Up-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence

Ito, Takaaki; Yamamoto, Shinya; Ohno, Yoshio; Namiki, Kazunori; Aizawa, Taku; Akiyama, Akihito; Tachibana, Masaaki

doi:10.3892/or.8.6.1221

Cited by 31 publications

(32 citation statements)

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“…It is well documented that clinical androgen-ablation therapy is associated with increased NE differentiation in prostate carcinomas (Jiborn et al 1998, Ito et al 2001, Ismail et al 2002, Hirano et al 2004. For example, Ito et al (2001) reported that in archival specimens from 137 PCa patients, 70.5% of presence or absence of different concentrations of PP2 as indicated and maintained for an additional 48 h. Total cellular proteins were separated by SDS/PAGE. The phosphorylation levels of c-Src and ERK1/2 were analyzed by antibodies specific to phospho-Tyr-418 c-Src and phospho-ERK1/2, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence suggest that NE differentiation is a common feature of prostate carcinogenesis (di Sant'Agnese 1992) and is often associated with tumor progression and poor prognosis (Abrahamsson 1999). For example, as seen in archival clinical specimens, the population of NE cells, both in terms of their numbers and as a percentage, increases, especially in hormonerefractory tumors (Jiborn et al 1998, Ito et al 2001, Ismail et al 2002, Hirano et al 2004. PCa that are composed solely of NE cells, for example small cell carcinomas and carcinoid tumors, are associated with high aggressiveness (Abrahamsson 1999).…”

Section: Introductionmentioning

confidence: 99%

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Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells

Yuan¹,

Veeramani²,

Lin³

et al. 2006

Endocr Relat Cancer

145

137

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Neuroendocrine (NE) cells are the minor cell populations in normal prostate epithelial compartments. During prostate carcinogenesis, the number of NE cells in malignant lesions increases, correlating with its tumorigenicity and hormone-refractory growth. It is thus proposed that cancerous NE cells promote prostate cancer (PCa) cell progression and its androgen-independent proliferation, although the origin of the cancerous NE cells is not clear. To investigate the role of cancerous NE cells in prostate carcinogenesis, we characterized three NE subclone cell lines-NE-1.3, NE-1.8 and NE-1.9, which were transdifferentiated from androgen-sensitive human PCa LNCaP cells by culturing in an androgen-depleted environment, resembling clinical androgenablation therapy. These subclone cells acquire many features of NE cells seen in clinical prostate carcinomas, for example exhibiting a neuronal morphology and expressing multiple NE markers, including neuron-specific enolase, chromogranin B, neurotensin, parathyroid hormone-related peptide, and to a lesser degree for chromogranin A, while lacking androgen receptor (AR) or prostate specific antigen (PSA) expression. These cells represent terminally differentiated stable cells because after 3 months of re-culturing in a medium containing androgenic activity, they still retained the NE phenotype and expressed NE markers. Despite these NE cells having a slow growth rate, they readily developed xenograft tumors. Furthermore, media conditioned by these NE cells exhibited a stimulatory effect on proliferation and PSA secretion by LNCaP cells in androgendeprived conditions. Additionally, we found that receptor protein tyrosine phosphatase a plays a role in upregulating multiple NE markers and acquiring the NE phenotype. These NE cells thus represent cancerous NE cells and could serve as a useful cell model system for investigating the role of cancerous NE cells in hormone-refractory proliferation of PCa cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells

Yuan¹,

Veeramani²,

Lin³

et al. 2006

Endocr Relat Cancer

145

137

View full text Add to dashboard Cite

show abstract

“…It has been shown that patients who had received a longer course of androgen ablation therapy would have higher levels of NE differentiation. 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 Celmentioning

confidence: 99%

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

Yuan¹,

Veeramani²,

Lin³

2007

Endocr Relat Cancer

211

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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“…Increases in NE phenotype and secretory products are closely correlated with tumor progression and androgen independence in prostate cancer (2,3). NE differentiation can be found in 10 -100% of prostate adenocarcinomas depending on the sample type (biopsy or prostatectomy specimen), method and extent of fixation, the antibody used, and the sensitivity of the technique applied (4).…”

Section: Introductionmentioning

confidence: 99%

NE-10 Neuroendocrine Cancer Promotes the LNCaP Xenograft Growth in Castrated Mice

et al. 2004

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Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with tumor progression and androgen-independent prostate cancer. However, the mechanisms by which NE cells influence prostate cancer growth and progression, especially after androgen ablation therapy, are poorly understood. To investigate the role of NE cells on prostate cancer growth, LNCaP xenograft tumors were implanted into nude mice. After the LNCaP tumors were established, the NE mouse prostate allograft (NE-10) was implanted on the opposite flank of these nude mice to test whether NE tumor-derived systemic factors can influence LNCaP growth. Mice bearing LNCaP tumors with or without NE allografts were castrated 2 weeks after NE tumor inoculation, and changes in LNCaP tumor growth rate and gene expression were investigated. After castration, LNCaP tumor growth decreased in mice bearing LNCaP tumors alone, and this was accompanied by a loss of nuclear androgen receptor (AR) localization. In contrast, in castrated mice bearing both LNCaP and NE-10 tumors, LNCaP tumors continued to grow, had increased levels of nuclear AR, and secreted prostate-specific antigen. Therefore, in the absence of testicular androgens, NE secretions were sufficient to maintain LNCaP cell growth and androgen-regulated gene expression in vivo. Furthermore, in vitro experiments showed that NE secretions combined with low levels of androgens activated the AR, an effect that was blocked by the antiandrogen bicalutamide. Because an increase in AR level has been reported to be sufficient to account for hormone refractory prostate cancers, the NE cell population ability to increase AR level/activity can be another mechanism that allows prostate cancer to escape androgen ablation therapy.

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Up-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence

Cited by 31 publications

References 0 publications

Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells

Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells

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

NE-10 Neuroendocrine Cancer Promotes the LNCaP Xenograft Growth in Castrated Mice

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