The Pathology Core is designed to provide three services to support the experimental aims of this Program Project application. First, the Core will ensure timely and reliable availability of tumor tissues collected from the preclinical studies with genetic models of prostate cancer used in each Project. This will involve schedule-dependent animal harvesting, necropsy, tissue dissection, and tissue processing, including bone lesions. The second objective of Core C is to provide histopathological evaluation of signaling pathways in localized and metastatic prostate cancer, as well as bone-tumor interplay after treatment with the various "network inhibitors" tested in Projects 1, 2, and 3. To accomplish these tasks. Core C will support quantitative and standardized immunohistochemical evaluation of tumor markers, determine parameters of apoptosis and cell proliferation, provide volumetric quantification of lung metastasis by stereologic microscopy, and examine a potential modulation of ancillary pathways of tumor growth, i.e. angiogenesis. Third, Core C will identify, characterize and test molecular biomarkers of pathway and target validation for the proposed preclinical studies, in vivo. This will involve analysis of markers of mitochondrial dysfunction and oxidative damage for Project 1, dynamic changes in integrin signaling for Project 2, and evaluation of a Runx2 "gene signature" for modulation of bone-tumor responses in Project 3. The tasks provided by Core C will support equally each Project, and will be accomplished under the supervision of two senior pathologists. Drs. Irwin Leav, Director of Core C, and Zhong Jiang, Co-Director of Core C, have extensive experience in histopathology of prostate cancer, disease models in rodents, and evaluation of molecular biomarkers of tumor responses. The centralization of the morphologic studies in Core C will facilitate collaborative research among the investigators on this application, while obviating the need for each Project to individually develop key techniques.
The services provided by Core C are pivotal to accomplish the specific aims contained in each Project, and to obtain a comprehensive evaluation of tumor responses after treatment with new molecular therapeutics, i.e. nebwork inhibitors. The combination of high-resolution molecular imaging (Core B) with quantitative and standardized histopathology (Core C) will enhance the synergistic integration of each Project, and strengthen the feasibility of their mechanistic and preclinical goals.
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