Tobacco smoke triggers COX-2 production in oral mucosa, fueling carcinogenesis

Levels of cyclooxygenase-2 (COX-2) in oral mucosa are increased roughly 4-fold in active cigarette smokers compared with never-smokers, investigators report in the January 15th issue of Cancer Research.

In comments to Reuters Health, Dr. Andrew J. Dannenberg, from the Weill Medical College of Cornell University in New York said "tobacco smoke activates the epidermal growth factor receptor (EGFR) leading to induction of COX-2 and enhanced prostaglandin synthesis."These findings "provide new insights into the pathogenesis of tobacco smoke-induced malignancy and provide a rationale for developing new approaches to prevent the carcinogenic effects of tobacco smoke," he added."For example, topical administration of an inhibitor of EGFR or COX-2 might reduce the risk of aerodigestive malignancies without causing systemic side effects," he suggested.Both the EGFR and COX-2 have been implicated in the pathogenesis of cancer. "EGFR drives a number of procarcinogenic mechanisms including cell proliferation and COX-2 can convert a broad array of carcinogens including those found in tobacco smoke to reactive metabolites, which form mutagenic DNA adducts," Dr. Dannenberg explained."It is possible, therefore, that tobacco smoke-mediated induction of COX-2 will amplify the effect of a given dose of tobacco smoke on mutagenesis," he said.In in vitro studies, Dr. Dannenberg and others observed that exposure of oral epithelial cells to a saline extract of tobacco smoke stimulated COX-2 transcription leading to increased levels of COX-2 mRNA, COX-2 protein, and prostaglandin E2 synthesis. It also caused a rapid increase in the release of two ligands of EGFR, increasing EGFR tyrosine kinase activity."Both an inhibitor of EGFR tyrosine kinase activity and a neutralizing anti-EGFR antibody blocked tobacco smoke-mediated induction of COX-2," the investigators report.Summing up, Dr. Dannenberg said "the fact that tobacco smoke exposure activates EGFR signaling leading to increased COX-2 levels suggests that inhibiting either of these molecules might reduce the harmful effects of tobacco smoke."(Source: Cancer Research 2005;65:664-670: Reuters Health: Oncolink: January 2005.)