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

Abstract

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.

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

“…It has been verified that lymphangiogenesis, which is correlated with LN metastasis and metastasis-free survival in bladder cancer, is a necessary step for LN metastasis of human cancer (9)(10)(11). Accumulating evidence has shown that upregulated VEGF-C, a lymphangiogenic growth factor, positively correlates with regional LN metastasis and poor survival in multiple human malignancies, including bladder cancer (9,(11)(12)(13)(14)(15). Several groups have reported that when VEGF-C signaling is blocked via either small interfering RNAs or a neutralizing antibody to VEGF-C or VEGF-R3, the lymphatic-based metastatic spread of human malignancies can be inhibited (9,(16)(17)(18).…”

Concurrent Expression of VEGF-C and Neuropilin-2 Is Correlated with Poor Prognosis in Glioblastoma

“…Previous studies proved that VEGF-C could promote the lymphangiogenesis via NRP2 in colorectal carcinoma and oral squamous cell carcinomas et al (Ou et al 2015;Zhang et al 2015), and that VEGF-C/NRP2 axis could regulate several biological processes like autophagy besides lymphangiogenesis (Stanton et al 2013). Moreover, current evidence had revealed the oncogenic role of VEGF-C/NRP2 axis in malignancy such as bladder cancer (Keck et al 2015). Our finding showed that only concurrent high expression of VEGF-C and NRP2 could influence the prognosis of glioblastoma, which suggested the hypothesis that VEGF-C may stimulate NRP2 and downstream signaling pathway in a paracrine or autocrine pathway in glioblastoma, which is not a rare stimulating mechanism in glioma.…”

“…Moreover, autocrine VEGF-VEGFR2-NRP1 signaling was demonstrated to promote glioma stemlike cell viability and tumor growth. However, the exploration of NRP2 effect on glioblastoma is almost vacant compared to the study of NRP1 in glioma, though there were sporadic reports about ectopic expression of NRP2 in other malignancies, including gastric cancer, oral squamous cell carcinomas and bladder cancer (Kim et al 2009;Keck et al 2015;Zhang et al 2015). To the best of our knowledge, we verified the clinical significance of NRP2 in glioblastoma and demonstrated that concurrent high expression of VEGF-C and NRP2 led to poorer prognosis of glioblastoma for the first time.…”

“…However, the underlying mechanisms of the correlation between NRP2 expression and sex hormone level is still misty. Although the prognostic value of VEGF-C/NRP signaling pathway was demonstrated or hinted in several previous studies (Keck et al 2015;Kim et al 2015;Perez et al 2015;Zhang et al 2015), the effects of existing VEGF/VEGFR inhibitors such as bevacizumab or sorafenib on glioblastoma treatment are still in clinical trial. We hope our new findings could help identify NRP as a potential drug and help improve the survival time for patients with glioblastoma.…”

How Octogenarians with Bladder Cancer Are Treated in a Maximum-Care Hospital: The Real-Life Experience

“…It also has to be considered that even bladdersparing approaches are associated with side effects, such as a risk of local recurrence, shrinkage of the bladder and other radiation-associated side effects [37] . To achieve better patient selection for bladder-sparing multimodality therapy, especially in the potentially more vulnerable population of octogenarians, the clinical implementation of promising molecular predictive biomarkers such as ERCC1, VEGF-C and neuropilin-2 needs to be further validated [38][39][40] .…”