OTTAWA, Ontario - In November 1999, Josef Penninger, an immunologist at Princess Margaret Hospital and the Amgen Institute, and his team reported on the molecular cause of bone and cartilage deterioration characteristic of many inflammatory diseases.

In their continuing work in this area, the researchers turned up a protein that appeared to suppress colorectal cancer in mice and human cell cultures. Penninger said this was a completely novel and unexpected finding and defines an entirely new field that eventually could lead to therapeutic intervention. It is estimated that half of all people will develop colon tumors by age 70.

"We were studying mice that were genetically engineered to lack the protein p110g and they started to get very sick and die," he said. "It was a surprise discovery because we were examining how p110g regulates the movement of white blood cells in the immune system, not how it affects cancer cells.

"From our investigations of this phenomenon, we found they had invasive colorectal cancer; we never, ever would have expected that because every prediction about p110g had been that it actually caused cancer," Penninger added.

Reporting on their findings in the Aug. 24, 2000, issue of Nature, the researchers found that if p110g is absent it can cause spontaneous development of colorectal cancer in mice, and when it is present it stops tumor growth.

The signaling protein p110g is described as a catalytic subunit of phosphoinositide-3-OH-kinases, a family of evolutionary conserved lipid kinases that regulate a vast array of cellular responses. Genetic inactivation of 110g leads to the development of invasive colorectal adenocarcinomas in mice.

After this first indication that p110g suppressed tumor growth in genetically engineered mice, the research team led by postdoctoral fellow Takehiko Sasaki extended the study to human colorectal cancer cells taken from patients' tissue. They found no evidence of the protein in approximately 25 percent of the colorectal cancer samples. Then they investigated the results of putting p110g back in colorectal cancer cells that did not have it. The addition of the protein stopped tumor cell growth in the human cancer cell cultures, regardless of any other genetic mutations those cells had.

This is an encouraging finding since it means even if people have diverse mutations that predispose them to colorectal cancer, the protein might have the possibility to shut them all down.

In a further experiment, the researchers injected the human colorectal cancer cells into normal mice, who quickly grew tumors, and then added the protein to the cancer cells. Again, growth of colon cancer was suppressed.

"These results are a good argument that this is the real thing and it is strong evidence for the protein's role in humans," said Penninger.

One of the next steps, Penninger said, will be to study the exact workings of the p110g system in colon cancer, which could lead to future drug therapies that replicate or stimulate the protein's action in stopping tumor growth. Researchers will also investigate whether some people have a genetic mutation that causes them to not have p110g and therefore be predisposed to colorectal cancer.

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