Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation.
Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation.
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DOI：
10.1186/s13046-020-01762-0
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发表时间：
2020-11-30
期刊：
影响因子：
--
通讯作者：
Kanai Y
中科院分区：
文献类型：
--
作者：
Quan L;Ohgaki R;Hara S;Okuda S;Wei L;Okanishi H;Nagamori S;Endou H;Kanai Y
肿瘤血管生成被认为是一个合理的抗癌靶点。然而，抗血管生成疗法在临床实践中的疗效和适应症相对有限。因此，仍然需要揭示肿瘤内皮的独特特性，这对于病理性血管生成至关重要。L型氨基酸转运蛋白1（LAT 1）在肿瘤细胞中被广泛上调，以支持其生长和增殖。在这项研究中，我们的目的是建立一个新的肿瘤相关的内皮细胞的一般特征，以及LAT 1的上调，并探讨在肿瘤血管生成的功能相关性。在人胰腺导管腺癌（PDA）和异种移植和同基因小鼠肿瘤模型中，对肿瘤相关内皮细胞中LAT 1的表达进行了免疫组织学研究。在主动脉环测定、基质胶塞测定和小鼠肿瘤模型中检查内皮LAT 1的药理学和基因消融的效果。通过使用人脐静脉内皮细胞在体外研究了LAT 1抑制剂和基因敲低对细胞增殖、翻译调节以及对VEGF-A依赖的血管生成过程和细胞内信号传导的影响。LAT 1在人PDA血管内皮细胞中高表达，而在正常胰腺中不表达。类似地，在小鼠肿瘤模型中观察到高内皮LAT 1表达。通过废除LAT 1的功能或表达来抑制离体/体内测定中的血管生成。通过靶向内皮细胞LAT 1抑制血管生成，小鼠肿瘤生长显著受损。LAT 1介导的氨基酸转运是体外支持内皮细胞增殖和翻译起始的基础。此外，LAT 1是VEGF-A依赖性迁移、侵袭、管形成和mTORC 1激活所必需的，这表明在内皮细胞中促血管生成信号传导和营养感测之间存在新的串扰。这些结果表明，内皮细胞LAT 1是一种新的关键球员在肿瘤血管生成，调节增殖，翻译，和促血管生成的VEGF-A信号。这项研究进一步表明了对LAT 1在肿瘤细胞和间质内皮细胞中肿瘤进展中的双重功能的新见解。LAT 1的治疗性抑制可能为加强抗血管生成疗法提供理想的选择。在线版本包含补充材料，可通过10.1186/s13046-020-01762-0获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s13046-020-01762-0.
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影响因子：
8.8
作者：
Kaira, K.;Oriuchi, N.;Imai, H.;Shimizu, K.;Yanagitani, N.;Sunaga, N.;Hisada, T.;Tanaka, S.;Ishizuka, T.;Kanai, Y.;Endou, H.;Nakajima, T.;Mori, M.
通讯作者：
Mori, M.
影响因子：
4.1
作者：
Abhinand, Chandran S.;Raju, Rajesh;Sudhakaran, Perumana R.
通讯作者：
Sudhakaran, Perumana R.
影响因子：
4.6
作者：
de Lange, Willem J.;Halabi, Carmen M.;Sigmund, Curt D.
通讯作者：
Sigmund, Curt D.
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
--
作者：
Haining Z;Kawai N;Miyake K;Okada M;Okubo S;Zhang X;Fei Z;Tamiya T
通讯作者：
Tamiya T