Investigation of the role of CXCR7 on tumor angiogenesis and its mechanisms

• Main Authors: Yu-Chia Lien, 連妤嘉
• Other Authors: 謝佳宏
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/49hy95

碩士 === 中國醫藥大學 === 臨床醫學研究所碩士班 === 102 === The expression of chemokine receptor CXCR7 (RDC1) correlates with the malignant phenotype of various cancers. High expression levels of CXCR7 are present in tumor vasculature, but the role of CXCR7 in tumor angiogenesis is poorly understood. Therefore, we examined the role of CXCR7 on endothelial cell-mediated tumor angiogenesis and its potential molecular mechanisms. Here, we present evidence that tumor-secreted vascular endothelial growth factor (VEGF) activates CXCR7 expression in human umbilical vein endothelial cells (HUVECs) through PI3K/AKT signaling pathway. Modification of CXCR7 function in HUVECs via genetic and pharmacologic approaches confirms that CXCR7 induces cell endothelial cell proliferation, migration and tube formation via activation of β-catenin. Moreover, tumor-associated endothelial cells isolated from human breast cancer xenografts have high levels of CXCR7 expression and β-catenin activation compared to mouse normal skin endothelial cells. β-catenin activation also co-localized with high expression of CXCR7 in human breast cancer specimens, suggesting that CXCR7 expression leads to the activation of β-catenin in vivo. Finally, using CCX771, a small molecule with high affinity and selectivity for CXCR7, inhibited tumor angiogenesis and growth in breast cancer xenografts lacking CXCR7 in vivo, indicating the angiogenic role of CXCR7 in tumor vasculature. Collectively, these data provide new insight into CXCR7-mediated tumor angiogenesis. CXCR7 and its ligands interaction on endothelial cells induce β-catenin activation and this mechanism promotes tumor angiogenesis. Targeting CXCR7 function in tumor vasculature may be effective therapeutic strategy for tumor angiogenesis and growth.