CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment

血管生成 CCL5 癌症研究 骨肉瘤 血管内皮生长因子 肿瘤微环境 血管内皮生长因子A 趋化因子 转移 生物 化学 医学 免疫学 癌症 内科学 炎症 血管内皮生长因子受体 T细胞 免疫系统 白细胞介素2受体 肿瘤细胞
作者
Shih‐Wei Wang,Shih‐Chia Liu,Hui‐Lung Sun,Te‐Yang Huang,Chia-Han Chan,Chen‐Yu Yang,Hung‐I Yeh,Yuan‐Li Huang,Wen‐Yi Chou,Yu‐Min Lin,Chih-Hsin Tang
出处
期刊:Carcinogenesis [Oxford University Press]
卷期号:36 (1): 104-114 被引量:142
标识
DOI:10.1093/carcin/bgu218
摘要

Chemokines modulate angiogenesis and metastasis that dictate cancer development in tumor microenvironment. Osteosarcoma is the most frequent bone tumor and is characterized by a high metastatic potential. Chemokine CCL5 (previously called RANTES) has been reported to facilitate tumor progression and metastasis. However, the crosstalk between chemokine CCL5 and vascular endothelial growth factor (VEGF) as well as tumor angiogenesis in human osteosarcoma microenvironment has not been well explored. In this study, we found that CCL5 increased VEGF expression and production in human osteosarcoma cells. The conditioned medium (CM) from CCL5-treated osteosarcoma cells significantly induced tube formation and migration of human endothelial progenitor cells. Pretreatment of cells with CCR5 antibody or transfection with CCR5 specific siRNA blocked CCL5-induced VEGF expression and angiogenesis. CCL5/CCR5 axis demonstrably activated protein kinase Cδ (PKCδ), c-Src and hypoxia-inducible factor-1 alpha (HIF-1α) signaling cascades to induce VEGF-dependent angiogenesis. Furthermore, knockdown of CCL5 suppressed VEGF expression and attenuated osteosarcoma CM-induced angiogenesis in vitro and in vivo. CCL5 knockdown dramatically abolished tumor growth and angiogenesis in the osteosarcoma xenograft animal model. Importantly, we demonstrated that the expression of CCL5 and VEGF were correlated with tumor stage according the immunohistochemistry analysis of human osteosarcoma tissues. Taken together, our findings provide evidence that CCL5/CCR5 axis promotes VEGF-dependent tumor angiogenesis in human osteosarcoma microenvironment through PKCδ/c-Src/HIF-1α signaling pathway. CCL5 may represent a potential therapeutic target against human osteosarcoma.
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