Angiogenesis, Metastasis, and the Cellular Microenvironment Norepinephrine Promotes the b1-Integrin–Mediated Adhesion of MDA-MB-231 Cells to Vascular Endothelium by the Induction of a GROa Release

The migratory activity of tumor cells and their ability to extravasate from the blood stream through the vascular endothelium are important steps within the metastasis cascade.We have shown previously that norepinephrine is a potent inducer of the migration ofMDA-MB-468 human breast carcinoma cells and therefore investigated herein, whether the interaction of these cells as well as MDA-MB-231 andMDA-MB-435S human breast carcinoma cells with the vascular endothelium is affected by this neurotransmitter as well. By means of a flow-through assay under physiologic flow conditions, we show that norepinephrine induces an increase of the adhesion of the MDA-MB231 cells, but not of MDA-MB-468 and MDA-MB-435S cells to human pulmonary microvascular endothelial cells (HMVEC). The adhesion of MDA-MB-231 cells was based on a norepinephrine-mediated release of GROa from HMVECs. GROa caused a b1-integrin–mediated increase of the adhesion of MDA-MB-231 cells. Most interestingly, this effect of norepinephrine, similar to the aforementioned induction ofmigration inMDA-MB-468 cells, wasmediated byb-adrenergic receptors and therefore abrogated byb-blockers. In conclusion, norepinephrine has cell line–specific effects with regard to certain steps of the metastasis cascade, which are conjointly inhibited by clinically established b-blockers. Therefore, these results may deliver a molecular explanation for our recently published retrospective data analysis of patients with breast cancer which shows that b-blockers significantly reduce the development of metastases. Mol Cancer Res; 10(2); 197–207. 2011 AACR.