Cigarette Smoke Increases Breast Cancer Cell Adherence to Lung Endothelium
Prerna Rastogi, Janhavi Sharma, John Marentette, Jane McHowat. Saint Louis University School of Medicine, Saint Louis, MO
Background: Distant metastasis in breast cancer is nearly always indicative of incurable disease. Lungs are a common site of breast cancer metastasis. While the incidence of breast cancer in smokers is not increased the death rate appears to be much higher possibly due to increased distant metastasis. Smoking through its myriad effects adversely modulates the natural history of breast cancer and its metastasis to the lungs. 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 spread to distant sites through the hematogenous route.
Design: In this study, we used cigarette smoke extract (CSE) to inhibit endothelial cell platelet activating factor acetylhydrolase (PAF-AH) the enzyme that hydrolyzes and inactivates PAF). Furthermore, we determined whether this results in increased endothelial cell PAF production and breast cancer cell adherence.
Results: Incubation of human lung microvascular endothelial cells (HMVEC-L) with CSE (20 µg/ml) for up to 24 hours resulted in ∼11fold inhibition of PAF-AH activity (2.3 ± 0.1 to 0.2 ± 0.1 nmol/mg protein/min at 24h, p<0.01. n=6). This was accompanied by increased PAF production (3.1 ± 0.1 to 11.5 ± 0.4 ng/mg protein at 24h, p<0.01, n=8). Likewise, MDA-MB-231 a breast cancer cell line showed significant reduction of PAF-AH activity (3.2 ± 0.1 to 1.7 ± 0.1 nmol /mg protein/min, p<0.01, n=6) when incubated with CSE (20 µg/ml, 24 h). When the MDA-MB-231 breast cancer cells were layered on HMVEC –L treated with CSE (20 µg/ml, 24 h) increased adherence between the two was noted (10.6 ± 2.3 to 60.7 ± 2.9% at 24h, p<0.01, n=6, arbitrary units). Finally, incubation of MDA-MB-231 cells with CSE resulted in a 70% increase in PAF receptor expression.
Conclusions: Our data indicate that CSE exposure increases endothelial cell PAF production and breast tumor cell PAF receptor expression. This results in enhanced adherence of tumor cells to the endothelium. Our in vitro data suggest that increased tumor cell adherence that results in enhanced metastasis formation in smokers.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 284, Wednesday Morning