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

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...

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Bibliographic Details
Published in:International journal of cancer 2015-01, Vol.136 (2), p.443-451
Main Authors: Keck, B., Wach, S., Taubert, H., Zeiler, S., Ott, O.J., Kunath, F., Hartmann, A., Bertz, S., Weiss, C., Hönscheid, P., Schellenburg, S., Rödel, C., Baretton, G.B., Sauer, R., Fietkau, R., Wullich, B., Krause, F.S., Datta, K., Muders, M.H.
Format: Article
Language:English
Subjects:
Biomarkers, Tumor - metabolism
Bladder cancer
Cancer
Cancer therapies
Carcinoma in Situ - metabolism
Carcinoma in Situ - mortality
Carcinoma in Situ - pathology
Carcinoma in Situ - therapy
Chemoradiotherapy
Combined Modality Therapy
Female
Follow-Up Studies
Genes
Humans
Immunoenzyme Techniques
Male
Medical research
Middle Aged
Neoplasm Grading
Neoplasm Staging
Neuropilin-2 - metabolism
Neuropilin‐2
Organ Sparing Treatments
Postoperative Complications
Prognosis
radiochemotherapy
Retrospective Studies
Survival Rate
TURBT
Urinary Bladder Neoplasms - metabolism
Urinary Bladder Neoplasms - mortality
Urinary Bladder Neoplasms - pathology
Urinary Bladder Neoplasms - therapy
Vascular Endothelial Growth Factor C - metabolism
VEGF‐C
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Summary: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.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.28987