Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin.
Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin.
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DOI：
10.1158/0008-5472.can-13-0529
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发表时间：
2013-07-15
期刊：
影响因子：
11.2
通讯作者：
Mukhopadhyay D
中科院分区：
文献类型：
--
作者：
Cao Y;Hoeppner LH;Bach S;E G;Guo Y;Wang E;Wu J;Cowley MJ;Chang DK;Waddell N;Grimmond SM;Biankin AV;Daly RJ;Zhang X;Mukhopadhyay D
转移是癌症死亡的主要原因，需要肿瘤细胞内渗、通过血流迁移、在毛细血管内停滞和外渗以侵入远端组织。到目前为止，关于转移部位循环肿瘤细胞的外渗过程或再进入的机制细节报道很少。在这里，我们证明了神经纤毛蛋白-2（NRP-2），一种脑信号蛋白、血管内皮生长因子（VEGF）和其他生长因子的多功能非激酶受体，在癌细胞上表达，与内皮细胞上的α5整合素相互作用，介导斑马鱼和小鼠肾透明细胞癌（RCC）和胰腺癌异种移植模型的血管外渗和转移。在RCC患者的组织中，NRP-2表达与肿瘤分级呈正相关，并且在转移性肿瘤中最高。在前瞻性获得的胰腺癌患者队列中，NRP-2高表达与预后不良共分离。通过生物化学方法以及原子力显微镜（AFM），我们描述了一种独特的机制，通过这种机制，癌细胞上表达的NRP-2与内皮细胞上的α5整合素相互作用，介导血管粘附和外渗。总之，我们的研究揭示了NRP-2在癌细胞外渗和促进转移中的临床重要作用。
Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we demonstrate that neuropilin-2 (NRP-2), a multi-functional non-kinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from RCC patients, NRP-2 expression is positively correlated with tumor grade and highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression co-segregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis.