Mesenchymal stroma: Role in osteosarcoma progression.

The initiation and progression of malignant tumors are supported by their microenvironment: cancer cells per se cannot explain growth and formation of the primary or metastasis, and a combination of proliferating tumor cells, cancer stem cells, immune cells mesenchymal stromal cells and/or cancer-associated fibroblasts all contribute to the tumor bulk. The interaction between these multiple players, under different microenvironmental conditions of biochemical and physical stimuli (i.e. oxygen tension, pH, matrix mechanics), regulates the production and biological activity of several soluble factors, extracellular matrix components, and extracellular vesicles that are needed for growth, maintenance, chemoresistance and metastatization of cancer. In osteosarcoma, a very aggressive cancer of young adults characterized by the extensive need for more effective therapies, this aspect has been only recently explored. In this view, we will discuss the role of stroma, with a particular focus on the mesenchymal stroma, contributing to osteosarcoma progression through inherent features for homing, neovascularization, paracrine cross-feeding, microvesicle secretion, and immune modulation, and also by responding to the changes of the microenvironment that are induced by tumor cells. The most recent advances in the molecular cues triggered by cytokines, soluble factors, and metabolites that are partially beginning to unravel the axis between stromal elements of mesenchymal origin and osteosarcoma cells, will be reviewed providing insights likely to be used for novel therapeutic approaches against sarcomas.