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Increased platelet‐activating factor accumulation in the endothelium in response to cigarette smoke may contribute to breast cancer metastasis (405.5)
Author(s) -
Kispert Shan,
Marentette John,
German Konstantin,
McHowat Jane
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.405.5
Subject(s) - platelet activating factor , cancer research , endothelium , cancer cell , metastasis , breast cancer , endothelial stem cell , cell , medicine , angiogenesis , cancer , chemistry , biology , endocrinology , in vitro , biochemistry
Cancer deaths are more often caused by distant metastases than by growth of the primary tumor. We have previously demonstrated that endothelial cell platelet‐activating factor (PAF) production results in increased adherence of breast cancer cells to the endothelium and may play a role in cancer cell migration to locations distant to the primary tumor. In this study, we used cigarette smoke extract (CSE) to inhibit endothelial cell PAF‐acetylhydrolase (PAF‐AH, hydrolyzes and inactivates PAF) activity and determined whether this results in increased endothelial cell PAF production and breast cancer cell adherence. Incubation of human lung microvascular endothelial cells (HMVEC‐L) with CSE (20 µg/ml) for up to 24 hours 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 A 2 β (iPLA 2 β, initiates endothelial cell PAF production) prior to CSE exposure resulted in complete inhibition of MDA‐MB‐231 cells. Likewise, pretreatment of MDA‐MB‐231 cells with the PAF receptor antagonist Ginkgo biloba resulted in inhibition of adherence to the endothelium. Western blot analysis revealed increased PAF receptor expression in MDA‐MB‐231 cells with CSE exposure. Histological samples of human breast carcinoma show that PAF receptor expression is increased in tumor regions when compared to the surrounding epithelium. Taken together, our data indicate that CSE exposure increases endothelial cell PAF production resulting in enhanced adherence of breast tumor cells. Our in vitro data indicate that increased tumor cell adherence would lead to enhanced metastasis formation in smokers. Potential therapeutic targets include endothelial cell iPLA 2 β or the tumor cell PAF receptor.