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 of MDA-MB-468 human
breast carcinoma cells and therefore investigated herein, whether the interaction of these cells as well as MDA-MB-231 and MDA-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-MB-231 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 GROα from HMVECs. GROα caused a β1-integrin-mediated increase of the adhesion of MDA-MB-231 cells. Most interestingly, this effect of
norepinephrine, similar to the aforementioned induction of migration in MDA-MB-468 cells, was mediated by β-
adrenergic receptors and therefore abrogated by β-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 β-blockers. Therefore, these results may deliver a molecular explanation for our recently published retrospective data analysis of patients with
breast cancer which shows that β-blockers significantly reduce the development of
metastases.