From pathogenesis to prevention of castration resistant prostate cancer

Bonkhoff, Helmut; Berges, Richard

doi:10.1002/pros.21042

Cited by 67 publications

(59 citation statements)

References 63 publications

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“…Generally, it has been reported that the AR is expressed in nearly all types of cancers of the prostate, before and after androgen ablation therapy (11). The high levels of AR expression and the development of hypersensitive receptors have been recognized as a feature associated with the development of CRPC (13,16). Hobisch et al (17) showed that metastases from PCa expressed the AR following endocrine therapy.…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients

Komiya

Yasuda

Watanabe

et al. 2013

Molecular and Clinical Oncology

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Abstract. Prostate cancer (PCa) is a leading cause of mortality, and despite good response to androgen ablation this response is eventually lost. In the present study, androgen receptor (AR) expression and neuroendocrine differentiation (NED) were evaluated in hormone-sensitive (HSPC) and castration-resistant prostate cancers (CRPC). Prostate tissues were obtained from 20 HSPC patients at diagnosis and 28 CRPC patients at castration-resistant progression. AR, chromogranin A (CGA) and neuron-specific enolase (NSE) were evaluated by immunohistochemical staining (IHS) in representative positive cores for PCa. IHS intensity was graded as negative, 0; positive, 1+ and strongly positive, 2+. The proportion of the 1+ and 2+ areas in PCa cells was determined. PCa was considered to be in NED if ≥50% of the tumor cells were 1+ or 2+ for CGA or NSE. The observed IHS intensity (0/1+/2+) for AR, CGA and NSE was 0/4/16, 5/11/4 and 11/4/5 in HSPC patients and 9/3/16, 5/8/15

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Section: Discussionmentioning

confidence: 99%

The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients

Komiya

Yasuda

Watanabe

et al. 2013

Molecular and Clinical Oncology

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“…7 This notion is supported by the observation that the proliferation index of cancer cells surrounding NE cells is higher than that of distal cancer cells. 30,31 Pathogenetic factors responsible for the development of the androgen-resistant phenotype are detectable in PC tissues long before the clinical onset of the disease 32 but usually escape clinical detection and attention. Some authors have found that the acquisition of NE characteristics is fully reversible, 20 thus early detection and prevention of castration resistant PC may provide a new strategy to improve survival of patients diagnosed with PC at risk to fail standard androgen deprivation therapy.…”

Section: Discussionmentioning

confidence: 99%

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Ciarlo

Benelli

Barbieri

et al. 2011

Intl Journal of Cancer

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Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and b-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and b-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.PC is one of the most common malignancies among males in the western world and a major health problem in many industrialized countries. PC develops and progresses under the influence of androgenic steroids. This influence is consistent with the use of androgen depletion therapies to treat patients with advanced disease.1 However, most patients finally relapse with hormone-refractory prostate cancer and available treatment options are only palliative. Therefore, an understanding of what drives progression to androgen independence is critical. The prostate is known to be dependent not only on androgens but also on growth factors and neuropeptides secreted by NE cells that maintain normal prostate function and play a role in the development of pathological conditions.2 Adult prostate gland possesses basal (proliferating) cells, secretory (luminal) cells and the less abundant (<0.1%) NE cells. Approximately 10% of prostatic carcinoma reveals extensive and multifocal NE features and the presence of NE markers is usually associated with poor prognosis. 3,4 Interestingly, along with the androgen-independent status, an increase in the number of NE cells has been reported in some studies and long-term androgen ablation therapy tends to select prostate tumor populations that are enriched in NE cells.5 These cells lack nuclear androgen receptor 6 ; thus they represent an androgen-insensitive cell phenotype in the prostate and it has been hypothesized that NE cells can lead to the development and growth of androgen-refract...

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“…3; Taplin and Balk 2004;Attard et al 2009a;Bonkhoff and Berges 2010). Notably, castration-resistant tumors express AR as well as AR target genes such as PSA, indicating that pathway activity is intact (Gregory et al 1998).…”

Section: Retention Of Ar Signaling In Castration Resistancementioning

confidence: 99%

Molecular genetics of prostate cancer: new prospects for old challenges

Shen¹,

2010

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Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.

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From pathogenesis to prevention of castration resistant prostate cancer

Cited by 67 publications

References 63 publications

The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients

The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Molecular genetics of prostate cancer: new prospects for old challenges

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