Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis.

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.

Down-Regulated miR-30a in Clear Cell Renal Cell Carcinoma Correlated with Tumor Hematogenous Metastasis by Targeting Angiogenesis-Specific DLL4.

BACKGROUND: Endothelial DLL4 plays an important role in controlling of tumor angiogenesis, which is required for tumor invasive growth and metastasis. However, the regulation of DLL4 in clear cell renal cell carcinoma (ccRCC) has not yet been systematically elucidated. METHODOLOGY: We performed bioinformatical analysis to explore miRNAs targeting DLL4. miR-30a was selected as a representative to validate its functional association in endothelial cell. Then, the expressions of DLL4 and mature miR-30a from 90 cases of ccRCC and 28 cases of nonmatched adjacent non-tumor tissues were measured by quantitative real-time PCR. Finally, the expression of miR-30a was correlated with DLL4 expression, tumor features (metastatic condition and microvessel density), and patient metastasis-free survival. The univariate and multivariate analyses were performed to select the risk factors associated with hematogenous metastasis, respectively. PRINCIPAL FINDINGS: miR-30a negatively regulated DLL4 and inhibited the proliferation and migration of endothelial cells. DLL4 was up-regulated in ccRCC and further increased in hematogenous metastatic cases, while miR-30a was down-regulated in tumor tissues and further decreased in hematogenous metastatic ccRCC (student t test, all p<0.05). Additionally, expression of miR-30a was inversely correlated with expression of DLL4 and microvessel density (linear correlation analysis, both p<0.05). Low-level miR-30a also indicated a higher probability of developing metastasis (log-rank test, p = 0.010). Most importantly, miR-30a expression was an independent predictor of ccRCC hematogenous metastasis by the univariate analysis and binary logistic regression model (both p<0.05). CONCLUSIONS: Down-regulated miR-30a in ccRCC was associated with tumor hematogenous metastasis through increasing microvessel density by targeting angiogenesis-specific DLL4.

[Treatment of calculous pyonephrosis with percutaneous nephrolithotomy via the standard access].

OBJECTIVE: To investigate the feasibility of treatment for calculous pyonephrosis with first stage percutaneous nephrolithotomy under the standard access. METHODS: Thirty-six cases of calculous pyonephrosis and 36 cases of urolithiasis with no pyonephrosis were treated by percutaneous nephrolithotomy. In the nephrostomy, the caliber was dilated to F24. All the operations were preformed through the EMS lithotrity system. The intrapelvic pressure was detected in the operation. The hemoculture before and after operation, the germi culture of urine, and the temperature and blood leucocyte changes after operation were recorded. All the patients were treated by antibiotics before and after the operation. RESULTS: All the patients were treated successfully. The average intrapelvic pressure were 23.2 cmH(2)O in non-pyonephrosis group and 22.8 cmH(2)O in pyonephrosis group. Both of the groups had 1 case of transient bacteremia after the operation. No significant difference was found in the other indices between the two groups. CONCLUSION: EMS lithotrity system is safe and feasible for treating calculous pyonephrosis with stage I percutaneous nephrolithotomy via the standard access.