Fibroblast activation protein in osteosarcoma cells promotes angiogenesis via AKT and ERK signaling pathways

Although it is established as a marker of cancer-associated fibroblasts, the expression of fibroblast activation protein (FAP) is not restricted to stromal cells; its expression in multiple types of tumor cell and its pro-tumor functions have been reported. However, the role of FAP in angiogenesis in osteosarcoma remains uncharacterized. In the present study, it was identified that the mRNA and protein expression levels of FAP and vascular endothelial growth factor-A (VEGF-A) corresponded to each other in MG63, U2-OS and HOS osteosarcoma cells. Subsequent to upregulating FAP in MG63 cells, VEGF-A mRNA and protein expression significantly increased; subsequent to downregulating FAP in U2-OS cells, VEGF-A mRNA and protein expression significantly declined. These changes in VEGF-A level were also detected in the cell supernatant with ELISA. Conditioned medium (CM) from MG63 cells overexpressing FAP promoted the phosphorylation of AKT and extracellular signal-regulated kinase (ERK) in human umbilical vein endothelial cells (HUVECs), as well as the proliferation rate. The CM from U2-OS cells with FAP knockdown inhibited the proliferation rate of HUVECs. The phosphorylation of AKT and ERK was increased in MG63 cells overexpressing FAP, but reduced in U2-OS cells with FAP knockdown. Furthermore, treatment with the AKT inhibitor LY294002 or the ERK inhibitor U0126 inhibited the upregulation of VEGF-A induced by FAP expression. Collectively, the results suggest that FAP expression in osteosarcoma cells promotes angiogenesis.