Peng Hsin-Hsin, Hodgson Louis, Henderson Andrew J, Dong Cheng
Department of Bioengineering, the Pennsylvania State University, University Park, PA, USA.
Front Biosci. 2005 May 1;10:1597-606. doi: 10.2741/1643.
In this study, we report a phospholipase C (PLC)-mediated mechanism for the redistribution of interendothelial adherens junctions in response to melanoma cell contacts with the endothelium. We demonstrated that contact of melanoma cells to human umbilical vein endothelial cells (HUVEC) triggered rapid endothelial [Ca2+]i response through PLC-IP3 pathway. In addition, alternation of endothelial adherens junctions following contact of melanoma cells was evidenced by the changes in immunological staining patterns of vascular endothelial (VE)-cadherin. A PLC inhibitor, U73122 was shown to significantly diminish [Ca2+]i response and reduce the occurrence of melanoma cell-induced VE-cadherin reorganization. Moreover, inhibition of PLC attenuated melanoma cell transendothelial migration. However, melanoma cell-associated VE-cadherin breakdown was not sensitive to Ly294002, an inhibitor of phosphatidylinositol-3-kinase (PI3K), whereas inhibition of PI3K resulted in a reduction of melanoma cell transmigration. Taken together, our findings implicate that by inducing the PLC-Ca2+ signaling pathway, melanoma cells disrupt EC junctions to breach the endothelium and promote transvascular homing of tumor cells.
在本研究中，我们报告了一种磷脂酶C（PLC）介导的机制，该机制可使内皮细胞间黏附连接重新分布，以响应黑色素瘤细胞与内皮细胞的接触。我们证明，黑色素瘤细胞与人脐静脉内皮细胞（HUVEC）的接触通过PLC-IP3途径触发了快速的内皮细胞内钙离子（[Ca2+]i）反应。此外，黑色素瘤细胞接触后内皮细胞黏附连接的改变通过血管内皮（VE）-钙黏蛋白免疫染色模式的变化得以证实。一种PLC抑制剂U73122被证明可显著减少[Ca2+]i反应，并减少黑色素瘤细胞诱导的VE-钙黏蛋白重组的发生。此外，抑制PLC可减弱黑色素瘤细胞的跨内皮迁移。然而，黑色素瘤细胞相关的VE-钙黏蛋白降解对磷脂酰肌醇-3-激酶（PI3K）抑制剂Ly294002不敏感，而抑制PI3K则导致黑色素瘤细胞迁移减少。综上所述，我们的研究结果表明，黑色素瘤细胞通过诱导PLC-Ca2+信号通路破坏内皮细胞连接，从而突破内皮屏障并促进肿瘤细胞的跨血管归巢。
