論文 - 詳細
| RRC ID | 88446 |
|---|---|
| 著者 | Quan L, Ohgaki R, Hara S, Okuda S, Wei L, Okanishi H, Nagamori S, Endou H, Kanai Y. |
| タイトル | Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation. |
| ジャーナル | J Exp Clin Cancer Res |
| Abstract |
BACKGROUND: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 LAT1 as a novel general characteristic of tumor-associated endothelial cells as well, and to explore the functional relevance in tumor angiogenesis. METHODS:Expression of LAT1 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 LAT1 were examined in aortic ring assay, Matrigel plug assay, and mouse tumor models. The effects of LAT1 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. RESULTS:LAT1 was highly expressed in vascular endothelial cells of human PDA but not in normal pancreas. Similarly, high endothelial LAT1 expression was observed in mouse tumor models. The angiogenesis in ex/in vivo assays was suppressed by abrogating the function or expression of LAT1. Tumor growth in mice was significantly impaired through the inhibition of angiogenesis by targeting endothelial LAT1. LAT1-mediated amino acid transport was fundamental to support endothelial cell proliferation and translation initiation in vitro. Furthermore, LAT1 was required for the VEGF-A-dependent migration, invasion, tube formation, and activation of mTORC1, suggesting a novel cross-talk between pro-angiogenic signaling and nutrient-sensing in endothelial cells. CONCLUSIONS:These results demonstrate that the endothelial LAT1 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 LAT1 in tumor progression both in tumor cells and stromal endothelium. Therapeutic inhibition of LAT1 may offer an ideal option to potentiate anti-angiogenic therapies. |
| 巻・号 | 39(1) |
| ページ | 266 |
| 公開日 | 2020-11-30 |
| DOI | 10.1186/s13046-020-01762-0 |
| PII | 10.1186/s13046-020-01762-0 |
| PMID | 33256804 |
| PMC | PMC7702703 |
| MeSH | Amino Acid Transport System y+L / metabolism Amino Acid Transport Systems / metabolism* Animals Carcinoma, Pancreatic Ductal / blood supply* Carcinoma, Pancreatic Ductal / metabolism Cell Line, Tumor Cell Proliferation / physiology Endothelium, Vascular / metabolism* Endothelium, Vascular / pathology Female HEK293 Cells Human Umbilical Vein Endothelial Cells Humans Large Neutral Amino Acid-Transporter 1 / metabolism* Mechanistic Target of Rapamycin Complex 1 / metabolism* Melanoma, Experimental / blood supply Melanoma, Experimental / metabolism Mice Mice, Inbred C57BL Neovascularization, Pathologic / metabolism Neovascularization, Pathologic / pathology Pancreatic Neoplasms / blood supply* Pancreatic Neoplasms / metabolism Signal Transduction Vascular Endothelial Growth Factor A / metabolism* |
| IF | 7.068 |
| リソース情報 | |
| 実験動物マウス | RBRC04495 |