title: Mice expressing activated PI3K rapidly develop advanced colon cancer.
abstract: Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway play a key role in the pathogenesis of numerous cancers by altering cellular growth, metabolism, proliferation, and apoptosis. 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. However, the effects of constitutively activated PI3K upon the intestinal mucosa have not been previously studied in animal models. Here, we show 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 histologic 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.
authors.affiliation: Department of Oncology, University of Wisconsin, Madison 53792, USA.
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Leystra
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Deming
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Zahm
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farhoud
authors.forename: Terrah J Paul
authors.initials: TJ
authors.lastname: Olson
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Hadac
authors.forename: Laura A
authors.initials: LA
authors.lastname: Nettekoven
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Albrecht
authors.forename: Linda
authors.initials: L
authors.lastname: Clipson
authors.forename: Ruth
authors.initials: R
authors.lastname: Sullivan
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Jose R
authors.initials: JR
authors.lastname: Torrealba
authors.forename: Jamey P
authors.initials: JP
authors.lastname: Weichert
authors.forename: Richard B
authors.initials: RB
authors.lastname: Halberg
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D005838:Genotype; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt