Department of Clinical and Biological Sciences and Oncological Sciences, University of Torino, and Institute for Cancer Research and Treatment, Candiolo, Turin, Italy.
Cancer Res. 2010 Jul 15;70(14):5759-69. doi: 10.1158/0008-5472.CAN-10-0507. Epub 2010 Jun 22.
The integrin alpha6 subunit is part of the alpha6beta1 and alpha6beta4 integrin complexes, which are known to be receptors for laminins and to mediate several biological activities such as embryogenesis, organogenesis, and invasion of carcinoma cells. However, the precise role of alpha6 integrin in angiogenesis has not yet been addressed. We observed that both vascular endothelial growth factor-A and fibroblast growth factor-2 strongly upregulate alpha6 integrin in human endothelial cells. Moreover, alpha6 integrin was positively modulated in angiogenic vessels in pancreatic neuroendocrine carcinoma. In this transgenic mouse model of spontaneous tumorigenesis, alpha6 integrin expression increased in the angiogenic stage, while being expressed at low levels in normal and hyperplastic tissue. We studied the functional role of alpha6 integrin during angiogenesis by lentivirus-mediated gene silencing and blocking antibody. Cell migration and morphogenesis on basement membrane extracts, a laminin-rich matrix, was reduced in endothelial cells expressing low levels of alpha6 integrin. However, we did not observe any differences in collagen matrices. Similar results were obtained in the aortic ring angiogenesis assay. alpha6 integrin was required for vessel sprouting on basement membrane gels but not on collagen gels, as shown by stably silencing this integrin in the murine aorta. Finally, a neutralizing anti-alpha6 integrin antibody inhibited in vivo angiogenesis in chicken chorioallantoic membrane and transgenic tumor mouse model. In summary, we showed that the alpha6 integrin participated in vascular endothelial growth factor-A and fibroblast growth factor-2-driven angiogenesis in vitro and in vivo, suggesting that it might be an attractive target for therapeutic approaches in angiogenesis-dependent diseases such as tumor growth.
整合素 α6 亚基是 α6β1 和 α6β4 整合素复合物的一部分，已知其为层粘连蛋白的受体，并介导多种生物学活性，如胚胎发生、器官发生和癌细胞浸润。然而，α6 整合素在血管生成中的精确作用尚未得到解决。我们观察到血管内皮生长因子-A 和成纤维细胞生长因子-2 均可强烈上调人内皮细胞中的 α6 整合素。此外，α6 整合素在胰腺神经内分泌癌的血管生成血管中被正向调节。在这种自发性肿瘤发生的转基因小鼠模型中，α6 整合素的表达在血管生成阶段增加，而在正常和增生组织中表达水平较低。我们通过慢病毒介导的基因沉默和阻断抗体研究了 α6 整合素在血管生成中的功能作用。在表达低水平 α6 整合素的内皮细胞中，细胞在基底膜提取物（富含层粘连蛋白的基质）上的迁移和形态发生减少。然而，我们在胶原基质上没有观察到任何差异。在主动脉环血管生成测定中也得到了类似的结果。α6 整合素对于基底膜凝胶上的血管发芽是必需的，但对于胶原凝胶上的血管发芽不是必需的，如通过在小鼠主动脉中稳定沉默该整合素所证明的那样。最后，中和抗 α6 整合素抗体抑制鸡绒毛尿囊膜和转基因肿瘤小鼠模型中的体内血管生成。总之，我们表明 α6 整合素参与了体外和体内血管内皮生长因子-A 和成纤维细胞生长因子-2 驱动的血管生成，表明它可能是血管生成依赖性疾病（如肿瘤生长）治疗方法的一个有吸引力的靶点。
