INTESTINAL GROWTH-INDUCING CHEMICAL USES RECEPTOR LINKED TO WOUND HEALING, CANCER GROWTH, UCI STUDY FINDS
Findings May Lead to New Drugs to Fight Colon, Stomach Cancers
Irvine, Calif., March 6, 2002 -- An intestinal chemical triggers cell growth--helping to heal ulcers but also to promote cancer--by stimulating a receptor on intestinal cells, a UCI College of Medicine and VA Medical Center, Long Beach team has found.
The researchers' study, published in the March 2002 issue of Nature Medicine, is the first to demonstrate how these intestinal chemicals, called prostaglandins, can promote the cell growth that leads to cancer, which may lead to a new class of drugs that could prevent or reduce the incidence of colon cancer.
Dr. Andrzej Tarnawski, professor of medicine at UCI and chief of the division of gastroenterology UCI and at the Veterans Affairs Medical Center in Long Beach, and his colleagues found that prostaglandins promote cancer cell growth by ultimately stimulating a key intestinal receptor called EGF-R. Once stimulated, EGF-R triggers a series of reactions that may lead to excessive cell growth and potentially cancer.
"For more than 20 years, we've known that prostaglandins normally help cells row in the lining of the stomach and intestine. On one hand, this helps with wound and ulcer healing. On the other, while not inducing cancer themselves, prostaglandins can promote cancer growth, especially in people who have a higher genetic risk of getting cancer," Tarnawski said.
Colon cancer is one of the most common cancers and is diagnosed in more than 150,000 Americans every year. Each year, about 50,000 people in the United States die from colon or rectal cancer. In cancer, levels of COX-2, the enzyme that helps produce prostaglandins, has been found at much higher levels than in non-cancerous cells.
Physicians often prescribe anti-inflammatory drugs called COX-2 inhibitors to patients with colon cancer or precancerous polyps because the drugs help reduce prostaglandin levels and lower incidences of cancer. However, it was not known how prostaglandins could stimulate and promote cancer growth. Using normal rat cells and human colon cancer cells, Tarnawski's team found that prostaglandins accelerated cell growth in both normal and cancerous cells by communicating with cellular proteins that activated the EGF receptor. Specific inhibitors along the biochemical pathway used by the EGF receptor provided further evidence that prostaglandin-induced cell growth was significantly regulated by the EGF receptor.
Prostaglandins are produced by enzymes called COX-1 and COX-2. Their biological activities include protecting the lining of the stomach and intestine, as well as the pancreas, liver and kidneys. They are known to promote ulcer healing but also can create inflammation in joints. In cancer cells, however, high levels of both COX-2 and prostaglandins contribute to abnormal cell growth by activating EGF-R.
By blocking the EGF receptor, Tarnawski's results suggest that drugs could reduce prostaglandins' ability to stimulate cancer growth.
Tarnawski's study also helps explain the results of previous studies demonstrating that popular anti-inflammatory drugs called NSAIDs can help curb the growth of cancer cells. NSAIDs include aspirin, ibuprofen, naproxen and several prescription drugs.
"In ulcer healing, EGF-R is activated only for two to four weeks, and is then inhibited. In cancer cells, EGF-R is continuously activated, leading to uncontrolled growth. This study shows how maintaining the inhibition of EGF-R and COX-2 may effectively reduce cancer development," said Tarnawski, who is a physician and chief of gastroenterology at both UCI Medical Center and the VA Medical Center. "Depending on its success in human trials, inhibitors may at least be part of a series of therapeutic agents used against the disease."
Tarnawski and his team have spent more than 25 years determining how, on a cellular level, prostaglandins and other growth-inducing chemicals protect the stomach and intestinal lining, and which biochemical pathways stimulate ulcer healing. Recently, they have also focused on how inhibiting COX-2 and prostaglandins may help suppress colon and stomach cancer. Tarnawski's team was one of the first to demonstrate a successful gene therapy technique for treating ulcers.
Tarnawski's colleagues in the study include Rama Pai, Dolgor Baatar, Meredith Pavelka, Brian Soreghan and Imre Szabo, all of UCI and the VA Medical Center.
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