kat Arney, Science Update Blog, Cancer Research UK, December 17, 2008. Excerpt:
More experiments need to be done before we know for sure whether stem cells play a vital role in human bowel cancer. For now, these results are a promising step in the right direction – and a confirmation that the stem cell theory may well hold true for at least one type of cancer.2) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation by Liqin Zhu and 9 co-authors, including Richard J Gilbertson, Nature 2008(Dec17) [Epub ahead of print]. Abstract:
If we can understand more about the molecular pathways that control cancer, we can start to design new, more effective ways to prevent and treat the disease.
Cancer stem cells are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, for example, prominin 1 (PROM1, also called CD133)[reference 1]. What remains unclear is whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that reacquire stem cell properties during tumour formation. Answering this question will require knowledge of whether normal stem cells are susceptible to cancer-causing mutations; however, this has proved difficult to test because the identity of most adult tissue stem cells is not known. Here, using an inducible Cre, nuclear LacZ reporter allele knocked into the Prom1 locus (Prom1C-L), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1+/C-L mice containing the Rosa26-YFP reporter allele showed that Prom1+ cells are located at the base of crypts in the small intestine, co-express Lgr5 [reference 2], generate the entire intestinal epithelium, and are therefore the small intestinal stem cell. Prom1 was reported recently to mark cancer stem cells of human intestinal tumours that arise frequently as a consequence of aberrant wingless (Wnt) signalling[references 3, 4, 5]. Activation of endogenous Wnt signalling in Prom1+/C-L mice containing a Cre-dependent mutant allele of beta-catenin (Ctnnb1lox(ex3)) resulted in a gross disruption of crypt architecture and a disproportionate expansion of Prom1 cells at the crypt base. Lineage tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1+ cells in these mice, only 7% of tumour cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine that are susceptible to transformation into tumours retaining a fraction of mutant Prom1+ tumour cells.See also: Molecular marker identifies normal stem cells as intestinal tumor source, News Release, St. Jude Children's Research Hospital, December 17, 2008. Excerpt:
Scientists at St. Jude Children’s Research Hospital have answered a central question in cancer biology: whether normal stem cells can give rise to tumors. Stem cells are immature cells that can renew themselves and give rise to mature differentiated cells that compose the range of body tissues. In recent years, researchers have developed evidence that cancers may arise from mutant forms of stem cells.