Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients

作者：Keck B; Wach S; Taubert H; Zeiler S; Ott O J; Kunath F; Hartmann A; Bertz S; Weiss C; Hoenscheid P; Schellenburg S; Roedel C; Baretton G B; Sauer R; Fietkau R; Wullich B; Krause F S; Datta K; Muders M H^*

来源：International Journal of Cancer, 2015, 136(2): 443-451.

DOI：10.1002/ijc.28987

• bladder cancer
• Neuropilin-2
• radiochemotherapy
• TURBT
• VEGF-C

The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder-sparing therapy can be performed by transurethral resection (TURBT) and radio-chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin-2 (NRP2)/VEGF-C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF-C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n=198) or RT (n=49) and a follow-up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 - 7.86; p=0.004) and was associated with a 3.85-fold increased risk of an early cancer specific death (95% CI: 0.91 - 16.24; p=0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p=0.037). Patients with high VEGF-C expression have a 2.29-fold increased risk of shorter CSS (95% CI: 1.03-5.35; p=0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF-C expression (p=0.041). Additionally, NRP2 and VEGF-C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57-36.23; p=0.012). Stratification for muscle invasiveness (T1 vs. T2-T4) confirmed the prognostic role of NRP2 and NRP2/VEGF-C co-expression in patients with T2-T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF-C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.
What's new? Neuropilin-2 (NRP2) and VEGF-C may play an important role in resistance to treatment. They can induce anti-apoptotic and autophagic signaling pathways, which protects cancer cells from chemotherapeutic stress in vitro. Therefore, these proteins might be useful as biomarkers for predicting a patient's response to therapy. In this study of bladder cancer patients, the authors demonstrate that NRP2 and VEGF-C expression are indeed prognostic markers. This may allow more patients to be treated with bladder-sparing surgery rather than radical cystectomy, and may also be applicable to other types of cancer.

• 出版日期2015-1-15