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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.
Highlights
Mesenchymal Stem Cells (MSC) originating from different tissues or organs are multipotent progenitor cells that have the capacity of self-renewal and differentiation into different cell types of the mesenchymal lineage such as chondrocytes, osteoblasts, adipocytes, fibroblasts and endothelial cells [1,2,3]
Bone-Marrow Mesenchymal Stem Cells (BM-MSC) promote lymphangiogenesis in vivo Murine bone marrow (BM)-MSC isolated from C57Bl/6J or C57BL/6
The tumor growth was strongly enhanced when tumor cells were mixed with BM-MSC (Figure 1A)
Summary
Mesenchymal Stem Cells (MSC) originating from different tissues or organs are multipotent progenitor cells that have the capacity of self-renewal and differentiation into different cell types of the mesenchymal lineage such as chondrocytes, osteoblasts, adipocytes, fibroblasts and endothelial cells [1,2,3]. In a murine skin carcinoma model, we recently demonstrated that alpha-smooth muscle actin positive cells issued from BM-MSC are the unique source of matrix metalloproteinase-13, a stromal mediator of cancer cell invasion [11]. These data support the concept of fibroblast subset specialization depending upon their cellular origin. Accumulating evidences demonstrate that BM-MSC promote angiogenesis through the recruitment of endothelial progenitor cells [17], the differentiation into endothelial cells and pericyte-like cells [18,19], the secretion of soluble angiogenic factors such as Vascular Endothelial Growth Factor(VEGF)-A or basic Fibroblast Growth Factor (bFGF), and the release of exosomes as well [20,21,22,23]
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