Crosstalk between tumor cells and endothelial cells via the tetraspanin D6.1A

快速生长的肿瘤基本上依赖于血管生成，这是由称为血管生成开关的促血管生成因子的优势启动的。我们最近发现四跨膜蛋白D6.1A是最有效的血管生成诱导剂。在体内，四跨膜蛋白D 6. 1A在大鼠胰腺癌细胞系（AS-D 6.1A）上的过表达伴随着弥散性血管内凝血和过度的血管形成，其延伸到无肿瘤的邻近器官，并被D 6. 1A特异性抗体完全抑制。ASD 6.1A细胞及其上清液还在体外诱导内皮细胞生长和分支。ASD 6.1A诱导的血管生成不仅仅是由于肿瘤本身分泌血管生成因子。相反，D6.1A诱导的血管生成伴随着新形成的毛细血管中强烈的D6.1A、VEGF和VEGFR表达，从而产生血管生成环。为了阐明潜在的机制，我们将重点关注两个问题：1。四跨膜蛋白D6.1A的选择性特征是什么？这个问题将通过与不支持血管生成的相关四跨膜蛋白的比较来回答。2. D6.1A或相关分子如何诱导肿瘤环境中的血管生成开关？第一个证据指向外泌体介导的细胞间通讯。四跨膜蛋白D6.1A在全身水平启动血管生成转换的发现具有重要的临床意义，并需要阐明潜在的机制。由于D6.1A在增殖的内皮细胞中高度表达，并且血管生成被D6.1A特异性抗体完全抑制，因此需要证实有效和选择性治疗药物的选择。

Rapidly growing tumors essentially depend on angiogenesis, which is initiated by the dominance of proangiogenic factors, called the angiogenic switch. We recently identified the tetraspanin D6.1A as a most potent angiogenesis inductor. In vivo, over-expression of the tetraspanin D6.1A on a rat pancreatic adenocarcinoma line (AS-D6.1A) is accompanied by disseminated intravascular coagulation and excessive vessel formation, which extends to tumor-free adjacent organs and is completely inhibited by a D6.1A-specific antibody. ASD6.1A cells and supernatant thereof also induce endothelial cell growth and branching in vitro. ASD6.1A- induced angiogenesis is not solely due to the secretion of angiogenic factors by the tumor itself. Instead, D6.1A-induced angiogenesis is accompanied by strong D6.1A, VEGF and VEGFR expression in newly formed capillaries, thus creating an angiogenic loop. To clarify the underlying mechanism, we will focus on two questions: 1. What are the selective features of the tetraspanin D6.1A, that provoke angiogenesis? The question will be answered by a comparison with related tetraspanins, that do not support angiogenesis. 2. How does D6.1A or associated molecules induce the angiogenic switch in the tumor environment? First evidences point towards an exosome-mediated intercellular communication. The finding that the tetraspanin D6.1A initiates the angiogenic switch at a systemic level is of major clinical importance and demands for clarifying the underlying mechanism. Because D6.1A is highly expressed in proliferating endothelial cells and angiogenesis is completely suppressed by a D6.1A-specific antibody, the option of an effective and selective therapeutic drug needs to be substantiated.