CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells.

Li-Hong Wang,Chia-Han Chan,Shih-Wei Wang,Shih-Chia Liu,Chih-Hsin Tang,Guan-Ting Liu,Jih-Jung Chen,Yen-Ling Chen,Chih-Yang Lin,Shiou-Sheng Chen,Chi-Kuan Chen,Guo-Hong Xu,Ting-Yi Lin

doi:10.18632/oncotarget.9213

Abstract

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumor lymphangiogenesis and lymphatic metastasis. Chemokine CCL5 has been reported to facilitate angiogenesis and metastasis in chondrosarcoma. However, the effect of chemokine CCL5 on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has largely remained a mystery. In this study, we showed a clinical correlation between CCL5 and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that CCL5 promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium (CM) from CCL5-overexpressed cells significantly induced tube formation of human lymphatic endothelial cells (LECs). Mechanistic investigations showed that CCL5 activated VEGF-C-dependent lymphangiogenesis by down-regulating miR-507. Moreover, inhibiting CCL5 dramatically reduced VEGF-C and lymphangiogenesis in the chondrosarcoma xenograft animal model. Collectively, we document for the first time that CCL5 induces tumor lymphangiogenesis by the induction of VEGF-C in human cancer cells. Our present study reveals miR-507/VEGF-C signaling as a novel mechanism in CCL5-mediated tumor lymphangiogenesis. Targeting both CCL5 and VEGF-C pathways might serve as the potential therapeutic strategy to block cancer progression and metastasis in chondrosarcoma.

Highlights

Human chondrosarcoma is the second most common sarcoma arising in bone malignancy which occurs in adults over 40 years of age [1]
These results suggest that chemokine CCL5 and its receptors are strongly associated with Vascular endothelial growth factor-C (VEGF-C) expression and tumor progression of human chondrosarcoma
Lymphngiogenesis is an indispensable step for cancer metastasis, facilitating cancer development by the generation of new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes and beyond [4]

Summary

Introduction

Human chondrosarcoma is the second most common sarcoma arising in bone malignancy which occurs in adults over 40 years of age [1]. The metastatic spread of tumor cells to sentinel lymph nodes represents the first step of tumor dissemination in most human cancers [4]. Lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones, is crucial for the development of tumor metastasis [5]. Tumors can actively promote the formation of lymphatic vessels through secretion of lymphangiogenic factors, and that tumor lymphangiogenesis has been implicated in the correlation with lymph node metastasis in many types of human cancer [6]. Vascular endothelial growth factor-C (VEGF-C) is the best-characterized lymphangiogenic factor, acting predominantly via VEGF receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells (LECs). Recent studies have revealed that VEGF-C production by tumor cells is recognized as the chief promoter of tumor-associated lymphangiogenesis and lymphatic metastasis [5]. The identification of mechanisms underlying VEGF-Cmediated lymphangiogenesis is essential for developing novel prognostic and therapeutic strategies in the treatment of cancer [13, 14]

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