Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown.
Researchers at the Shanghai Jiao Tong University of Medicine report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, the researchers found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, their investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.
Tumour cell-derived exosomes endowed BM-MSCs with the ability to promote tumour growth in vivo.
(a) A representative electron microscope (PHILIPS CM120, Eindhoven, Netherlands) image of tumour cell-derived exosomes. (b) Tumour cells and tumour cell-derived exosomes were lysed with RIPA lysis buffer. (c) Exosomes derived from tumour cells labelled with PKH26 Dye (Sigma) were cultured with BM-MSCs isolated from GFP transgenic mouse for 24 h. (d) B16-F0 melanoma cells (1 × 106) were inoculated into the hind legs of C57BL/6 mice intramuscularly alone or with BM-MSCs or TE-MSCs (2 × 105), which were derived by culturing BM-MSCs with B16-F0-derived exosomes for 6 days (exosomes were added daily at a final protein concentration of 5 μg/ml).