Tumor-Elicited Secretion of IL6 and of IL8 from Reactive Mesenchymal Stroma is Enhanced Under the Acidic Microenvironment of Glycolytic Cancer Cells and Promotes Osteosarcoma Stemness

Osteosarcoma (OS) is an aggressive malignancy of childhood with a high relapse rate. Mesenchymal stromal cells (MSC) in OS microenvironment concur to tumor metabolic reprogramming¹. Recently, we have also reported that OS is highly glycolytic, thereby resulting into extracellular acidosis2 that, in turn, may favor the release of pro-tumorigenic paracrine factors. Here, we evaluated if OS-elicited activation of MSC impacts on the stem-like tumor fraction, both under neutral and acidic conditions. We maintained MSC at pH 6.8, or in co-culture with OS cells (Saos‐2 and HOS). By deep‐sequencing analysis, and ELISA, we found in stressed MSC the activation of NF-kB pathway, and the consequential secretion of cytokines (IL6 and IL8), and chemokines (CCL5, CXCL5, CXCL1), especially under acidosis. The secreatome from reactive MSC induced chemoattraction of other MSC, clone formation of OS cells, and, most importantly, an increased number of floating spheres and stem-related gene expression (Sox2, Nanog) in OS cells. Such enhanced stemness was associated with higher chemoresistance and a remarkable increase in migratory potential. In conclusion, we demonstrated that, once attracted at the tumor site, especially in acidic regions, reactive MSC enhance OS aggressiveness and progression through an auto-feeding process. Indeed, reactive MSC induce the expansion of tumor stem-like fraction, meanwhile attracting circulating MSC, eventually dramatically accelerating progression. Altogether, our data highlight the need of a comprehensive knowledge of the interplay between tumor and stroma for effective anticancer therapies in OS.

ACKNOWLEDGMENTS

Supported by AIRC (15608) and by Ministry of Health and Education (FIRB RBAP10447J) to NB.

REFERENCES

[1] Bonuccelli et al. Oncotarget 2014;5:7575-88

[2] Perut et al. Exp Cell Res 2014;320:21‐32