MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway
MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway
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DOI：
10.1038/onc.2011.487
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发表时间：
2012-06-01
期刊：
影响因子：
8
通讯作者：
Mongiat, M.
中科院分区：
文献类型：
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作者：
Lorenzon, E.;Colladel, R.;Mongiat, M.
MULTIMERIN2 (MMRN2)，也被称为Endoglyx-1，是一种细胞外基质糖蛋白，其功能至今仍不清楚。鉴于其与内皮密切相关的特异性定位，我们假设该蛋白可以调节新血管生成。通过多次实验，我们发现MMRN2显著损害内皮细胞（EC）的迁移和功能性血管网络的组织。ECs与MMRN2的相互作用诱导了VEGFR1和VEGFR2激活的显著损伤。我们将注意力集中在血管生成的主要调节因子VEGFR2上，并阐明了MMRN2通过与VEGF- a的直接结合干扰VEGF/VEGFR2轴。这种新的相互作用在几个试验中进行了评估，并估计了亲和力（Kd近似于50 nM）。我们接下来质疑MMRN2的抗血管生成特性是否会损害肿瘤生长。HT1080细胞过表达MMRN2在体外不影响其生长和凋亡率，但在体内显著影响其生长。事实上，mmrn2阳性细胞不能有效生长并形成血管化良好的肿瘤；在用MMRN2腺病毒构建物治疗已建立的肿瘤后，观察到类似的结果。肿瘤切片免疫染色显示VEGF-A与异位表达的MMRN2有很强的共定位。这些新发现表明，VEGF可能被MMRN2隔离，与受体结合的可用性较低。综上所述，这些结果表明MMRN2在EC功能、新血管生成和肿瘤生长的调控中起着至关重要的作用。我们假设分泌和沉积的MMRN2可能作为一种体内平衡屏障，阻止新血管的生长，并建议这些研究可能体现了开发癌症治疗新工具的潜力。中华肿瘤杂志，2012,31,336 - 347；doi: 10.1038 / onc.2011.487;2011年10月24日在线发布
MULTIMERIN2 (MMRN2), also known as Endoglyx-1, is an extracellular matrix glycoprotein whose function has so far remained elusive. Given its specific localization in tight association with the endothelium we hypothesized that this protein could modulate neo-angiogenesis. By multiple assays we showed that MMRN2 significantly impaired endothelial cell (EC) migration and organization of a functional vessel network. The interaction of ECs with MMRN2 induced a striking impairment of VEGFR1 and VEGFR2 activation. We focused our attention on VEGFR2, a chief regulator of angiogenesis, and clarified that MMRN2 interfered with the VEGF/VEGFR2 axis through a direct binding with VEGF-A. This novel interaction was assessed in several assays and the affinity was estimated (Kd similar to 50 nM). We next questioned whether the anti-angiogenic properties of MMRN2 could impair tumor growth. Although overexpression of MMRN2 by HT1080 cells did not affect their growth and apoptotic rate in vitro, it remarkably affected their growth in vivo. In fact, MMRN2-positive cells failed to efficiently grow and form well-vascularized tumors; a similar outcome was observed following treatment of established tumors with a MMRN2 adenoviral construct. Tumor-section immunostaining revealed a strong co-localization of VEGF-A with the ectopically expressed MMRN2. These novel findings suggest that VEGF may be sequestered by MMRN2 and be less available for the engagement to the receptors. Taken together these results highlight MMRN2 as a crucial player in the regulation of EC function, neo-angiogenesis and hence tumor growth. We hypothesize that secreted and deposited MMRN2 may function as a homeostatic barrier halting the sprouting of novel vessels, and suggest that these studies may embody the potential for the development of novel tools for cancer treatment. Oncogene (2012) 31, 3136-3147; doi:10.1038/onc.2011.487; published online 24 October 2011