期刊
PLOS ONE
卷 9, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0106976
关键词
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资金
- Fonds de la Recherche Scientifique - FNRS (F.R.S.-FNRS, Belgium) [7.4583.12, 7.4531.11, 7.4529.11]
- Fondation contre le Cancer (foundation of public interest, Belgium)
- Fonds speciaux de la Recherche (University of Liege)
- Centre Anticancereux pres l'Universite de Liege
- Fonds Leon Fredericq (University of Liege)
- Direction Generale Operationnelle de l'Economie, de l'Emploi et de la Recherche from the Service Public de Wallonie (SPW, Belgium)
- Interuniversity Attraction Poles Programme - Belgian Science Policy (Brussels, Belgium)
- Plan National Cancer (Service Public Federal)
- Actions de Recherche Concertees (University of Liege, Belgium)
- Televie-FNRS grant
It is now well accepted that multipotent Bone-Marrow Mesenchymal Stem Cells (BM-MSC) contribute to cancer progression through several mechanisms including angiogenesis. However, their involvement during the lymphangiogenic process is poorly described. Using BM-MSC isolated from mice of two different backgrounds, we demonstrate a paracrine lymphangiogenic action of BM-MSC both in vivo and in vitro. Co-injection of BM-MSC and tumor cells in mice increased the in vivo tumor growth and intratumoral lymphatic vessel density. In addition, BM-MSC or their conditioned medium stimulated the recruitment of lymphatic vessels in vivo in an ear sponge assay, and ex vivo in the lymphatic ring assay (LRA). In vitro, MSC conditioned medium also increased the proliferation rate and the migration of both primary lymphatic endothelial cells (LEC) and an immortalized lymphatic endothelial cell line. Mechanistically, these pro-lymphangiogenic effects relied on the secretion of Vascular Endothelial Growth Factor (VEGF)-A by BM-MSC that activates VEGF Receptor (VEGFR)-2 pathway on LEC. Indeed, the trapping of VEGF-A in MSC conditioned medium by soluble VEGF Receptors (sVEGFR)-1, -2 or the inhibition of VEGFR-2 activity by a specific inhibitor (ZM 323881) both decreased LEC proliferation, migration and the phosphorylation of their main downstream target ERK1/2. This study provides direct unprecedented evidence for a paracrine lymphangiogenic action of BM-MSC via the production of VEGF-A which acts on LEC VEGFR-2.
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