Neuroendocrine Differentiation in Hormone Refractory Prostate Cancer Following Androgen Deprivation Therapy

Hirano, Daisaku; Okada, Yasuhiro; Minei, Sadatsugu; Takimoto, Yukie; Nemoto, Norimichi

doi:10.1016/j.eururo.2003.11.032

Cited by 270 publications

(197 citation statements)

References 27 publications

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“…Ito et al (2001) reported that in archival specimens from 137 PCa patients, 70.5% of 68 patients who had received hormonal therapy for more than 13 months exhibited NE differentiation, higher than 44% of 25 patients with hormonal therapy less than 12 months and 31.8% in 44 patients without therapy. A similar result was also shown in Hirano et al (2004) study, which supports the notion that androgen ablation therapy increases NE differentiation of PCa cells.…”

Section: Multipathways Involved In Ne Transdifferentiation Of Pca Celsupporting

confidence: 91%

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

Yuan¹,

Veeramani²,

Lin³

2007

Endocr Relat Cancer

213

184

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Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as 'NE-like PCa cells'. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.

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Section: Multipathways Involved In Ne Transdifferentiation Of Pca Celsupporting

confidence: 91%

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

Yuan¹,

Veeramani²,

Lin³

2007

Endocr Relat Cancer

213

184

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“…Long-term androgen ablation therapy tends to select prostate tumor cell populations that are enriched in NE cells. 5,28 Tumors with increased NE cells are often more aggressive and correlate with poor prognosis. 3,4,29 It has been hypothesized that NE cells can lead to the development and growth of androgen-refractory prostate tumors through the secretion of neuropeptides that induce the proliferation of adjacent carcinoma cells in an androgendepleted condition.…”

Section: Discussionmentioning

confidence: 99%

“…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-refractory prostate tumors through the secretion of neuropeptides that induce the proliferation of adjacent carcinoma cells in an androgendepleted environment. 7 The importance of immuno-histological detection of NED in prostatic adenocarcinoma with respect to disease at presentation and Gleason grade is gaining acceptance, and a correlation of immunohistochemically detected markers of neuroendocrine differentiation with clinical predictors of disease progression in prostate cancer has been reported.…”

mentioning

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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“…The role of NE cells in normal or in pathologic prostate is not fully understood and their participation in PCa progression is a matter of debate. Although some authors associate the presence of an increased number of NE cells with tumor progression and consequently with a poor prognosis, 44 other suggest a more complex role for NE cells and PCa. 45 Pure NE prostate tumors are very rare (<0.1%) and highly aggressive but tumors with focal NE differentiation are more common.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

Quiros

Sáinz

Hevia

et al. 2009

Intl Journal of Cancer

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Despite improvements in diagnosis of advanced prostate cancer (PCa), treatment is not efficient and 5-year survival is still low. Initially, the less abundant of cell types, neuroendocrine cells (NE), are involved in regulatory process but their physiological role is not fully understood. Among others, an increase in NE cells along with tumor progression has been commonly reported but their role in tumorigenesis or the molecular mechanisms of transdifferentiation is still a matter of debate. We have used human PCa cells (LNCaP) induced to differentiate to NE cells with several stimuli: androgen withdrawal, cyclic AMP or treatment with the antioxidant pineal hormone melatonin. PCa patients' specimens were also analyzed by western blotting and by immunocytochemistry. NE-like LNCaP cells express high levels of mitochondrial superoxide dismutase (MnSOD/SOD2) in addition to NE markers. MnSOD upregulation is mediated by NFjB transcription factor, mainly through p65 translocation into the nuclei. More importantly, overexpression of MnSOD induces the rise of NE-markers in LNCaP cells, showing that MnSOD upregulation might be instrumental for NE differentiation in PCa cells. Furthermore, MnSOD is highly expressed in advanced tumors of patients' when compared with control, nonpathological samples or with low-grade tumors, along with the presence of synaptophysin, a common NE marker. Also, fluorescence immunohistochemical analysis revealed that MnSOD colocalizes with NE markers in most of NE cells observed in PCa specimens. The present findings indicate that MnSOD is essential for NE transdifferentiation and mediates in part the differentiation process, which appears also to be critical in vivo. ' 2009 UICC

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Neuroendocrine Differentiation in Hormone Refractory Prostate Cancer Following Androgen Deprivation Therapy

Cited by 270 publications

References 27 publications

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

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

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

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