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

Abstract

There is growing evidence to suggest that bone marrow‐derived mesenchymal stem cells (BM‐MSCs) are key players in tumour stroma. Here, we investigated the cross‐talk between BM‐MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM‐MSCs 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‐MSCs 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 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 transendothelial migration abilities, OS cells stimulated by BM‐MSCs 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.

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

“…To confirm the role of tumor-secreted IL-6 and TGF-β in modulating CBs expression, HPFs were treated with conditioned media from DU-145 cells in the presence of and without blocking antibodies for IL-6 (α-IL-6) and a selective inhibitor of TGF-β receptor 1 (A8301). We previously proved that α-IL-6 is functional at the concentration of 5 µg/mL [27], while the dose 1 µM of A8301 was established by evaluating activation of SMAD2/3 in a dose-response experiment ( Figure S1a). As expected, CB 2 expression is regulated by both IL-6 and TGF-β pathways (Figure 2e).…”

“…Invasion and migration assays were performed in transwells (8 µm pore polyvinylpyrrolidone-free polycarbonate filters, #number CC3422, Corning, Corning, NY, USA) with or without pre-coating with 50 µg/cm 2 of reconstituted Matrigel, as previously described [27]. Briefly, CAFs and HPFs activated in vitro by TGF-β 10 ng/mL, were serum-starved for 24 h and then treated with WIN 55-212.2 mesylate and CBD 2.5 µM for an additional 24 h. Then, 1 × 10 5 fibroblasts were added to the upper chamber of Matrigel-coated transwells and allowed to invade at 37 • C for 24 h towards complete medium (20% FBS).…”

Bone marrow‐derived mesenchymal stem cell‐derived exosomal microRNA‐208a promotes osteosarcoma cell proliferation, migration, and invasion

“…malignancy (Pietrovito et al, 2018). Therefore, it is urgent to elucidate the exact role of BMSCs in osteosarcoma.…”

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

“…In OS, interactions between the tumor parenchyma and the non-tumor stroma are required during tumor development and metastatic progression [60]. MSCs are sensors of their microenvironment as they express multiple growth factors and chemokine signaling receptors.…”

“…However, we do not know how MSCs influence OS cells and how MSC-educated OS cells may in turn influence their surrounding cells, leading to more osteoid matrix and higher immune infiltration. In this context, Pietrovito et al described how MSCs in contact with OS cells gained a cancer-associated fibroblast phenotype and, in turn, how OS-activated MSCs promoted OS cell motility, invasiveness, and transendothelial migration [60]. OS-activated MSCs increased the secretion of monocyte chemoattractant protein (MCP)-1 (alias CCL2), growth-regulated oncogene (GRO)-α (also known as CXCL1), and IL-6 and -8.…”