Enhanced breast cancer cell adherence to the lung endothelium via PAF acetylhydrolase inhibition: a potential mechanism for enhanced metastasis in smokers.

Cancer deaths are primarily caused by distant metastases, rather than by primary tumor growth; however, the role of smoking in metastasis remains unclear. We demonstrated previously that endothelial cell platelet-activating factor (PAF) production results in enhanced inflammatory cell recruitment to the lung. We propose that endothelial cell PAF accumulation plays a role in cancer cell migration to distal locations. We used cigarette smoke extract (CSE) to inhibit the activity of endothelial cell PAF acetylhydrolase (PAF-AH), which hydrolyzes and inactivates PAF, and determined whether this results in increased endothelial cell PAF accumulation and breast cancer adherence. Incubation of human lung microvascular endothelial cells (HMVEC-L) with CSE resulted in a significant inhibition of PAF-AH activity that was accompanied by increased PAF production and adherence of highly invasive MDA-MB-231 breast cancer cells. Pretreatment of HMVEC-L with (S)-bromoenol lactone to inhibit calcium-independent phospholipase A2β (iPLA2β, which initiates endothelial cell PAF production) prior to CSE exposure resulted in complete inhibition of MDA-MB-231 cell adherence. Similarly, pretreatment of MDA-MB-231 cells with the PAF receptor antagonist Ginkgo biloba resulted in inhibition of adherence to the endothelium. Immunoblot analysis indicated an increase in MDA-MB-231 cell PAF receptor expression with CSE exposure. Taken together, our data indicate that CSE exposure increases endothelial cell PAF production, resulting in enhanced adherence of tumor cells to the endothelium. Our in vitro data indicate that increased tumor cell adherence would lead to enhanced metastasis formation in smokers. Potential therapeutic targets include endothelial cell iPLA2β or the tumor cell PAF receptor.