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Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation
- Source :
- Journal of Experimental & Clinical Cancer Research : CR, Journal of Experimental & Clinical Cancer Research, Vol 39, Iss 1, Pp 1-17 (2020)
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
Vascular Endothelial Growth Factor A
Cancer Research
Stromal cell
Endothelium
Amino Acid Transport Systems
Angiogenesis
Melanoma, Experimental
mTORC1
Mechanistic Target of Rapamycin Complex 1
lcsh:RC254-282
Tumor angiogenesis
VEGF-A
Large Neutral Amino Acid-Transporter 1
03 medical and health sciences
Mice
0302 clinical medicine
Endothelial cell
Cell Line, Tumor
medicine
Human Umbilical Vein Endothelial Cells
Animals
Humans
Cell Proliferation
Tube formation
Neovascularization, Pathologic
Cell growth
Chemistry
Amino acid transporter
Research
Amino Acid Transport System y+L
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Endothelial stem cell
Mice, Inbred C57BL
Pancreatic Neoplasms
030104 developmental biology
medicine.anatomical_structure
HEK293 Cells
Oncology
Tumor progression
030220 oncology & carcinogenesis
Cancer research
Female
Endothelium, Vascular
Carcinoma, Pancreatic Ductal
Signal Transduction
Subjects
Details
- ISSN :
- 17569966
- Volume :
- 39
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of experimentalclinical cancer research : CR
- Accession number :
- edsair.doi.dedup.....20af519454fbaf622a9bdc8f3dd27747