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Updated: Jul 15, 2026
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kgamma
T Sasaki1, J Irie-Sasaki, Y Horie
1Ontario Cancer Institute, and Department of Medical Biophysics and Immunology, University of Toronto, Canada.
Abstract:
Phosphoinositide-3-OH kinases (PI(3)Ks) constitute a family of evolutionarily conserved lipid kinases that regulate a vast array of fundamental cellular responses, including proliferation, transformation, differentiation and protection from apoptosis. PI(3)K-mediated activation of the cell survival kinase PKB/Akt, and negative regulation of PI(3)K signalling by the tumour suppressor PTEN (refs 3, 4) are key regulatory events in tumorigenesis. Thus, a model has arisen that PI(3)Ks promote development of cancers. Here we report that genetic inactivation of the p110gamma catalytic subunit of PI(3)Kgamma (ref. 8) leads to development of invasive colorectal adenocarcinomas in mice. In humans, p110gamma protein expression is lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines. Overexpression of wild-type or kinase-dead p110gamma in human colon cancer cells with mutations of the tumour suppressors APC and p53, or the oncogenes beta-catenin and Ki-ras, suppressed tumorigenesis. Thus, loss of p110gamma in mice leads to spontaneous, malignant epithelial tumours in the colorectum and p110gamma can block the growth of human colon cancer cells.
Insights
Loss of the p110gamma subunit of phosphoinositide-3-OH kinase (PI(3)K) triggers invasive colorectal cancer in mice. Restoring p110gamma expression inhibits human colon cancer cell growth, suggesting a tumor-suppressive role.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Phosphoinositide-3-OH kinases (PI(3)Ks) are critical lipid kinases regulating cell proliferation, survival, and apoptosis.
- PI(3)K signaling, particularly via PKB/Akt activation and PTEN regulation, is implicated in tumorigenesis.
- A prevailing model suggests PI(3)Ks promote cancer development.
Purpose of the Study:
- To investigate the role of the p110gamma catalytic subunit of PI(3)Kgamma in colorectal cancer.
- To determine if p110gamma loss contributes to colorectal tumorigenesis.
- To evaluate the therapeutic potential of p110gamma in human colon cancer.
Main Methods:
- Genetic inactivation of the p110gamma catalytic subunit in mice.
- Analysis of p110gamma protein expression in human colorectal adenocarcinomas and colon cancer cell lines.
- Overexpression of wild-type and kinase-dead p110gamma in human colon cancer cells with specific genetic mutations.
Main Results:
- Genetic inactivation of p110gamma in mice resulted in invasive colorectal adenocarcinomas.
- Loss of p110gamma protein expression was observed in human primary colorectal adenocarcinomas and colon cancer cell lines.
- Overexpression of p110gamma suppressed tumorigenesis in human colon cancer cells, irrespective of APC, p53, beta-catenin, or Ki-ras mutations.
Conclusions:
- Loss of p110gamma drives spontaneous malignant epithelial tumor development in the colorectum.
- p110gamma acts as a tumor suppressor in colorectal cancer.
- Restoring p110gamma function may represent a therapeutic strategy for colon cancer.
