Mice Expressing Activated PI3K Develop Advanced Colon Cancer
Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de la protéine PI3K dans l'intestin induit des néoplasies de stade avancé
Aberrations in the phosphatidylinositide-3-kinase (PI3K) signaling pathway play a key role in the pathogenesis of numerous cancers by altering cellular growth, metabolism, proliferation, and apoptosis (1). Mutations in the catalytic domain of PI3K that generate a dominantly active kinase are commonly found in human colorectal cancers and have been thought to drive tumor progression, but not initiation (2). However, the effects of constitutively activated PI3K upon the intestinal mucosa have not been previously studied in animal models. Here, we demonstrate that the expression of a dominantly active form of the PI3K protein in the mouse intestine results in hyperplasia and advanced neoplasia. Mice expressing constitutively active PI3K in the epithelial cells of the distal small bowel and colon rapidly developed invasive adenocarcinomas in the colon that spread into the mesentery and adjacent organs. The histological characteristics of these tumors were strikingly similar to invasive mucinous colon cancers in humans. Interestingly, these tumors formed without a benign polypoid intermediary, consistent with the lack of aberrant WNT signaling observed. Together, our findings indicate a noncanonical mechanism of colon tumor initiation that is mediated through activation of PI3K. This unique model has the potential to further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.
Cancer Research 2012