Endothelial progenitor cells promote osteosarcoma progression and invasiveness via AKT/PI3K signaling

Osteosarcoma (OS) mortality is attributed to lung metastases occurring in 20% of OS patients. The treatment of choice remains chemotherapy and surgery. Endothelial progenitor cells (EPCs) mediate the angiogenic switch in several cancers. EPCs reside in the bone marrow, where OS develops. Therefore, we herein hypothesized that EPCs-OS interactions may possibly promote OS progression and aggressiveness due to their spatial proximity. EPCs conditioned-medium (EPC-CM) enhanced OS MMP9 expression, invasiveness and migration via the PI3K/AKT pathway. EPC-CM proteomics analysis revealed an angiogenic profile. Addition of bevacizumab and an anti-FGF2 antibody to the EPC-CM, diminished OS cell migration. The autocrine role of VEGF-A was assessed using bevacizumab and VEGF-A silencing in OS cells, resulting in decreased AKT phosphorylation, and consequently diminished invasiveness and migration. Consistently, OS tumors in mice displayed high VEGF-A and FGF2 levels. Moreover, human lung metastasis specimens exhibited marked immunostaining of the endothelial cell marker CD31 as well as VEGF-A and FGF2. Collectively, our findings reveal that EPCs promote OS progression not only by physically incorporating into blood vessels, but also via paracrine secretion of cytokines that induce MMP9 overexpression, enhanced invasion and migration. These findings may propel the rational development of novel therapies targeting OS metastasis.