Alterations in Phospholipase A2‐Mediated Pathways in Smokers: A Potential Mediator of Skin Cancer Development

Abstract

Cigarette smoking is a major preventable cause of disease that maintains a disproportionate prevalence in populations distinguished by socioeconomic status, race, and gender. Much remains unknown about the biochemical effects of smoking on the development of skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). However, a recent meta‐analysis study demonstrated that cigarette smoking is associated with a 52% increase in the risk for SCC, but does not appear to modify the risk for BCC. Our previous studies have demonstrated that cigarette smoking is associated with changes in phospholipase A2 (PLA2)‐mediated pathways that are implicated in cancer development and progression. More specifically, PLA2 activation leads to increased platelet‐activating factor (PAF) and prostaglandin E2 (PGE2) synthesis, metabolites that are increased in cancer cells and mediate tumor growth, survival and invasion. To assess the effects of cigarette smoking in non‐melanoma skin cancer, we analyzed PAF and PGE2 expression in skin biopsies from six smokers and six non‐smokers with SCC, and six smokers and six non‐smokers with BCC using immunohistochemistry. PAF was not detectable in BCC patient samples. SCC patient samples revealed positive PAF expression with nuclear localization in all patient samples, but there was no significant difference between expression in samples of smokers when compared to nonsmokers. PGE2 expression was detected in BCC patient samples, with no difference between smokers and nonsmokers. PGE2 expression was greater in SCC when compared to BCC, with a 50% increase in expression in SCC samples from smokers compared to nonsmokers. Increased PGE2 accumulation was accompanied by a 25% increase in COX‐2 expression in SCC samples from smokers compared to nonsmokers. Increased COX‐2 and PGE2 production can stimulate the production of vascular endothelial growth factor (VEGF), accelerating tumor growth, survival and invasion. We detected a 40% increase in VEGF expression in SCC samples from smokers when compared to nonsmokers. COX‐2 and VEGF expression remained unchanged between BCC samples taken from smokers or nonsmokers. Taken together, our data suggest that increased PGE2 accumulation may contribute to the increased risk of SCC in smokers.