Cigarette Smoke‐Induced Bladder Cancer Initiation

Tobacco smoking is a major risk factor associated with the development and metastasis of bladder cancer. Muscle‐invasive bladder cancer with a high risk of metastasis is the most common cause of mortality amongst bladder cancer patients, with a 5‐year survival rate below 10%. Cigarette smoking and increased metastasis correlate, but the underlying mechanism is unknown. Platelet activating factor (PAF) is a potent inflammatory mediator that we have shown to be involved in attachment of tumor cells to the endothelium lining the vasculature following cigarette smoke extract exposure. Attachment to endothelial cells occurs through the interaction between the tumor cell PAF‐receptor (PAFR) and PAF on the endothelial cell surface. The PAF/PAFR interaction facilitates transendothelial cell migration of tumor cells into the circulation to establish secondary tumor sites. PAF has also been shown to promote growth of the primary tumor via angiogenesis, allowing for increased nutrient supply to the developing tumor. Pigment epithelium‐derived factor (PEDF) is an anti‐angiogenic protein that has been shown to be down regulated in higher grade tumors. Preliminary experiments in which we exposed mice to cigarette smoke for 4 weeks indicated signs of urothelial cell hyperplasia, increased basal PAF expression, reduced PEDF expression and nuclear localization of β‐catenin. These observed changes indicate that PAF accumulation and PEDF down regulation could increase growth of primary bladder tumors as well as increase the potential for metastasis. This work highlights two potentially exciting therapeutic targets for managing bladder cancer: targeting the PAF‐PAFR interaction or increasing expression of PEDF.