title: Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis.
abstract: Both epidemiological and experimental studies indicate that ethanol exposure enhances tumor progression. Ethanol exposure promotes cancer cell invasion and is implicated in tumor metastasis. Metastasis consists of multiple processes involving intravasation and extravasation of cancer cells across the blood vessel walls. The integrity of the vascular endothelial barrier that lines the inner surface of blood vessels plays a critical role in cancer cell intravasation/extravasation. We examined the effects of ethanol on the endothelial integrity in vitro. Ethanol at physiologically relevant concentrations did not alter cell viability but disrupted the endothelial monolayer integrity, which was evident by a decrease in the electric resistance and the appearance of intercellular gaps in the endothelial monolayer. The effect of ethanol was reversible once ethanol was removed. The disruption of the endothelial monolayer integrity was associated with an increased invasion of cancer cells through the endothelial monolayer. Ethanol induced the formation of stress fibers; stabilization of actin filaments by jasplakinolide prevented ethanol-induced disruption of endothelial integrity and cancer cell invasion. VE-cadherin is a critical component of the adherens junctions, which regulates vascular endothelial integrity. Ethanol induced the endocytosis of VE-cadherin and the effect was blocked by jasplakinolide. Our results indicate that ethanol may facilitate cancer metastasis by disrupting the vascular endothelial barrier.
authors.affiliation: Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Mingjun
authors.initials: M
authors.lastname: Liao
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bower
authors.forename: Shengyun
authors.initials: S
authors.lastname: Fang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000633:toxicity*; D047630:Depsipeptides / Q000494:pharmacology; D018450:Disease Progression; D017097:Electric Impedance; D004705:Endocytosis / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D017629:Gap Junctions / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D022502:Stress Fibers / Q000187:drug effects
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D015820:Cadherins; D002492:Central Nervous System Depressants; D047630:Depsipeptides; C057531:jasplakinolide; D000431:Ethanol