Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis
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Qing Bo Huang1,*, Xin Ma1,*, Hong Zhao Li1, Qing Ai1, Shang Wen Liu2, Yu Zhang1, Yu Gao1, Yang Fan1, Dong Ni3, Bao Jun Wang1 and Xu Zhang1
1 Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
2 Department of Urology, Chinese PLA 303 Hospital, Nanning, China.
3 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Xu Zhang, email:
Keywords: Kidney neoplasms, Neoplasm metastasis, Cell communication, Signal transduction, Angiogenesis
Received: January 2, 2014 Accepted: March 14, 2014 Published: March 14, 2014
The Notch ligand Delta-like 4 (DLL4) plays an important role in tumor angiogenesis, which is required for tumor invasion and metastasis. Here we showed that DLL4 was elevated in endothelium and Notch signaling was activated in renal cell carcinoma (RCC). Exogenous DLL4 induced RCC cell migration and invasion by activating intercellular Notch signaling. Importantly, the DLL4/Notch/Hey1/MMP9 cascades connecting the endothelium to the cancer cells in metastasis were identified. Knockdown of Hey1 decreased expression of MMP9 and attenuated tumor invasion. The clinical investigation on 120 cases of RCC specimens indicated that expressions of Hey1 and MMP9 correlated with DLL4 density. Moreover, univariate and multivariate analyses showed that tumor hematogenous metastasis not only was depended on microvessel density but was also associated with tumor size and DLL4 density. During 4-year surveillance, high-level of DLL4 density was associated with a higher probability of developing metastasis and being sensitive to target therapies. Our data suggest that RCC progression is caused in part by activated DLL4/Notch signaling, interaction of endothelium and cells, which can be therapeutically targeted.
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