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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.

Background In the widespread adoption of chemotherapy, drug resistance has been the major obstacle to tumor elimination in cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma-associated chemoresistance. Methods We performed a cytotoxicity analysis of methotrexate (MTX) and cisplatin (CIS) in TGF-β-treated osteosarcoma cells. Then, the metabolite profile of the core metabolic energy pathways in Saos-2 and MG-63 cell extracts was analyzed by 1H-NMR. We detected the expression of succinate dehydrogenase (SDH), STAT1, and hypoxia-inducible factor 1α (HIF1α) in TGF-β-treated osteosarcoma cells and further tested the effects of these molecules on the cytotoxicity induced by chemotherapeutic agents. Using in vivo experiments, we examined the tumor growth and survival time of Saos-2-bearing mice treated with a combination of chemotherapeutic agents and a HIF1α inhibitor. Results The metabolic analysis revealed enhanced succinate production in osteosarcoma cells after TGF-β treatment. We further found a decrease in SDH expression and an increase in HIF1α expression in TGF-β-treated osteosarcoma cells. Consistently, blockade of SDH efficiently enhanced the resistance of Saos-2 and MG-63 cells to MTX and CIS. Additionally, a HIF1α inhibitor significantly strengthened the anticancer efficacy of the chemotherapeutic drugs in mice with osteosarcoma cancer. Conclusion Our study demonstrated that TGF-β attenuated the expression of SDH by reducing the transcription factor STAT1. The reduction in SDH then caused the upregulation of HIF1α, thereby rerouting glucose metabolism and aggravating chemoresistance in osteosarcoma cells. Linking tumor cell metabolism to the formation of chemotherapy resistance, our study may guide the development of additional treatments for osteosarcoma.

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Reportedly, the elevated expression of survivin has been observed in several tumor types, strictly involved in tumor development. In the present study, we detected elevated survivin expression in tumor tissues derived from patients with chemoresistant osteosarcoma when compared with those from chemosensitive patients. Importantly, knockdown of survivin in osteosarcoma cells significantly suppressed cell proliferation and chemoresistance both in vitro and in vivo. Simultaneously, chemotherapy mediates the upregulation of survivin in osteosarcoma cells through a survivin‐based selective killing effect, resulting in the development of multidrug resistance. The utilization of tumor‐derived microparticles to coencapsulate the survivin inhibitor YM155 and chemotherapeutic agents could effectively reverse multidrug resistance, leading to improved anticancer effects, as well as reduced systemic toxicity. In summary, the expression of survivin contributes to resistance toward osteosarcoma drugs, whereas employing survivin inhibiting combination therapy, based on a microparticle codelivery system, could efficiently reverse resistance and avoid potential systemic toxicity.