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. 2018 Apr 30;8:133. doi: 10.3389/fonc.2018.00133

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Copyright © 2018 Verrecchia and Rédini.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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The crucial role of transforming growth factor-βs (TGF-βs) in osteosarcoma tumor growth and metastatic dissemination. Following bone degradation, the TGF-βs trapped in the bone matrix are released and promote osteosarcoma growth and metastatic dissemination by targeting both osteosarcoma tumor cells and their microenvironment. TGF-βs target osteosarcoma cells: TGF-βs stimulate “epithelial–mesenchymal transition-like” (EMT), cell migration, and invasion in part by increasing matrix metalloproteinase-2 (MMP-2) expression. TGF-βs target tumor microenvironment: TGF-βs upregulate the expression of osteolytic factors such as receptor activator of nuclear factor kappa-B ligand (RANKL) and interleukin-11 (IL-11) and therefore stimulate bone osteolysis and the secretion of protumoral factors. TGF-βs upregulate platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) expression, and therefore angiogenesis. Finally, TGF-βs exert immunosuppressive effects by regulating immune cell proliferation and activity.