Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin
Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin
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DOI：
10.1002/ijc.29252
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发表时间：
2015-03-15
影响因子：
6.4
通讯作者：
Lacal, Pedro M.
中科院分区：
文献类型：
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作者：
Ruffini, Federica;Graziani, Grazia;Lacal, Pedro M.
在黑色素瘤进展过程中，肿瘤细胞对血管壁的粘附性增加，侵入细胞外基质（ECM），并经常形成类似血管的功能通道（血管源性模仿）。这些特性主要是由整合素与ECM成分的相互作用介导的。由于我们之前已经发现神经匹素1 （NRP-1）是血管内皮生长因子a （VEGF-A）的一种辅助受体，是黑色素瘤侵袭性的重要决定因素，因此本研究的目的是确定与NRP-1表达细胞的高侵袭表型相关的特异性整合素，并研究它们作为对抗黑色素瘤进展的靶点的作用。在体外评估黑色素瘤的侵袭性，通过细胞通过ECM层迁移和使用转染细胞形成小管样结构的能力。使用特异性阻断抗体鉴定与这些过程相关的整合素。研究发现，v5整合素负责约80%的NRP-1表达细胞粘附在玻璃体连接蛋白上的能力。在这些细胞中，v5的表达水平比低侵入性对照细胞高两倍，并有助于黑色素瘤细胞在基质上形成小管样结构的能力。西伦吉肽是一种有效的整合素激活抑制剂，可减少黑色素瘤细胞的ECM侵袭、血管生成模拟和VEGF-A和金属蛋白酶9的分泌。总之，我们证明5整合素参与了表达NRP-1的黑色素瘤细胞的高侵袭性表型。此外，我们还发现了一种新的机制，该机制有助于v整合素抑制剂西伦吉肽的抗黑色素瘤活性，该机制基于对血管生成模拟的抑制。有什么新鲜事吗?在黑色素瘤中，侵袭性是由称为整合素的细胞粘附分子介导的。一种叫做神经肽-1 （NRP-1）的受体也会导致这些肿瘤变得更具攻击性。在这项研究中，作者发现了特异性的v-整合素，它参与了表达NRP-1的黑色素瘤细胞向转移表型的转换。该研究还确定了肽药物西伦吉肽可能发挥抗黑色素瘤活性的新机制：西伦吉肽通过抑制v5整合素的激活，阻断肿瘤细胞形成血管网络。反过来，这应该会减少肿瘤的侵袭性。
During melanoma progression, tumour cells show increased adhesiveness to the vascular wall, invade the extracellular matrix (ECM) and frequently form functional channels similar to vascular vessels (vasculogenic mimicry). These properties are mainly mediated by the interaction of integrins with ECM components. Since we had previously identified neuropilin 1 (NRP-1), a coreceptor of vascular endothelial growth factor A (VEGF-A), as an important determinant of melanoma aggressiveness, aims of this study were to identify the specific integrins involved in the highly invasive phenotype of NRP-1 expressing cells and to investigate their role as targets to counteract melanoma progression. Melanoma aggressiveness was evaluated in vitro as cell ability to migrate through an ECM layer and to form tubule-like structures using transfected cells. Integrins relevant to these processes were identified using specific blocking antibodies. The v5 integrin was found to be responsible for about 80% of the capability of NRP-1 expressing cells to adhere on vitronectin. In these cells v5 expression level was twice higher than in low-invasive control cells and contributed to the ability of melanoma cells to form tubule-like structures on matrigel. Cilengitide, a potent inhibitor of integrins activation, reduced ECM invasion, vasculogenic mimicry and secretion of VEGF-A and metalloproteinase 9 by melanoma cells. In conclusion, we demonstrated that 5 integrin is involved in the highly aggressive phenotype of melanoma cells expressing NRP-1. Moreover, we identified a novel mechanism that contributes to the antimelanoma activity of the v integrin inhibitor cilengitide based on the inhibition of vasculogenic mimicry.What's new? In melanoma, invasiveness is mediated by cell-adhesion molecules called integrins. A receptor called neuropilin-1 (NRP-1) also causes these tumors to become more aggressive. In this study, the authors identified specific v-integrins that are involved in the switching of melanoma cells that express NRP-1 to a metastatic phenotype. The study also identified a novel mechanism by which the peptide drug cilengitide may exert anti-melanoma activity: By inhibiting the activation of v5 integrin, cilengitide blocks the formation of vascular networks by the tumor cells. This should, in turn, reduce the invasiveness of the tumors.