Cell-death receptor links cancer susceptibility and inflammation

December 27, 2007

PHILADELPHIA - For over 10 years, Wafik S. El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology at the University of Pennsylvania School of Medicine, has been pursuing a cancer-targeting molecule called TRAIL and its molecular partners. TRAIL is normally produced by immune cells and curtails tumor spread by binding to a specialized receptor on a tumor's surface.

"However, in cancer patients who often have suppressed immunity, and for reasons we still don't understand, there isn't enough TRAIL being produced, so tumors are not suppressed," explains El-Deiry, who is also Co-Program Leader of the Radiation Biology Program for the Abramson Cancer Center at Penn.

Most recently, El-Deiry and colleagues demonstrated for the first time a link between TRAIL's receptor and cancer susceptibility, as reported online December 13, 2007 in the Journal of Clinical Investigation in advance of the January 2008 print issue. Unexpectedly, they also found a connection - via Trail - between inflammation and cancer susceptibility.

Mice engineered without the TRAIL receptor on their cells versus healthy controls developed larger and more tumors in their livers and other organs after being challenged with a chemical carcinogen or radiation. The team also bred TRAIL receptor knock-out mice with mice genetically engineered to get B-cell lymphomas that metastasize to the liver. Their offspring displayed more liver tumors compared to controls. "This is the first direct in vivo evidence that loss of the tumor death-inducing TRAIL receptor confers cancer susceptibility," says El-Deiry.

When intact, TRAIL and its receptor decrease the influx of inflammatory cells and molecules that can lead to cancer. New models of cancer have suggested a link between inflammation and cancer in the last five years, and El-Deiry is in the early stages of trying to understand this connection with respect to the TRAIL pathway.

For example, in this study, the mice without the TRAIL receptor that were irradiated developed chronic pneumonia, an inflammatory response, as well tumors, evidence pointing to the connection between cancer and inflammation via TRAIL. "One benefit of this work is that it provides a new and unanticipated model implicating a TRAIL pathway deficiency in the chronic toxicity of radiation therapy," he notes. Inflammation is a common late and serious side-effect of radiation treatment in people.

El-Deiry and his team are now looking within tumor tissue for inflammatory molecules as clues to how cancer and inflammation are coupled. "Our work with TRAIL and its receptor in mouse models represents a new way to look at cancer susceptibility and its potential therapy in humans as well as new ways to decrease debilitating radiation side-effects experienced by cancer patients," says El-Deiry.

Co-authors in addition to El-Deiry are Niklas Finnberg from Penn and Andres J.P. Klein-Szanto from Fox Chase Cancer Center, Philadelphia. This research was funded in part by the National Cancer Institute.

This release can be found at www.pennhealth.com/news.
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PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #3 in the nation in U.S. News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals -- its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center -- a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, comprised of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 300 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.

University of Pennsylvania School of Medicine

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