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 gene called SPRR1. That gene is a building block of squamous cell differentiation, a precancerous lesion. The study appeared 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 usually not detected until it has reached an advanced stage.

In previous studies, the Johns Hopkins researchers 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 squamous cells are thought to be precancerous, they are initially a response to injury: They "cornify," or interlock, to form a tough extra barrier against toxic exposures. ("Squamous" means "scales" or "scaly.") A protein whose production is triggered by the SPRR1 gene is involved in this cornification of epithelial cells. If the function of the injured cells is not properly regulated, the persistent presence of toxins will change squamous cells to cancerous ones.

The study reported here details the exact molecular pathways whereby a toxin signals the airway cells to promote formation of a protective sheet of squamous cells. According to senior author Sekhar Reddy, "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 trying to learn not only 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 turned off and SPRR1 production dries up. Dr. Reddy believes the rise in production--and then the quick disappearance--of the SPRR1 protein is related to the development of lung cancer.