title: ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer.
abstract: Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of nerve growth factor (proNGF) is overexpressed in prostate cancer and involved in the ability of prostate cancer cells to induce axonogenesis. A series of 120 prostate cancer and benign prostate hyperplasia (BPH) samples were analyzed by IHC for proNGF. ProNGF was mainly localized in the cytoplasm of epithelial cells, with marked expression in cancer compared with BPH. Importantly, the proNGF level positively correlated with the Gleason score (n = 104, τB = 0.51). A higher level of proNGF was observed in tumors with a Gleason score of ≥8 compared with a Gleason score of 7 and 6 (P < 0.001). In vitro, proNGF was detected in LNCaP, DU145, and PC-3 prostate cancer cells and BPH-1 cells but not in RWPE-1 immortalized nontumorigenic prostate epithelial cells or primary normal prostate epithelial cells. Co-culture of PC12 neuronal-like cells or 50B11 neurons with PC-3 cells resulted in neurite outgrowth in neuronal cells that was inhibited by blocking antibodies against proNGF, indicating that prostate cancer cells can induce axonogenesis via secretion of proNGF. These data reveal that ProNGF is a biomarker associated with high-risk prostate cancers and a potential driver of infiltration by nerves.
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Jay
authors.initials: J
authors.lastname: Pundavela
authors.affiliation: INSERM U908, University Lille 1, Villeneuve d'Ascq, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Demont
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Jobling
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Haematology Research Group, Calvary Mater Hospital, Waratah, New South Wales, Australia.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Lincz
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Severine
authors.initials: S
authors.lastname: Roselli
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Rick F
authors.initials: RF
authors.lastname: Thorne
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Bond
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Bradshaw
authors.affiliation: Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Marjorie M
authors.initials: MM
authors.lastname: Walker
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia. Electronic address: hubert.hondermarck@newcastle.edu.au.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hondermarck
mesh_terms: D001369:Axons / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D060787:Neoplasm Grading; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011467:Prostate / Q000294:innervation*; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D020932:Nerve Growth Factor