Tumor cells have evolved a crafty scheme for protecting themselves from the killing power of the host immune system; in part, they disable the immune response.

New studies from a group of Vanderbilt University Medical Center investigators implicate a receptor for prostaglandin E2 (PGE2) in this phenomenon of tumor-induced immune suppression.

The findings, published in the Journal of Clinical Investigation, suggest that drugs that block the PGE2 receptor, called EP2, might restore the immune system's tumor-killing capacity.

"In two different transplantable tumor models in mice, it looks like the EP2 receptor is a key mediator of the tumor's immunosuppressive action," said Richard M. Breyer, Ph.D., associate professor of Medicine and Pharmacology.

The team of investigators, including Breyer, Dr. David P. Carbone, Ingram Professor of Cancer Research at the Vanderbilt-Ingram Cancer Center, and graduate student Li Yang, injected colon and lung cancer cells into two groups of mice-normal mice and mice lacking the EP2 receptor (EP2 knockout mice). Tumors were smaller in the EP2 knockout mice, and these mice survived for longer periods of time compared to control mice.

"Not having an EP2 receptor appears to slow cancer growth and improve survivability," Breyer said. The researchers tracked the EP2 receptor effect to a difference in immune system function-the EP2 knockout mice appeared to mount an effective tumor-killing immune response; the control mice did not.

Breyer's focus on the EP2 receptor stems from his long-standing interest in the biological effects of prostaglandins, a family of locally acting hormones produced by the cyclooxygenase (COX) enzymes. COX enzymes are the targets of aspirin and other non-steroidal anti-inflammatory drugs, which work to relieve pain and inflammation by blocking the production of prostaglandins.

The connection between COX and cancer was made in the early 1990s, Breyer said, when researchers noted that people who took aspirin on a regular basis had a 40 to 50 percent drop in the relative risk of developing colorectal cancer. Dr. Raymond N. DuBois, Mina Cobb Wallace Professor of Gastroenterology and Cancer Prevention, and colleagues subsequently found high levels of one of the COX enzymes (COX-2) in cancerous colon tissue and demonstrated that blocking the enzyme could stop colon cancer cell growth.

An international trial established the effectiveness of the COX-2 inhibitor Celebrex in reducing the number of pre-cancerous polyps in individuals with familial adenomatous polyposis. Multiple trials are now underway testing COX-2 inhibitors for a broader range of cancer prevention and treatment options.

SOURCES:
Journal of Clinical Investigation, March 1, 2003
Vanderbilt University Medical Center (http://www.vanderbilt.edu)