title: Norepinephrine promotes the β1-integrin-mediated adhesion of MDA-MB-231 cells to vascular endothelium by the induction of a GROα release.
abstract: 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.
authors: Institute of Immunology, ZBAF, Witten/Herdecke University, Witten, Germany.
authors: Carina
authors: C
authors: Strell
authors: Bernd
authors: B
authors: Niggemann
authors: Melanie J
authors: MJ
authors: Voss
authors: Desmond G
authors: DG
authors: Powe
authors: Kurt S
authors: KS
authors: Zänker
authors: Frank
authors: F
authors: Entschladen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019012:Integrin beta1; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D011433:Propranolol; D009638:Norepinephrine