PTEN-deficient intestinal stem cells initiate intestinal polyposis.

The failure of most current therapies to cure cancer has led to the hypothesis that treatments targeted at malignant proliferation spare a more slowly cycling ‘cancer stem cell’ population that has the ability to regenerate the tumor1. Recently, cancer stem cells have been identified and shown to seed tumors upon transplantation into a secondary host2–4. However, little is known about the process by which mutation(s) in a stem cell result in primary tumor initiation. Although there are many ‘causes’ of intestinal cancer, it is well established that almost all cases begin with the development of benign polyps, mainly involving benign neoplastic proliferation of epithelium. The epithelium of the small intestine is composed of a proliferation compartment (crypt) and a differentiation compartment in the villus (Fig. 1a). ISCs, located near the crypt base and above Paneth cells5,6, give rise to enterocytes, goblet cells, enteroendocrine cells and Paneth cells6–8. Intestinal polyposis features a substantial increase in the number of crypts (crypt expansion) and a reduction in epithelial cell differentiation6,7,9,10. A key question7,9,11 is whether stem cells are involved in the abnormal crypt expansion during polyp initiation. Figure 1 Inactivation of PTEN leads to intestinal polyposis. (a) Illustration of crypt and villus regions of intestines in which intestinal stem cells (ISCs), proliferating progenitor cells and differentiated cells are located in spatially defined compartments. ... Studies of human hereditary intestinal polyposis syndromes (which typically, but not uniformly, predispose affected individuals to gastrointestinal cancers) and equivalent animal models have provided substantial insight into the genetic control of intestinal homeostasis, polyposis and cancer. Polyposis can result from impaired bone morphogenic protein (BMP) signaling9,10,12 or by overactivation of Wnt–β-catenin signaling13. Wnt–β-catenin signaling exerts positive control on multiplication of both stem cells and crypts13,14, whereas BMP signaling restricts stem cell number and prevents polyposis, in part by suppressing Wnt signaling9,10. Cowden disease (OMIM #158350) is a rare autosomal dominant disorder featuring multiple hamartomatous lesions, including intestinal polyps. Cowden disease results from mutation in the gene encoding PTEN15, a lipid and protein phosphatase that acts as a negative regulator of the phosphatidylinositol-3 kinase (PI3K)-Akt pathway16. The roles of PTEN and Akt in intestinal homeostasis and polyposis have not been defined, but there is evidence that they could be key players in the interplay between BMP and Wnt signals. Mutation of BMPR1A can result in a Cowden-like syndrome resembling loss of PTEN17. BMP signaling may in part be mediated by inhibition of PI3K-Akt activity via positive regulation of PTEN9,18,19. In turn, PTEN inhibits, whereas Akt enhances, the nuclear localization of β-catenin20,21, consistent with our previous model in which Akt assists Wnt signaling in activation of β-catenin in ISCs9,19. In this study, we used the PTEN conditional inactivation mouse model22 to define the role of the PTEN-Akt pathway in the intestine. We implicate PTEN-deficient stem cells in the origin of polyposis and establish a molecular mechanism by which the PTEN-Akt and Wnt–β-catenin pathways coordinate to regulate intestinal homeostasis.