By Sean Henahan, Access Excellence

PHILADELPHIA- An enzyme dubbed Pla2s (secretory type II phospholipase A2) appears to provide protection against colon cancer, while mutations in the gene associated with the enzyme are associated with an increased cancer incidence, report researchers from Thomas Jefferson University.

The Pla2s enzyme is present in the intestines of both mice and humans. Researchers at the Jefferson Cancer Center conducted studies with a strain of mice bred to have a predisposition for intestinal polyp development. Mice born with a mutated form of the enzyme developed multiple polyps within their intestines, while mice with high levels of the enzyme developed far fewer polyps.

This is the first time a link between mutations in Pla2s and intestinal cancer has been demonstrated. The finding has immediate relevance for the study of colon cancer in humans. The "Min" strain of mice used in this study is an established animal model for studying a human disease known as familial adenomatous polyposis. This inherited condition leads to the growth of hundreds or even thousands of intestinal polyps, which left untreated typically progress to colon and rectal cancer.

Inherited predisposition to colorectal cancers has been shown to be associated with a gene called Apc (adenomatous polyposis coli) in humans. "Min" mice carry a dominant mutation in the homolog of the Apc, and develop multiple polyps throughout their intestines. Individual "Min" mice show a wide variation in the number of polyps they develop, a pattern that is also seen in the human form of the disease. The current study suggests Pla2s may be the missing modifier gene researchers have been looking for.

The Pla2s enzyme appears to modify polyp formation by altering the cellular microenvironment within the intestine. One possible protective action of Pla2s could involve the inactivation of the harmful effects of dietary fatty acids. A strong correlation is known to exist between the intake of certain types of fat and an increased risk for colorectal cancer. Studies suggest that fat in the diet may interact with the lining of the intestines to stimulate polyp formation.

Pla2s also appears to play an important role in maintaining the normal flora of the intestines. Pla2s appears to contribute to the elimination of harmful anaerobic bacteria known to develop in association with saturated fat intake. These anaerobic bacteria produce toxins and carcinogens

"Pla2s may be the missing link between high-fat diets and increased incidence of colon cancer. Numerous epidemiological and laboratory studies have suggested that diets high in certain fats may increase colorectal cancer risk; yet there has been no genetic evidence of a connection until now," notes Dr. Arthur Buchberg, assistant professor of microbiology and immunology at Jefferson Medical College.

The current findings have numerous implications for diagnosis and treatment of colorectal cancer. Screening patients for Pla2s could allow clinicians to identify patients at high risk for developing these kinds of cancers. It may also be possible to supplement Pla2s in patients with low levels of the enzyme, helping protect them against cancer. Pla2s also may have potential as a treatment for existing polyps.

For more information, see: Cell, Vol. 81, 6/16/95, MacPhee et al.