Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. On the other hand, angiogenesis is a critical step in tumor growth and metastasis. However, the relationship of adiponectin with vascular endothelial growth factor-A (VEGF-A) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study we first demonstrated that the expression of adiponectin was correlated with tumor stage of human chondrosarcoma tissues. In addition, we also found that adiponectin increased VEGF-A expression in human chondrosarcoma cells and subsequently induced migration and tube formation in human endothelial progenitor cells (EPCs). Adiponectin promoted VEGF-A expression through adiponectin receptor (AdipoR), phosphoinositide 3 kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF)-1α signaling cascades. Knockdown of adiponectin decreased VEGF-A expression and also abolished chondrosarcoma conditional medium-mediated tube formation in EPCs in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. Therefore, adiponectin is crucial for tumor angiogenesis and growth, which may represent a novel target for anti-angiogenic therapy in human chondrosarcoma.

Hyalocytes may be involved in various vitreoretinal diseases by increasing HIF-1alpha protein stability and HIF-1alpha-DNA binding, and thus increasing VEGF production under pathological conditions. Dexamethasone seems to be capable of inhibiting hypoxic and TNF-alpha dependent VEGF production, presumably via its inhibitory effects on HIF-1alpha protein levels and its DNA-binding activity.

Vascular endothelial growth factor (VEGF) is an angiogenic mediator in tumors and has been implicated in the pathogenesis and progression of cancer. Adiponectin is a protein hormone secreted by adipose tissue. We recently found that adiponectin increased metastasis in human chondrosarcoma. However, the effect of adiponectin on VEGF expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here we found that adiponectin promoted VEGF expression in human chondrosarcoma and subsequently increased migration and tube formation in endothelial progenitor cells (EPCs). Pretreatment of cells for 30 min with PI3K inhibitors (LY294002 and wortmannine), Akt inhibitor, mTOR inhibitor (Rapamycin) or HIF-1α inhibitor abolished adiponectin-induced VEGF expression, EPC migration and tube formation. In addition, transfection of cells with PI3K, Akt, mTOR, or HIF-1α siRNA also reduced adiponectin-induced VEGF expression, EPC migration and tube formation. Knockdown adiponectin decreased VEGF expression in vitro as well as angiogenesis effects the chick chorioallantoic membrane and matrigel-plug nude mice model in vivo. In addition, using xenograft tumor angiogenesis model, knockdown adiponectin significantly reduced tumor growth and tumor angiogenesis. Finally, we analyzed from chondrosarcoma patients by immunohistochemical staining and found that the expression of adiponectin and VEGF was significantly higher in chondrosarcoma tissue than normal cartilage. Taken together this study showed that adiponectin mediates VEGF expression and angiogenesis of human chondrosarcoma cells. One of the mechanisms underlying adiponectin induced VEGF expression and angiogenesis was activation of PI3K, Akt, mTOR and HIF1-α pathways. Citation Format: Jhao-Sheng Shih, Chih-Hsin Tang. Adiponectin increases VEGF expression and promotes angiogenesis in human chondrosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 20. doi:10.1158/1538-7445.AM2014-20