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

Ta Chun Yuan, Suresh Veeramani, Fen Fen Lin, Dmitry Kondrikou, Stanislav Zelivianski, Tsukasa Igawa, Dev Karan, Surinder Kumar Batra, Ming-Fong Lin

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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 androgen-ablation 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 androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase α 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.

Original languageEnglish (US)
Pages (from-to)151-167
Number of pages17
JournalEndocrine-Related Cancer
Volume13
Issue number1
DOIs
StatePublished - Mar 1 2006

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Neuroendocrine Cells
Androgens
Prostate
Prostatic Neoplasms
Prostate-Specific Antigen
Carcinogenesis
Chromogranin B
Phenotype
Parathyroid Hormone-Related Protein
Chromogranin A
Neurotensin
Protein Tyrosine Phosphatases
Phosphopyruvate Hydratase
Androgen Receptors
Conditioned Culture Medium
Heterografts
Growth Hormone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

Cite this

Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. / Yuan, Ta Chun; Veeramani, Suresh; Lin, Fen Fen; Kondrikou, Dmitry; Zelivianski, Stanislav; Igawa, Tsukasa; Karan, Dev; Batra, Surinder Kumar; Lin, Ming-Fong.

In: Endocrine-Related Cancer, Vol. 13, No. 1, 01.03.2006, p. 151-167.

Research output: Contribution to journalArticle

Yuan, Ta Chun ; Veeramani, Suresh ; Lin, Fen Fen ; Kondrikou, Dmitry ; Zelivianski, Stanislav ; Igawa, Tsukasa ; Karan, Dev ; Batra, Surinder Kumar ; Lin, Ming-Fong. / Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. In: Endocrine-Related Cancer. 2006 ; Vol. 13, No. 1. pp. 151-167.
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AU - Zelivianski, Stanislav

AU - Igawa, Tsukasa

AU - Karan, Dev

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AB - 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 androgen-ablation 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 androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase α 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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