Mouse Colorectal Cancer Model Demonstrates a Critical Role for P53 in Invasiveness Control

Cancer researchers have highlighted the role of the p53 tumor suppressor by using a model system that blocked the activity of casein kinase I-alpha (CKI-alpha), a critical regulator of the Wnt signaling pathway, which is frequently hyperactivated in colorectal cancer.

Investigators at the Hebrew University of Jerusalem (Israell) worked with a mouse model that had been genetically engineered to mimic human colorectal cancer. Further genetic manipulation enabled them to eliminate the gene that encodes CKI-alpha, which triggered massive Wnt activation in the gut, but surprisingly without causing tumorigenesis. CKI-alpha-deficient epithelium showed many of the features of human colorectal tumors in addition to Wnt activation, in particular the induction of the DNA damage response and cellular senescence, both of which are thought to provide a barrier against malignant transformation.

The investigators then removed the gene encoding the tumor suppressor-protein p53. Results published in the February 17, 2011, issue of the journal Nature revealed that in the p53-deficient gut, loss of heterozygosity of the gene encoding CKI-alpha caused a highly invasive carcinoma, indicating that CKI-alpha functioned as a tumor suppressor when p53 was inactivated. A set of genes (the p53-suppressed invasiveness signature, PSIS) that was activated by the loss of both p53 and CKI-alpha probably accounted for the brisk induction of invasiveness.

The maintenance of intestinal homeostasis in the CKI-alpha-deficient gut required p53-mediated growth control, because the combined elimination of the CKI-alpha gene and either p53 or its target gene p21 triggered high-grade dysplasia with extensive proliferation. Inhibition of these genes also induced nonproliferating cells to invade neighboring normal tissue rapidly, producing invasive carcinomas throughout the small bowel.

"One of the earliest signs of cancer progression is this invasion process," said senior author Dr. Yinon Ben-Neriah, professor of basic cancer research at the Hebrew University of Jerusalem. "Normally, it is slow. In humans, it takes 10 to 15 years for colorectal cancer to develop. Even in mouse models, it takes at least six months. But when we knocked out p53, we started observing the malignant process within seven days, and it happens throughout the gut. There was something fundamental going on that had to do with p53.”

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