title: Bone marrow-derived mesenchymal stem cells drive lymphangiogenesis.
abstract: 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.
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Maertens
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Erpicum
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Detry
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Laboratory of Cardiovascular Research, Centre de Recherche Public de la santé (CRP-santé), Luxembourg, Luxembourg.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lenoir
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Oriane
authors.initials: O
authors.lastname: Carnet
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Christel
authors.initials: C
authors.lastname: Péqueux
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Lecomte
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Jenny
authors.initials: J
authors.lastname: Paupert
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D042583:Lymphangiogenesis; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor