CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation
CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation
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DOI：
10.1002/ijc.29370
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发表时间：
2015-07-01
影响因子：
6.4
通讯作者：
Leroyer, Aurelie S.
中科院分区：
文献类型：
--
作者：
Jouve, Nathalie;Bachelier, Richard;Leroyer, Aurelie S.
CD 146是一种由黑色素瘤和内皮细胞表达的粘附分子，因此可以很好地控制黑色素瘤外渗。然而，在黑色素瘤转移过程中，从未分析过肿瘤微环境中表达的CD 146的参与。为了研究宿主CD 146是否介导黑素瘤细胞穿过内皮的外渗，我们产生了CD 146 KO小鼠。我们证明宿主CD 146不影响黑色素瘤生长或肿瘤血管生成，但促进血行性黑色素瘤转移到肺。因此，CD 146缺陷型小鼠的生存期在黑素瘤转移期间显著延长。有趣的是，血管内皮生长因子诱导的血管通透性在CD 146 KO小鼠中显著降低。我们还提供了证据表明，VEGF诱导的黑色素瘤细胞跨CD 146 KO肺微血管内皮细胞（LMEC）的跨内皮迁移显著减少。CD 146缺陷降低了VEGFR-2/Ve-钙粘蛋白的表达，并改变了对VEGF的响应的粘着斑激酶（FAK）活化。此外，FAK磷酸化的抑制降低了B16黑素瘤细胞在WT LMEC中的迁移，其水平与在CD 146 KO LMEC中相同。总之，我们提出了一种新的机制，涉及VEGF/CD 146/FAK/Ve-钙粘蛋白网络在黑色素瘤外渗通过血管屏障，确定CD 146靶向治疗作为一种潜在的策略，用于治疗黑色素瘤转移。
CD146 is an adhesion molecule expressed by both melanoma and endothelial cells and thus is well positioned to control melanoma extravasation. Nevertheless, during melanoma metastasis, the involvement of CD146 expressed within tumor microenvironment has never been analyzed. To investigate whether host CD146 mediates the extravasation of melanoma cells across the endothelium, we generated CD146 KO mice. We demonstrated that host CD146 did not affect melanoma growth or tumor angiogenesis but promoted hematogenous melanoma metastasis to the lung. Accordingly, the survival of CD146-deficient mice was markedly prolonged during melanoma metastasis. Interestingly, vascular endothelial growth factor-induced vascular permeability was significantly decreased in CD146 KO mice. We also provided evidence that VEGF-induced transendothelial migration of melanoma cells was significantly reduced across CD146 KO lung microvascular endothelial cells (LMEC). CD146 deficiency decreased the expression of VEGFR-2/Ve-cadherin and altered focal adhesion kinase (FAK) activation in response to VEGF. In addition, inhibition of FAK phosphorylation reduced transmigration of B16 melanoma cells across WT LMEC at the same level that across CD146 KO LMEC. Altogether, we propose a novel mechanism involving the VEGF/CD146/FAK/Ve-cadherin network in melanoma extravasation across the vessel barrier that identifies CD146-targeted therapy as a potential strategy for the treatment of melanoma metastasis.