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¹ Department of Biochemistry and Molecular Biology,
² Section of Urologic Surgery, College of Medicine and
³ Eppley Institute for Cancer Research, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA

(Requests for offprints should be addressed to M-F Lin at the Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center; Email: mlin{at}unmc.edu)

(S Zelivianski is now at Children’s Memorial Institute for Education and Research, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 2430 N Halsted Street, MB218, Chicago, IL 60614, USA)
(T Igawa is now at Department of Urology, School of Medicine, Nagasaki University, Sakamoto 1-7-1 Nagasaki 852-8501, Japan)

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 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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