腫瘍間質の血管内皮細胞に高発現するアミノ酸トランスポーターLAT1は細胞増殖の促進と血管新生促進因子VEGF-AによるmTORC1活性化の制御を介して腫瘍血管新生に寄与する

抄録

Angiogenesis is essential for development and progression of tumors, and regarded as a rational target in anti-cancer treatment. We recently reported that L-type amino acid transporter 1 (LAT1) is upregulated in tumor-associated vascular endothelium of human pancreatic cancer and in vivo animal models. We also reported that tumor growth in animal model was significantly impaired through the inhibition of angiogenesis by targeting endothelial LAT1. To reveal the molecular mechanisms underlying the contribution of LAT1 in tumor angiogenesis, we investigated the effects of abrogating endothelial LAT1 on proliferation and intracellular signaling pathways in human umbilical vein endothelial cells. Pharmacological and genetic inhibition LAT1 drastically suppressed cell proliferation, causing a down-regulation of signaling pathways, GCAA- and mTORC1 pathways that are regulating the translation initiation. Furthermore, LAT1 was fundamental to promote migration, invasion, and tube formation induced by pro-angiogenic factor VEGF-A through the activation of mTORC1 in a manner independent to the tyrosine kinase receptor VEGFR2. These findings highlight a cross-talk between pro-angiogenic signaling and nutrient-sensing in tumor-associated endothelial cells, and may provide novel rational strategies for anti-angiogenic therapy.