Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition

There is growing evidence to suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumor stroma. Here, we investigated the cross-talk between BM-MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM-MSCs towards these tumor cells, and identified MCP-1, GRO-α and TGF-β1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs transdifferentiate into cancer-associated fibroblasts, further increasing MCP-1, GRO-α, IL-6 and IL-8 levels in the tumor microenvironment. These cytokines promote mesenchymal to amoeboid transition (MAT), driven by activation of the small GTPase RhoA, in OS cells, as illustrated by the in vitro assay and live imaging. The outcome is a significant increase of aggressiveness in OS cells, in terms of motility, invasiveness, and transendothelial migration. In keeping with their enhanced trans-endothelial migration abilities, OS cells stimulated by BM-MSCs also sustain migration, invasion and formation of in vitro capillary network of endothelial cells. Thus, BM-MSCs recruitment to OS site and the consequent cytokine-induced MAT are crucial events in OS malignancy.