He XC et al. (2007) PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 39: 189–198
Intestinal polyposis (a benign precursor of intestinal cancer) is caused by an abnormal increase in crypt number and a concomitant reduction in the differentiation of epithelial cells that arise from crypt intestinal stem cells (ISCs); however, the processes by which mutations in ISCs result in primary tumor initiation are poorly understood. He and colleagues have conducted a study in mice that clarifies some of the molecular events involved in hamartomatous polyp formation. They found that deletion of the tumor-suppressor gene Pten (phosphatase and tensin homolog) increases the proliferation and alters the distribution of ISCs in intestinal crypts.
A conditional inactivation mouse model was used, which allows the inactivation of a chosen gene through site-specific recombination only in response to a triggering event; test mice were homozygous for inactive Pten (Pten−/−). These mice developed multiple polyps 1 month after Pten inactivation, but control mice (Pten+/−, or mice without the conditional inactivation capacity) did not. Significantly increased proliferation of ISCs was observed in Pten-deficient mice compared with control mice (proliferative index 19.4% vs 53.2%, P <0.01), and polyp formation was found to originate from such cells.
The authors conclude that a therapy that targets cancer stem cells (but not normal stem cells) is desirable to prevent regeneration of intestinal tumors, although improved knowledge of the differences between these stem-cell populations is required. This study has identified possible signaling pathways that are negatively regulated by Pten, which could have a key role in the development of successful therapies.
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Pten deficiency causes intestinal polyposis in mutant mice. Nat Rev Gastroenterol Hepatol 4, 241 (2007). https://doi.org/10.1038/ncpgasthep0780
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DOI: https://doi.org/10.1038/ncpgasthep0780