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

快速生长的肿瘤本质上依赖于血管生成，而血管生成是由前血管生成因子主导的，称为血管生成开关。我们最近发现Tetraspanin D6.1a是一种最有效的血管生成诱导剂。在体内，Tetraspanin D6.1a在大鼠胰腺癌细胞株(AS-D6.1a)上的过度表达伴随着弥漫性血管内凝血和过度的血管形成，这些凝血和过度的血管形成延伸到无肿瘤的邻近器官，并完全被D6.1a特异性抗体抑制。ASD6.1a细胞及其培养上清在体外也能诱导内皮细胞生长和分枝。ASD6.1a诱导的血管生成不仅仅是肿瘤本身分泌血管生成因子所致。相反，D6.1a诱导的血管生成伴随着D6.1a、VEGF和VEGFR在新形成的毛细血管中的强烈表达，从而形成一个血管生成循环。为了阐明其潜在的机制，我们将集中在两个问题上：1.Tetraspanin D6.1a有哪些刺激血管生成的选择性特征？这个问题将通过与相关的不支持血管生成的Tetraspanins进行比较来回答。2.D6.1a或相关分子如何在肿瘤环境中诱导血管生成开关？最初的证据指向外切体介导的细胞间通讯。Tetraspanin D6.1a在系统水平上启动血管生成开关的发现具有重要的临床意义，并要求澄清潜在的机制。由于D6.1a在增殖的内皮细胞中高度表达，血管生成完全被D6.1a特异性抗体抑制，因此需要证实有效和选择性的治疗药物的选择。

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.