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

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    Author
    Tse, BWC; Volpert, M; Ratther, E; Stylianou, N; Nouri, M; McGowan, K; Lehman, ML; McPherson, SJ; Roshan-Moniri, M; Butler, MS; ...
    Date
    2017-06-15
    Source Title
    Oncogene
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Williams, Elizabeth
    Affiliation
    Surgery (St Vincent's)
    Metadata
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    Document Type
    Journal Article
    Citations
    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. ,... Hollier, B. G. (2017). Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. ONCOGENE, 36 (24), pp.3417-3427. https://doi.org/10.1038/onc.2016.482.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258021
    DOI
    10.1038/onc.2016.482
    Abstract
    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.

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