Small‐cell carcinoma (SCC) of the prostate is an AR‐negative variant of prostate cancer found at progression in 10–20% of castrate‐resistant disease. Its finding predicts a distinct clinical course and a poor prognosis. Large‐cell neuroendocrine carcinoma (LCNEC) is a much rarer variant that behaves similarly to SCC. The biological mechanisms that drive these disease variants are poorly understood.

Eight tumor fragments from the salvage pelvic exenteration specimen of a patient with castrate‐resistant prostate carcinoma were subcutaneously implanted into 6‐ to 8‐week‐old male CB17 SCID mice. Serial tissue sections and tissue microarrays of the resulting MDA PCa 144 xenograft lines were used for histopathologic and immunohistochemical characterization of the xenografts and their tissue of origin. RNA from two representative xenograft sublines was used for gene‐expression profiling.

All eight fragments formed tumors: four of the MDA PCa 144 xenograft sublines had morphologic characteristics of SCC and four, of LCNEC. All retained high fidelity to their parent tumor tissue, which remained stable through serial passages. Morphological transitions in the specimen of origin suggested LCNEC represents an intermediate step between adenocarcinoma and SCC. Over 2,500 genes were differentially expressed between the SCC (MDA PCa 144‐13) and the LCNEC (MDA PCa 144‐4) sublines and enriched in “Nervous System Development” Gene Ontology subtree.

The eight xenograft models described represent the spectrum of neuroendocrine carcinomas in prostate cancer and will be valuable preclinical tools to study the pathogenesis of and therapy targets for this increasingly recognized subset of lethal prostate cancer. Prostate 71:846–856, 2011. © 2010 Wiley‐Liss, Inc.