PTEN-deficient intestinal stem cells initiate intestinal polyposis

Abstract

Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTENdeficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector β-catenin. Akt phosphorylates β-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of β-catenin. Accession codes. Gene Expression Omnibus (GEO): GSE6078.URLs. GEO: http://www.ncbi.nlm.nih.gov/projects/geo/.Supplementary information is available on the Nature Genetics website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. HHS Public AccessAuthor manuscript Nat Genet. Author manuscript; available in PMC 2015 December 16. Published in final edited form as:Nat Genet. 2007 February ; 39(2): 189-198. doi:10.1038/ng1928. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe 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 tumor 1 . Recently, cancer stem cells have been identified and shown to seed tumors upon transplantation into a secondary host [2][3][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 cells 5,6 , give rise to enterocytes, goblet cells, enteroendocrine cells and Paneth cells [6][7][8] . Intestinal polyposis features a substantial increase in the number of crypts (crypt expansion) and a reduction in epithelial cell differentiation 6,7,9,10 . A key question 7,9,11 is whether stem cells are involved in the abnormal crypt expansion during polyp initiation.Studies of human hereditary intestinal polyposis syndromes (which typically, but not uniformly, predispose affected individuals to gastrointes...

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

“…It has been shown that Akt activity, as shown by Akt phosphorylation, is critical for the expansion of intestinal crypts and epithelial stem cells [23][24][25] . Therefore, we hypothesized that blebbistatin might activate Akt in Lgr5 þ stem cells.…”

Regulation of adult intestinal epithelial stem cell development by thyroid hormone during Xenopus laevis metamorphosis

“…Indeed, the Shh/BMP-4 signaling pathway shown to be involved in the amphibian intestinal remodeling has also been proposed to play roles in the embryonic gut organogenesis of terrestrial vertebrates (Roberts, 2000;Zhang et al, 2001; and the postembryonic epithelial cell-renewal of the mammalian intestine (Howe et al, 2001;Madison et al, 2004;Haramis et al, 2004;He et al, 2004He et al, , 2007Batts et al, 2006). Mutations in members of this pathway are known to be associated with the numerous malformations (Litingtung et al, 1998;Ramalho-Santos et al, 2000) and diseases (Howe et al, 2001;de Santa Barbara et al, 2002Berman et al, 2003;Beachy et al, 2004;He et al, 2004;Nielsen et al, 2004).…”

EGF signaling activates proliferation and blocks apoptosis of mouse and human intestinal stem/progenitor cells in long-term monolayer cell culture

“…12 Moreover, growth factor receptor signaling that initiates PtdIns (3,4,5) kinase (PI3K) pathway induces phosphorylation of Akt and activates proliferation of immature cells in the crypt, a process that is strictly regulated by the function of phosphatase and tensin homologue (PTEN). 12,13 The lack of PTEN results in de novo crypt formation because of an excess of ISCs, leading to initiation of intestinal polyposis. 13 Akt induces cell survival and cell cycle progression through phosphorylation of multiple target proteins, including b-catenin, an effector of canonical Wnt signaling.…”

“…12,13 The lack of PTEN results in de novo crypt formation because of an excess of ISCs, leading to initiation of intestinal polyposis. 13 Akt induces cell survival and cell cycle progression through phosphorylation of multiple target proteins, including b-catenin, an effector of canonical Wnt signaling. 13 Therefore, the cross-talk among Wnt/b-catenin, BMP, and PTEN/PI3K/Akt signaling is critical for the control of intestinal tissue homeostasis.…”