Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation

概要

〔目的（Purpose）］
Tumor angiogenesis is regarded as a rational anti-cancer target. The efficacy and indications of anti-angiogenic therapies in clinical practice, however, are relatively limited. Therefore, there still exists a demand for revealing the distinct characteristics of tumor endothelium that is crucial for the pathological angiogenesis. L-type amino acid transporter 1 (LAT1) is well known to be highly and broadly upregulated in tumor cells to support their growth and proliferation. In this study, we aimed to establish the upregulation of LATI as a novel general characteristic of tumor-associated endothelial cells as well, and to explore the functional relevance in tumor angiogenesis.

〔方法ならびに成績（Methods/Results）〕
Expression of LATI in tumor-associated endothelial cells was immunohistologically investigated in human pancreatic ductal adenocarcinoma (PDA) and xenograft- and syngeneic mouse tumor models. The effects of pharmacological and genetic ablation of endothelial LATI were examined in aortic ring assay, matrigel plug assay, and mouse tumor models. The effects of LATI inhibitors and gene knockdown on cell proliferation, regulation of translation, as well as on the VEGF-A-dependent angiogenic processes and intracellular signaling were investigated in in vitro by using human umbilical vein endothelial cells.

LATI was highly expressed in vascular endothelial cells of human PDA but not in normal pancreas. Similarly, high endothelial LATI expression was observed in mouse tumor models. The angiogenesis in ex/in vivo assays was suppressed by abrogating the function or expression of LATl. Tumor growth in mice was significantly impaired through the inhibition of angiogenesis by targeting endothelial LATI. LAT1-mediated amino acid transport was fundamental to support endothelial cell proliferation and translation initiation in vitro. Furthermore, LATI was required for the VEGF-A-dependent migration, invasion, tube formation, and activation of mTORCI, suggesting a novel cross-talk between pro-angiogenic signaling and nutrient-sensing in endothelial cells.

〔総括（Conclusion）〕
These results demonstrate that the endothelial LATI is a novel key player in tumor angiogenesis, which regulates proliferation, translation, and pro-angiogenic VEGF-A signaling. This study furthermore indicates a new insight into the dual functioning of LATI in tumor progression both in tumor cells and stromal endothelium. Therapeutic inhibition of LATI may offer an ideal option to potentiate anti-angiogenic therapies.