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Androgen-Independent Growth and Tumorigenesis of Prostate Cancer Cells Are Enhanced by the Presence of PKA-Differentiated Neuroendocrine Cells

Departments of ¹ Microbiology and Cancer Center and ² Department of Pathology, University of Virginia Health System, Charlottesville, Virginia; ³ Biology Department, Mary Baldwin College, Staunton, Virginia; ⁴ The Prostate Center at Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada; and ⁵ Laboratory for Cancer Ontogeny and Therapeutics, Department of Biological Sciences, University of Delaware, Newark, Delaware

Requests for reprints: Sarah J. Parsons, Department of Microbiology, University of Virginia Health System, P.O. Box 800734, Charlottesville, VA 22908-0734. Phone: 434-924-2352; Fax: 434-982-0689; E-mail: sap{at}virginia.edu.

The neuroendocrine status of prostatic adenocarcinomas is considered a prognostic indicator for development of aggressive, androgen-independent disease. Neuroendocrine-like cells are thought to function by providing growth and survival signals to surrounding tumor cells, particularly following androgen ablation therapy. To test this hypothesis directly, LNCaP cells were engineered to inducibly express a constitutively activated form of the cyclic AMP–dependent protein kinase A catalytic subunit (caPKA), which was previously found upon transient transfection to be sufficient for acquisition of neuroendocrine-like characteristics and loss of mitotic activity. Clonal cells that inducibly expressed caPKA enhanced the growth of prostate tumor cells in anchorage-dependent and anchorage-independent in vitro assays as well as the growth of prostate tumor xenografts in vivo, with the greatest effects seen under conditions of androgen deprivation. These results suggest that neuroendocrine-like cells of prostatic tumors have the potential to enhance androgen-independent tumor growth in a paracrine manner, thereby contributing to progression of the disease. [Cancer Res 2007;67(8):3663–72]

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