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Receptor Could Be Target For Cancer Therapy; Blocking Prostaglandin Might Restore Immune Response To Tumors

Date:
March 6, 2003
Source:
Vanderbilt University Medical Center
Summary:
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.

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 March 1 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 cancer prevention and treatment. COX inhibitors may not be ideal anti-cancer drugs, Breyer said, because they block the production of all prostaglandins. "Some of these prostaglandins could have beneficial effects," he said. "We were interested in discovering which prostaglandins are participating in the tumor-promoting effect, and more importantly, which prostaglandin receptors."

It was known that tumor tissue produces the prostaglandin PGE2, Breyer said. And since his laboratory had already engineered mice lacking the EP2 receptor, one of the four known receptors for PGE2, it made sense to look at tumor growth in these mice. Indeed, following injection of colon or lung cancer cells, the EP2 knockout mice grew smaller tumors and lived longer than control mice, suggesting that PGE2 works through the EP2 receptor to promote cancer growth.

Because they suspected a difference in immune system response, the investigators compared the function of various types of immune cells. A series of experiments demonstrated that white blood cells called T cells were normal in number and function in both wild-type and EP2 knockout mice. The investigators found differences though, in the function of dendritic cells, special immune system cells that stimulate the production of tumor-killing T cells. In tumor-bearing normal mice, the number of dendritic cells was reduced. But in EP2 knockout mice, the number of dendritic cells was increased, as would be expected in animals mounting an immune response, Breyer said.

Dendritic cells police the body for intruders (like tumor cells) and "present" tumor cell proteins to T cells, stimulating them to become killer T cells that can seek out and destroy the infringing tumor cells. The investigators showed that EP2 knockout mice, but not wild-type mice, produce these killer T cells in response to tumor cells. When the EP2 receptor is active, as it is in normal mice, Breyer said, it participates in suppressing the immune response that produces killer T cells. The studies suggest that blocking the EP2 receptor would be a useful strategy to improve immune system killing of tumor cells, he said.

Because previous studies from other groups had linked PGE2 to angiogenesis, the growth of new blood vessels, the investigators also explored this possibility in the EP2 knockout mice. They found no difference in the number of tumor blood vessels or the levels of blood vessel growth factors in normal and EP2 knockout mice. Breyer suspects that other PGE2 receptors may be involved in promoting tumor blood vessel growth.

Other contributors to the studies include Noboru Yamagata, Rajwardhan Yadav, Suzanne Brandon, Regina L. Courtney, Dr. Jason D. Morrow, Yu Shyr, Ph.D., Dr. Mark R. Boothby, and Sebastian Joyce, Ph.D. The research was launched under the auspices of the National Institutes of Health-funded Research Center for Pharmacology and Drug Toxicology, directed by Morrow. It was also supported by other NIH grants and by the Vanderbilt-Ingram Cancer Center.


Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Vanderbilt University Medical Center. "Receptor Could Be Target For Cancer Therapy; Blocking Prostaglandin Might Restore Immune Response To Tumors." ScienceDaily. ScienceDaily, 6 March 2003. <www.sciencedaily.com/releases/2003/03/030306075656.htm>.
Vanderbilt University Medical Center. (2003, March 6). Receptor Could Be Target For Cancer Therapy; Blocking Prostaglandin Might Restore Immune Response To Tumors. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2003/03/030306075656.htm
Vanderbilt University Medical Center. "Receptor Could Be Target For Cancer Therapy; Blocking Prostaglandin Might Restore Immune Response To Tumors." ScienceDaily. www.sciencedaily.com/releases/2003/03/030306075656.htm (accessed July 29, 2014).

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