A new way to look at lung cancer and tobacco carcinogens

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Two types of cancer-causing agents in cigarettes—a nicotine-derived chemical and polycyclic aromatic hydrocarbons (PAHs) are the main culprits in lung cancer. Exposure to tobacco smoke – both mainstream and second-hand – is a leading cause of cancer death in the United States.

Previous studies have shown how PAHs damage DNA, with the emphasis on how PAHs bind directly to DNA itself, leading to the mutations in critical genes that cause disease. Now, researchers at the University of Pennsylvania’s School of Medicine’s Center of Excellence in Environmental Toxicology (CEET) have shown that PAHs, via oxidative stress, can also led to mutations in critical genes important in lung cancer. The findings were published online last week in the Proceedings of the National Academy of Sciences.

“This is the first demonstration of this link,” says co-author Ian Blair, PhD, Professor and Vice Chair of the Department of Pharmacology . “This is a second, but indirect, way in which PAHs can cause cancer. We also know that PAHs can also cause cancer directly.”

Several genetic studies have also shown that the enzymes responsible for generating the oxidative stress from PAHs are overexpressed in lung cancer tumor tissue and esophageal cancers, explains Trevor Penning, PhD, CEET’s director and the study’s senior author. “Our study also shows that those same enzymes, called AKRs, are responsible for the oxidative stress from PAHs in the human lung cells we used in our experiments.”

Oxidative stress is the accumulation of destructive molecules called free radicals that can lead to cell death. Free radicals damage cell membranes, proteins, or genetic material by “oxidizing” them, the same way oxygen causes iron to rust.

The AKR enzymes transform PAHs to produce oxygen free radicals. These oxygen radicals bind to DNA, and if this damage is not repaired it leads to mutations that are carried through to the next generation of cells.

Penning also mentions another genetic ramification due to this association. A recent microarray study of all 30,000 human genes asked what genes were most over-expressed in non-small cell lung carcinoma. Of the eight genes that were most abundantly overexpressed, two were AKR enzymes.

“Because this study relates AKR overexpression to oxidative damage of DNA with lung cancer, it makes you wonder if the 10 percent of smokers that are most prone to lung cancer, have either dysregulated AKR expression or genetic differences in their AKRs that predispose them to disease,” says Penning. Since oxidative stress is also linked to tumor promotion, it is possible that his link may also explain other stages of the disease process.

“These findings go beyond the first step of DNA damage and may provide a reason why disease progresses,” says Penning.

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Penn coauthors are Jong-Heum Park , Kirk A. Tacka, and Amy M. Quinn, and Dipti Mangal and Ronald G. Harvey from the University of Chicago. This work was funded by the National Institutes of Environmental Health Sciences and the National Cancer Institute.

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 #4 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.

Contact: Karen Kreeger

215-349-5658
University of Pennsylvania School of Medicine

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