Data_Sheet_1_Endothelial Agrin Is Dispensable for Normal and Tumor Angiogenesis.PDF

Recently, the extracellular matrix protein agrin has been reported to promote tumor angiogenesis that supports tumorigenesis and metastasis; however, there is a lack of in vivo genetic evidence to prove whether agrin derived from the tumors or endothelial cells (ECs) systemically should be the therapeutic target. To date, the physiological role of endothelial agrin has also not been investigated. In the EC-specific agrin knockout mice, we observed normal endothelial and haematopoietic cell development during embryogenesis. Moreover, these mice develop normal vascular barrier integrity and vasoreactivity at the adult stage. Importantly, the growth of localized or metastatic cancer cells was not affected after implantation into endothelial agrin depleted mice. Mechanistically, agrin did not regulate endothelial ERK1/2, YAP or p53 activation in vivo that is central to support endothelial proliferation, survival and invasion. Cumulatively, our findings may suggest that agrin could play a redundant role in endothelial development during physiological and tumor angiogenesis. Targeting the endothelial derived agrin might not be effective in inhibiting tumor angiogenesis.

近期，有研究表明细胞外基质蛋白（extracellular matrix protein）集聚蛋白（agrin）可促进肿瘤血管生成，而该过程可支持肿瘤发生与转移。然而，目前尚缺乏体内遗传学证据，无法证实究竟应以肿瘤来源或是系统性内皮细胞（endothelial cells, ECs）来源的集聚蛋白作为治疗靶点。截至目前，内皮细胞来源的集聚蛋白的生理学功能也尚未得到研究。在EC特异性敲除集聚蛋白的小鼠中，我们观察到其胚胎发育过程中内皮细胞与造血细胞的发育均正常。此外，成年小鼠的血管屏障完整性与血管反应性均维持正常。值得注意的是，将实体瘤或转移性癌细胞移植至内皮细胞集聚蛋白缺失的小鼠体内后，癌细胞的生长并未受到影响。从机制上来看，集聚蛋白在体内并未调控内皮细胞的细胞外调节蛋白激酶1/2（ERK1/2）、Yes相关蛋白（YAP）或p53激活——而这些通路是支撑内皮细胞增殖、存活与侵袭的核心通路。综合来看，我们的研究结果表明，集聚蛋白在生理性血管生成与肿瘤血管生成的内皮细胞发育过程中可能仅发挥冗余功能。靶向内皮细胞来源的集聚蛋白或许无法有效抑制肿瘤血管生成。