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      Molecular and cellular mechanisms of castration resistant prostate cancer

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          Abstract

          With increases in the mortality rate and number of patients with prostate cancer (PCa), PCa, particularly the advanced and metastatic disease, has been the focus of a number of studies globally. Over the past seven decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed a poor prognosis stage of castration resistant prostate cancer (CRPC), which eventually led to mortality. Due to CRPC being incurable, laboratory investigations and clinical studies focusing on CRPC have been conducted worldwide. Clarification of the molecular pathways that may lead to CRPC is important for discovering novel therapeutic strategies to delay or reverse the progression of disease. A sustained androgen receptor (AR) signal is still regarded as the main cause of CRPC. Increasing number of studies have proposed different potential mechanisms that cause CRPC, and this has led to the development of novel agents targeting the AR-dependent pathway or AR-independent signaling. In the present review, the major underlying mechanisms causing CRPC, including several major categories of AR-dependent mechanisms, AR bypass signaling, AR-independent mechanisms and other important hypotheses (including the functions of autophagy, PCa stem cell and microRNAs in CRPC progression), are summarized with retrospective pre-clinical or clinical trials to guide future research and therapy.

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          Most cited references104

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          Molecular determinants of resistance to antiandrogen therapy.

          Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.
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            Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.

            Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
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              The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis.

              The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                May 2018
                27 February 2018
                27 February 2018
                : 15
                : 5
                : 6063-6076
                Affiliations
                Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
                Author notes
                Correspondence to: Dr Xianhan Jiang, Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Guangzhou, Guangdong 510700, P.R. China, E-mail: jiangxianhan@ 123456gzhmu.edu.cn
                Article
                OL-0-0-8123
                10.3892/ol.2018.8123
                5876469
                29616091
                59fea715-5e2f-46a5-bb1d-65d6d4f92b6c
                Copyright: © Huang et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 01 April 2017
                : 26 January 2018
                Categories
                Review

                Oncology & Radiotherapy
                castration resistant prostate cancer,mechanism,androgen receptor splice variants,prostate stem cells,autophagy,micrornas

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