Researchers with the University of Pittsburgh Cancer Institute (UPCI) have identified a gene that may play a role in promoting radiation-induced intestinal damage. The research, published by Cell Press in the June issue of the journal Cell Stem Cell, could lead to new strategies for protecting normal tissues from radiation during cancer treatment.

Although radiation is one of the most effective treatments for cancer, damage to cells lining the gastrointestinal tract is a major limiting factor for patients undergoing pelvic or abdominal radiotherapy. The specific mechanisms that underlie radiation-induced gastrointestinal toxicity, known as gastrointestinal (GI) syndrome, are not well understood. Previous studies have suggested that damage to intestinal stem cells or blood vessel cells, which are called endothelial cells, may be involved in the development of GI syndrome.

Jian Yu, Ph.D., assistant professor of pathology, and Lin Zhang, Ph.D., associate professor of pharmacology and chemical biology, both of UPCI and the University of Pittsburgh School of Medicine, led the research team. They found that the expression of the gene p53 upregulated modulator of apoptosis (PUMA) plays a key role in the process of radiation-induced cell death in intestinal stem cells. These results are consistent with previous research by Drs. Yu and Zhang that determined PUMA plays an essential role in apoptosis, a process in which cells undergo a type of programmed self-destruction.

In the current study, Dr. Yu and her colleagues found that deficiency of PUMA in mice impaired cell death in intestinal stem and progenitor cells, enhanced regeneration of intestinal tissue and prolonged survival following lethal doses of radiation.

These results provide a mechanistic explanation of intestinal radiosensitivity and suggest that the death of epithelial cells is the primary event that underlies the rapid onset of GI syndrome.

"We are very excited to learn that deficiency in a single gene significantly protects against GI syndrome," said Dr. Yu. "Selectively curbing radiosensitivity in the normal tissues transiently by PUMA inhibitors might be particularly beneficial in cancer therapy. Such inhibitors might also mitigate radiation injury in an event of accidental or intentional exposure."

The study was funded by grants from the National Institutes of Health and private foundations. Co-authors of the study include Wei Qiu, Ph.D., Michael Epperly, Ph.D., Joel S. Greenberger, M.D., and Hongato Liu, B.S., from UPCI, Eleanor B. Carson-Walter, Ph.D., University of Rochester, and Gerard P. Zambetti, Ph.D., St. Jude Children's Research Hospital.

Founded in 1984, the University of Pittsburgh Cancer Institute became a National Cancer Institute (NCI) designated Comprehensive Cancer Center in record time (by 1990). UPCI, the only cancer center in western Pennsylvania with this elite designation, serves the region's population of more than 6 million. Presently, UPCI receives a total of $154 million in research grants and is ranked 10th in funding from the NCI.

University of Pittsburgh Medical Center