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October 16, 2000

Scientists Zeroing in on a Cellular Pathway to Lung Cancer

In a major step toward understanding how air pollutants injure the lungs and trigger the cascade of molecular events leading to lung cancer, scientists at the Johns Hopkins School of Public Health have spelled out the molecular process whereby a tumor-promoting toxin, phorbol ester, can activate a particular gene, SPRR1, which is a building block of squamous cell differentiation, a precancerous lesion. The study appears in the October 2000 issue of The Journal of Biological Chemistry.

Lung cancer is currently the leading cause of cancer death in the United States and other developed countries. About 80 percent of patients diagnosed with lung cancer die within 12 months because this type of cancer is silent in its early years and so is usually not detected until it has reached an advanced stage. The exact molecular mechanisms leading to cancer cells' uncontrollable proliferation are not clearly understood.

In previous studies, the authors described how the lung's epithelial cells respond to a number of carcinogens and pro-carcinogens -- including phorbol esters, retinoic acid deprivation, and tobacco smoke -- by changing into squamous cells. Although thought to be precancerous, squamous cells are initially a response to injury: They "cornify," or interlock to form a tough extra barrier against toxic exposures ("squamous" means "scales" or "scaly"). The protein whose production is triggered by the SPRR1 gene is involved in this epithelial cell "cornification."

But if the function of the injured cells is not properly regulated, the persistent presence of toxins will change squamous cells to cancerous ones. The present study details the exact molecular pathways whereby a toxin sends signals to airway cells to promote formation of a protective sheet of squamous cells.

Senior author Sekhar Reddy, PhD, assistant professor, Environmental Health Sciences, the Johns Hopkins School of Public Health, says, "If we can understand these early precancerous cellular changes, we might be able to reverse them before it's too late. Or, if we can find a way to detect precancerous cells within a few months of their onset, we might be able to prevent the development of full-blown cancer, or provide effective treatment early on."

The researchers are not only trying to learn what induces the SPRR1 gene to express its products in the presence of a toxin but also why, once full-blown cancer cells appear, the gene is again turned off and SPRR1 production dries up. "We believe the rise in production, and then the quick disappearance, of the SPRR1 gene's protein is related to the development of lung cancer," said Dr. Reddy.

The researchers ultimately want to understand how tobacco smoke and other carcinogens in air pollutants cause airway epithelial cells to turn cancerous.

Support for this study was provided by the National Institutes of Health and the Maryland Thoracic Society.

Public Affairs Media Contacts for the Johns Hopkins Bloomberg School of Public Health: Tim Parsons or Kenna Brigham @ 410-955-6878 or paffairs@jhsph.edu.