title: Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model.
abstract: Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Matias
authors.initials: M
authors.lastname: Knuuttila
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland.
authors.forename: Emrah
authors.initials: E
authors.lastname: Yatkin
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kallio
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Saija
authors.initials: S
authors.lastname: Savolainen
authors.affiliation: Department of Mathematics and Statistics, University of Turku, Turku, Finland.
authors.forename: Teemu D
authors.initials: TD
authors.lastname: Laajala
authors.affiliation: Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Department of Oncology and Critical Care Research, Orion Pharma, Turku, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Oksala
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Häkkinen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Keski-Rahkonen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.affiliation: Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland. Electronic address: sarmak@utu.fi.
authors.forename: Sari
authors.initials: S
authors.lastname: Mäkelä
mesh_terms: D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002369:Castration; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen