WESTPORT, Aug 24 (Reuters Health) - Mice lacking the catalytic subunit of the lipid kinase phosphoinositide-3-OH kinase (PI(3)K) spontaneously develop invasive colorectal cancer, suggesting that the protein is a tumor suppressor, researchers report.
The results were a complete surprise, Dr. Josef M. Penninger, of the University of Toronto, Ontario, Canada, told Reuters Health.
"If we would have talked to 100 researchers who work in this field, they would have thought that the opposite would happen," he said. PI(3)K normally promotes cell growth and inhibits cell death, so it seemed likely that it would promote tumors rather than suppress them. There was also no evidence linking this protein to colorectal cancers, he pointed out.
As they describe in the August 24th issue of Nature, Dr. Penninger and colleagues created mice lacking the p110-gamma catalytic subunit of PI(3)K. These animals had shorter lifespans due to progressive weight loss and the development of colorectal cancers.
The cancers represented various stages of transformation ranging from benign polyps to metastatic carcinoma, Dr. Penninger noted. The tumors looked very similar to human cancers and were also in similar areas of the colon, he noted. Interestingly, the cancers were not associated with mutations or the loss of other genes previously implicated in the development of colorectal cancer.
"It looks like the single mutation did the trick," he said, noting that this did not rule out secondary mutations in other unknown genes.
To look at the relevance of p110-gamma in human tumors, the researchers looked at eight human colon cancer lines and found that none expressed detectable levels of p110-gamma protein. The protein was also undetectable in 3 of 12 primary adenocarcinomas isolated from patients.
The team then added the gene to several human colon cancer lines already harboring mutations in other genes associated with colorectal cancer. Adding either the normal gene or even a catalytically inactive form of the gene inhibited colony formation in vitro and tumor formation in mice, they report.
"It regulates the growth of cancer cells. So, basically, it's a new tumor suppressor for colon cancer," Dr. Penninger concluded. "Even if you have a mutation in other tumor suppressors you can still turn on another brake and cells stop growing. So this is quite nice for the future, I think, because it means if you have two or three mutations, it's not your death sentence. You might still be able to turn on the pathway which is still working."
Why the lack of p110-gamma leads specifically to colorectal cancer is still an open question, but Dr. Penninger suggested that other cancers may take longer to develop.
In the journal, he and colleagues point out that mice deficient in the G-alpha-i2 gene also develop colorectal cancer, and suggest that the G-alpha-i2 protein may be coupled to p110-gamma through a G-protein coupled receptor. "Identification of such a G-protein coupled receptor and downstream signaling pathway that control differentiation and proliferation of intestinal epithelial cells may be helpful in the design of novel strategies for colon cancer treatment," they write.
ReferenceNature 2000;406:897-902. (Abstract not currently available online.)