Extracellular Collagen Mediates Osteosarcoma Progression Through an Integrin α2β1/JAK/STAT3 Signaling Pathway

BACKGROUND: Osteosarcoma development is a complex set which is determined by various factors. Many patients suffered from sustained osteosarcoma growth and revealed poor response to clinical interventions. However, the underlying mechanisms of osteosarcoma development still remain unclear. METHODS: In our study, we isolated osteosarcoma tissues from clinical patients, which were divided into high degree group (stage G1~G2) and low degree group (stage G0). The expression of type I collagen, integrin and STAT3 in tumor tissues were analyzed by immunohistochemistry or immunofluorescence. The collagen-induced cells proliferation was detected by CCK8 and colony formation analysis. The activation of JAK/STAT3 signal was examined by Western blotting and immunofluorescence. The anticancer effects of integrin α2β1 peptide were analyzed by Sao-2-bearing mice model. RESULTS: Our results implicated that type I collagen could facilitate malignant osteosarcoma development in patients. In vitro, 2D collagen culture also efficiently mediated the stemness up-regulation of osteosarcoma cells, resulting in the strengthened capability of cells proliferation and tumorigenesis. In mechanism, we found that type I collagen could facilitate the activation of JAK/STAT3 signals through integrin α2β1, which elicited tumor-sustained growth and cancer relapse. In tumor-bearing mice model, integrin α2β1 signals inhibitor significantly suppressed the osteosarcoma cells proliferation and their tumorigenic ability, which improved the outcome of chemotherapy/radiotherapy. CONCLUSION: Our study demonstrated that type I collagen could mediate osteosarcoma development through an integrin α2β1/JAK/STAT3 signaling pathway. Blockade of integrin α2β1 by α2β1 inhibitor efficiently improved outcome of chemotherapy/radiotherapy, which provided new insights for eradicating tumors in clinic.