CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis

CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level...

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Veröffentlicht in:Blood 2012-09, Vol.120 (11), p.2330-2339
Hauptverfasser: Jiang, Tianxia, Zhuang, Jie, Duan, Hongxia, Luo, Yongting, Zeng, Qiqun, Fan, Kelong, Yan, Huiwen, Lu, Di, Ye, Zhongde, Hao, Junfeng, Feng, Jing, Yang, Dongling, Yan, Xiyun
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Sprache:eng
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Zusammenfassung:CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level and identify the structural basis of CD146 binding to VEGFR-2. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation, and thus promotion of endothelial cell migration and microvascular formation. Furthermore, we show that anti-CD146 AA98 or CD146 siRNA abrogates all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146EC-KO). Our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (bevacizumab) have an additive inhibitory effect on xenografted human pancreatic and melanoma tumors. The results of the present study suggest that CD146 is a new coreceptor for VEGFR-2 and is therefore a promising target for blocking tumor-related angiogenesis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-01-406108