title: Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.
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.
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: B W C
authors.initials: BWC
authors.lastname: Tse
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Volpert
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Ratther
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Stylianou
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Nouri
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: K
authors.initials: K
authors.lastname: McGowan
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Lehman
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: McPherson
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Roshan-Moniri
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M S
authors.initials: MS
authors.lastname: Butler
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Caradec
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: C Y
authors.initials: CY
authors.lastname: Gregory-Evans
authors.affiliation: Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: J
authors.initials: J
authors.lastname: McGovern
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and Freemason's Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Das
authors.affiliation: GenomeDX Biosciences, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Takhar
authors.affiliation: GenomeDX Biosciences, Vancouver, British Columbia, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Erho
authors.affiliation: GenomeDX Biosciences, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Alshalafa
authors.affiliation: GenomeDX Biosciences, Vancouver, British Columbia, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Urology, Northwestern University, Chicago, IL, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Schaeffer
authors.affiliation: Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: Gregory
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: E D
authors.initials: ED
authors.lastname: Williams
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: P S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Buttyan
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: J H
authors.initials: JH
authors.lastname: Gunter
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and Freemason's Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Selth
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Russell
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: C C
authors.initials: CC
authors.lastname: Nelson
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: B G
authors.initials: BG
authors.lastname: Hollier
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D064129:Prostatic Neoplasms, Castration-Resistant / Q000401:mortality*; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D000726:Androgen Antagonists; D039942:Neuropilin-1