Pathology of a Canine Model of Localized Prostate Carcinoma.

Abstract

BACKGROUND: Dogs spontaneously develop prostate carcinoma (PC) and share prostate gland anatomy, physiology, and size to men. Over the last 15 years, we have developed and refined a canine model of focal PC to evaluate therapeutic-diagnostic (theranostic) interventions. A comprehensive description of the pathology and synthesis of the various studies has not been performed. The goal of this manuscript was to describe the canine model tumor pathology within the framework of its methodological development to help guide future translational PC research. METHODS: In published and unpublished studies, we previously inoculated prostate glands of immunosuppressed, intact beagle dogs (n = 56) with a canine PC cell line (Ace-1) transduced with human or canine genes for targeted theranostics. Gross tumor assessment and histology were performed in all cases. Molecular tumor and microenvironmental pathology was investigated using digital image analysis, immunohistochemistry, laser-capture microdissection, and quantitative real-time PCR. RESULTS: The model reliably (85.7% engraftment rate) formed prostatic tumors resembling intermediate and high-grade localized PC, with poorly differentiated morphology, stromal invasion, and peripheral growth. Soft tissue metastasis occurred in 13/48 (27.1%) dogs. Most dogs formed multifocal prostatic tumors with occasional tumors outside the prostate gland. Tumor location influenced growth behavior and the microenvironment. Allografts were histologically classified as intraglandular intraprostatic, invasive intraprostatic, capsular, or extraprostatic. Compared to intraprostatic tumors, capsular/extraprostatic tumors had increased proliferation (Ki-67 index), epithelial-to-mesenchymal transition, and microenvironmental alterations that included increased collagenous stroma, fibroplasia, and reduced immune cell infiltration. CONCLUSIONS: The canine model of PC captured important pathologic features of men undergoing curative-intent therapy alongside model- and species-specific characteristics of interest to researchers. Beyond defining pathology, the results highlighted applications of the canine model in studying the tumor microenvironment and advancing preclinical, anti-cancer strategies in a large animal species.