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Lookup NU author(s): Professor Ian HicksonORCiD
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Introduction: In the majority of castration resistant prostate cancers (CRPC), the AR is still active despite low serum testosterone levels. Among other mechanisms of AR-activation, intratumoral androgen synthesis, either via conversion of adrenal androgens or de novo synthesis from cholesterol, is a mechanism of castration resistance. In a previous study, we found that clinical CRPC samples only expressed markers for conversion of adrenal androgens and not for de novo synthesis.In this study, we compared growth stimulation of hormone-naïve prostate cancer (PC) and CRPC cell lines by adrenal androgens (conversion) or androgen precursors (de novo synthesis) and subsequently tested a novel co-culture model to mimic adrenal stimulation of (CR)PC.Materials and methods: VCaP and DuCaP CRPC lines were generated by long-term culturing in steroid stripped medium (DCC) with or without the anti-androgens bicalutamide or flutamide.To test cell growth stimulation, VCaP and DuCaP cells and their CRPC sublines were cultured in the presence of androgen precursors (pregnenolone and progesterone) or adrenal androgens (DHEA and androstenedione) at levels found in men. Cells were treated with either vehicle, the CYP17A1-inhibitor Abiraterone (0.1 μM) or the anti-androgen MDV3100 (1 μM). Cell proliferation was assessed by MTT-assay on day 9 with each experiment performed in triplicate.In the co-culture model, VCaP cells were cultured with human adrenal (H295R) cells in separate compartments between which only medium could diffuse freely, and treated with vehicle, Abiraterone (1 μM) or DHT (0.1 nM).Results: In VCaP and DuCaP and their CRPC derivatives, androgen precursors pregnenolone and progesterone did not induce additional cell growth compared to cell growth in DCC. In contrast, physiological levels of adrenal androgens stimulated cell growth, comparable to optimal stimulus by DHT. Adrenal androgen concentrations found in serum of H295R-bearing mice induced a similar growth-response. Treatment with Abiraterone could not block adrenal androgen induced growth, while MDV3100 blocked steroid-induced growth in all conditions.Co-culturing of VCaP cells with H295R cells induced optimal cell growth, which could be inhibited by treatment with Abiraterone.Conclusion: In VCaP and DuCaP cells and the CRPC sublines, the substrate for conversion of adrenal androgens induced growth, while precursors of de novo androgen synthesis did not. These data support our observations that growth of (CR)PC seems to rely more on conversion than on de novo androgen synthesis.Co-culturing PC cells with human adrenal cells using a 2-compartment system is a relevant model to test CRPC stimulation in vitro. We are currently generating an in vivo model by inoculating PC and H295R cells simultaneously in nude mice more accurately reflect human CRPC.
Author(s): Moll JM, Teubel W, Hickson I, Graeser R, Jenster G, vanWeerden W
Publication type: Conference Proceedings (inc. Abstract)
Publication status: Published
Conference Name: Molecular Targets and Cancer Theraputics
Year of Conference: 2014
Pages: C133
Print publication date: 30/01/2014
Online publication date: 01/11/2013
Acceptance date: 01/11/2013
ISSN: 1538-8514
Publisher: AACR
URL: https://doi.org/10.1158/1535-7163.TARG-13-C133
DOI: 10.1158/1535-7163.TARG-13-C133
