Anoikis-resistant human osteosarcoma cells display significant angiogenesis by activating the Src kinase-mediated MAPK pathway

Tumor cells must resist anoikis to metastasize. There is a key role of angiogenesis in the growth and metastasis of tumors. However, the relationship between anoikis resistance and angiogenesis has not been well explored in human osteosarcoma. In the present study, we reported the higher expression of vascular endothelial growth factor-A (VEGF-A) in osteosarcoma cells that were resistant to anoikis than in parental osteosarcoma cells, promoting the proliferation, tube formation, and migration of human umbilical vein endothelial cells (HUVECs). Src, JNK (Jun amino-terminal kinase) and ERK (extracellular signal-regulated kinase) signaling pathway phosphorylation was activated in anoikis-resistant cells; Src inhibitor reduced the expression of VEGF-A and angiogenesis and inhibited JNK and ERK pathway activity. Overexpression of phosphorylated (p)-Src and VEGF-A was positively correlated to the metastatic potential in human osteosarcoma tissues, as quantified by immunohistochemistry. In addition, p-Src expression was directly correlated with VEGF-A expression and microvessel density in vivo. Our findings revealed that anoikis resistance in osteosarcoma cells increased the expression of VEGF-A and angiogenesis through the Src/JNK/ERK signaling pathways. Thus, Src may be a potential therapeutic alternative in osteosarcoma angiogenesis and metastasis.