Tobacco Smoke Increases Inflammatory Proteins

Researchers have found that tobacco smoke initiates a sequence of biochemical events in the cells of the oral mucosa that lead to increased production of cyclo-oxygenase (COX-2), an enzyme linked to inflammation and cancer due to its role in prostaglandin synthesis.

Investigators at Weill Medical College of Cornell University (New York, NY, USA) evaluated smokers and nonsmokers for COX-2 levels. They found that smokers produced up to four times more COX-2 than nonsmokers.

To determine the underlying biochemical cause for this difference, the investigators exposed oral mucosa cells growing in tissue culture to cigarette smoke. They reported in the January 15, 2005, issue of Cancer Research that cells exposed to smoke quickly began to produce two proteins, amphiregulin and TGF-alpha, which stimulated the activity of the epidermal growth factor receptor (EGFR).

The EGFR is a member of a family of four receptors: EGFR (HER1 or ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). These receptors are large proteins that reside in the cell membrane, and each has a specific external ligand-binding domain, a transmembrane domain and an internal domain that has tyrosine kinase enzyme activity.

When a ligand, for example EGF or TGF-alpha, binds to the EGFR, it causes receptor dimerization and autophosphorylation of the internal receptor domain. This initiates a cascade of cellular reactions that result in increased cell division and influences other aspects of malignant progression of a tumor: angiogenesis, metastasis, and an inhibition of apoptosis.

"These results provide new insights into the mechanism by which tobacco smoke causes cancer. Mutations can only occur in proliferating cells and activation of EGFR signaling enhances cell proliferation,” explained senior author Dr. Andrew J. Dannenberg, director of cancer prevention at Weill Medical College. "These results strengthen the rational for targeting not only COX-2, but also EGFR as approaches for reducing the risk of tobacco-related malignancies of the mouth and throat.”



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