The Semaphorin 4D-Plexin-B1-RhoA signaling axis recruits pericytes and regulates vascular permeability through endothelial production of PDGF-B and ANGPTL4.
The Semaphorin 4D-Plexin-B1-RhoA signaling axis recruits pericytes and regulates vascular permeability through endothelial production of PDGF-B and ANGPTL4.
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DOI：
10.1007/s10456-013-9395-0
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发表时间：
2014-01
期刊：
影响因子：
9.8
通讯作者：
Basile, John R.
中科院分区：
文献类型：
--
作者：
Zhou, Hua;Yang, Ying-Hua;Basile, John R.
关键词：
信号素4D(Semaphorin 4D，SEMA4D)是一个跨膜和分泌蛋白家族的成员，已被证明通过其受体Plexin-B1调节轴突生长锥引导、淋巴细胞激活和骨密度。SEMA4D也在一些恶性肿瘤中过度表达，并在肿瘤诱导的血管生成中发挥作用，类似于血管内皮生长因子(VEGF)，后者是一种已被作为某些癌症治疗靶点的蛋白质。为了检测这两种促血管生成因子对肿瘤生长和血管生成的不同影响，我们先前注意到，虽然抑制VEGF和SEMA4D都限制了肿瘤的血管和大小，但在VEGF阻断的条件下形成的血管保持了它们与周细胞的联系，而在SEMA4D/Plexin-B1缺乏的背景下形成的血管则没有，这是一个有趣的发现，考虑到周细胞与内皮细胞联系的改变是癌症治疗中抗血管生成干预的一个新兴方面。我们通过芯片分析、免疫印迹、迁移和共培养实验以及VE-钙粘附素免疫组织化学显示，头颈部肿瘤细胞产生SEMA4D，以依赖于Plexin-B1/Rho的方式诱导内皮细胞表达血小板衍生生长因子-B(PDGF-B)和血管生成素样蛋白4(ANGPTL4)，从而影响周细胞的增殖和分化以及血管通透性，而血管内皮生长因子缺乏这些作用。这些结果部分解释了SEMA4D和血管内皮生长因子在病理性血管生成方面的差异，提示靶向SEMA4D功能和血管内皮生长因子可能成为治疗实体瘤的一种新的抗血管生成治疗策略。
Semaphorin 4D (SEMA4D) is a member of a family of transmembrane and secreted proteins that have been shown to act through its receptor Plexin-B1 to regulate axon growth cone guidance, lymphocyte activation, and bone density. SEMA4D is also overexpressed by some malignancies and plays a role in tumor-induced angiogenesis similar to vascular endothelial growth factor (VEGF), a protein that has been targeted as part of some cancer therapies. In an attempt to examine the different effects on tumor growth and vascularity for these two pro-angiogenic factors, we previously noted that while inhibition of both VEGF and SEMA4D restricted tumor vascularity and size, vessels forming under conditions of VEGF blockade retained their association with pericytes while those arising in a background of SEMA4D/ Plexin-B1 deficiency did not, an intriguing finding considering that alteration in pericyte association with endothelial cells is an emerging aspect of anti-angiogenic intervention in the treatment of cancer. Here we show through array analysis, immunoblots, migration and co-culture assays and VE-cadherin immunohistochemistry that SEMA4D production by head and neck carcinoma tumor cells induces expression of platelet-derived growth factor-B (PDGF-B) and angiopoietin-like protein 4 (ANGPTL4) from endothelial cells in a Plexin-B1/ Rho-dependent manner, thereby influencing proliferation and differentiation of pericytes and vascular permeability, whereas VEGF lacks these effects. These results partly explain the differences observed between SEMA4D and VEGF in pathological angiogenesis and suggest that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of solid tumors.
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缺乏周细胞会导致内皮增生和异常血管形态发生。
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