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 ‐ MSC s) are key players in tumour stroma. Here, we investigated the cross‐talk between BM ‐ MSC s and osteosarcoma ( OS ) cells. We revealed a strong tropism of BM ‐ MSC s towards these tumour cells and identified monocyte chemoattractant protein ( MCP )‐1, growth‐regulated oncogene ( GRO )‐α and transforming growth factor ( TGF )‐β1 as pivotal factors for BM ‐ MSC chemotaxis. Once in contact with OS cells, BM ‐ MSC s trans‐differentiate into cancer‐associated fibroblasts, further increasing MCP ‐1, GRO ‐α, interleukin ( IL )‐6 and IL ‐8 levels in the tumour microenvironment. These cytokines promote mesenchymal to amoeboid transition ( MAT ), driven by activation of the small GTP ase 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 transendothelial migration abilities, OS cells stimulated by BM ‐ MSC s also sustain migration, invasion and formation of the in vitro capillary network of endothelial cells. Thus, BM ‐ MSC recruitment to the OS site and the consequent cytokine‐induced MAT are crucial events in OS malignancy.