Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality

• Published in: Oncogene Vol. 36; no. 24; pp. 3417 - 3427
• Main Authors: Tse, B W C, Volpert, M, Ratther, E, Stylianou, N, Nouri, M, McGowan, K, Lehman, M L, McPherson, S J, Roshan-Moniri, M, Butler, M S, Caradec, J, Gregory-Evans, C Y, McGovern, J, Das, R, Takhar, M, Erho, N, Alshalafa, M, Davicioni, E, Schaeffer, E M, Jenkins, R B, Ross, A E, Karnes, R J, Den, R B, Fazli, L, Gregory, P A, Gleave, M E, Williams, E D, Rennie, P S, Buttyan, R, Gunter, J H, Selth, L A, Russell, P J, Nelson, C C, Hollier, B G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.06.2017; Nature Publishing Group
• Subjects: 13/31; 38/39; 38/89; 38/91; 42/41; 631/67/1059; 631/67/1857; 631/67/322; 631/67/589/466; 631/80/84; 64/116; 82/51; 82/80; Androgen Antagonists - therapeutic use; Androgens; Angiogenesis; Apoptosis; Axon guidance; Biological markers; Cancer; Cancer surgery; Castration; Cell Biology; Cell culture; Cell Line, Tumor; Cell receptors; Development and progression; Disease Progression; DNA microarrays; Epithelial-Mesenchymal Transition; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Human Genetics; Humans; Internal Medicine; Invasiveness; Lymph; Lymph nodes; Male; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mortality; Multivariate analysis; Neoplasm Grading; Neoplasm Metastasis; Neurons; Neuropilin; Neuropilin-1 - genetics; Neuropilin-1 - metabolism; Oncology; Original; original-article; Patient outcomes; Prognosis; Prostate cancer; Prostatectomy; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - mortality; Prostatic Neoplasms, Castration-Resistant - mortality; Survival Analysis; Therapeutics; Tumor cells; Tumors; Up-Regulation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.482

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1 , we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo . In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.