Progress 01/01/08 to 12/31/08
Outputs
OUTPUTS: The research support by the Abate-Shen MMHCC consortium has provided us with access to and collaborations with a wide variety of samples positioning us as consultant arbartrators in evaluation of comparative pathology of mouse pathology. These experiences have been captured in a formal basis in several chapters and articles. Gene specific tumor phenotypes have been observed in almost all GEM organ systems. The prostate tumors Nkx mice differ from SV40-Tag and ras derived tumors. The key pathobiological discovery has involved the separation of the AKT-related models such as the Abate-Shen NKX and Sawyers Myc models from the SV40-Tag driven models. The Balmain laboratory, in the process of the study of complex traits, crossed the Probasin-driven SV40-Tag mice into seven different strains. All of the invasive, metastatic tumors proved to be neuroendocrine. The Chiaverotti paper provides formal experimental proof based on test-by-transplantation, using sub-renal recombinants, that the "luminal atypical hyperplasias" are not neoplastic but the neuroendocrine fit all the criteria for malignancy. We have been asked to participate in other studies which has reinforced our experience with the SV40 Tag models. In contrast, erbB2 and ras-based lesions in the same organs do not result in neuroendocrine tumors. PARTICIPANTS: The research support by the Abate-Shen MMHCC consortium has provided us with access to and collaborations with a wide variety of samples positioning us as consultant arbartrators in evaluation of comparative pathology of mouse pathology. These experiences have been captured in a formal basis in several chapters and articles. Gene specific tumor phenotypes have been observed in almost all GEM organ systems. The prostate tumors Nkx mice differ from SV40-Tag and ras derived tumors. The key pathobiological discovery has involved the separation of the AKT-related models such as the Abate-Shen NKX and Sawyers Myc models from the SV40-Tag driven models. The Balmain laboratory, in the process of the study of complex traits, crossed the Probasin-driven SV40-Tag mice into seven different strains. All of the invasive, metastatic tumors proved to be neuroendocrine. The Chiaverotti paper provides formal experimental proof based on test-by-transplantation, using sub-renal recombinants, that the "luminal atypical hyperplasias" are not neoplastic but the neuroendocrine fit all the criteria for malignancy. We have been asked to participate in other studies which has reinforced our experience with the SV40 Tag models. In contrast, erbB2 and ras-based lesions in the same organs do not result in neuroendocrine tumors. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Perhaps, the most unexpected observation was the development of stromal tumors in the T-121 model with the loss of p53 heterozygosity. However, the search for p53 LOH was based, in part, on our experience with EMT in mammary cancers where EMT appeared repeatedly in p53 null mice. Another interesting prostate project involving rats demonstrated that PhIP did not result in progressive prostate disease but the resulting inflammatory atrophy was associated with dysplasia. A major project has been the development of the caELMIR relational database for preclinical trials (see http://caelmir.compmed.ucdavis.edu/caelmir). The caELMIR database has been developed, alpha tested and is in beta testing within the major preclinical trial of Dr. Abate-Shen with JAX-West. In our laboratory, caELMIR has been merged with the Aperio Spectrum whole slide imaging system as previously proposed by Dr. Galvez. caELMIR is designed with with a five tier heirarchy (Study, Experiment, Cohort, Animal, Specimen). It is designed to be platform independent for cross species mapping. The modular design allows API connections with other applications so that all the data concerning an individual can be integrated and retrieved. See the Aperio-based demonstration of the MMHCC-based Rapamycin studies at http://1314-dsr.compmed.ucdavis.edu ID/PW=guest/guest. Initial testing and use has identified a key element missing from caELMIR. The MMHCC will need to develop and maintain a specimen repository for future use. The MHCC Repository is designed to eliminate wasteful redundancy by identifying resources available throught the consortion. The application ise currently being planned for implementation. The current caELMIR architecture does not allow for idenitification and utilization of specimens generated from one study in second study. Since genetically engineered mice generate more tissue/specimens then used in a single experiment or study, the resources need to be made available for other investigators. These valuable resources are not currently tracked within caELMIR. Therefore, at the direction of MMHCC leadership, we began to integrate caTissue with caELMIR to produce a single access point for MMHCC experimental data and tissue repository data. The merger with caTissue will allow investigators to find and procure tissues from others previous experiments. The inclusion of experimental data as repository metadata will also lead to a richer set of preliminary data for future experiments. caELMIR with the integration with caTISSUE is critical to the next phase of MMHCC programs. If the the mission of the MMHCC and goals of caELMIR and caBIG are to be realized, the carry-over funds, designated for caELMIR use, testing and debuging, are needed to continue its development. The caELMIR/caTISSUE integration represents a major milestone for the application and will be a major upgrade for caELMIR.
Publications
- Galvez JJ, Munn RJ, Garbutt AS, Hogarth MA, Tarnowski BI, Cardiff RD. Development of a Whole Slide Image Archive. In: Gu J, Ogilvie RW, eds. Virtual Microscopy and Virtual Slides in Teaching, Diagnosis, and Research. Boca Raton, London, New York, Singapore: Taylor and Francis; 2005:325-35. Simin K, Wu H, Lu L, et al. pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia. PLoS Biol 2004;2:E22.
- Couto SS, Cardiff RD. The Genomic Revolution and Endocrine Pathology. Endocr Pathol 2008.
- Chiaverotti T, Couto SS, Donjacour A, et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol 2008;172:236-46.
- Cardiff RD, Ward JM, Barthold SW. 'One medicine---one pathology': are veterinary and human pathology prepared Lab Invest 2008;88:18-26.
- Cardiff RD. Genomic pathology for genomic biology. Pathologica 2008;100:3-5.
- Fritz WA, Lin TM, Cardiff RD, Peterson RE. The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice. Carcinogenesis 2007;28:497-505.
- Damonte P, Gregg JP, Borowsky AD, Keister BA, Cardiff RD. EMT tumorigenesis in the mouse mammary gland. Lab Invest 2007;87:1218-26.
- Cardiff RD. Epilog: comparative medicine, one medicine and genomic pathology. Breast disease 2007;28:107-10.
- Cecena G, Wen F, Cardiff RD, Oshima RG. Differential sensitivity of mouse epithelial tissues to the polyomavirus middle T oncogene. Am J Pathol 2006;168:310-20.
- Cardiff RD, Munn RJ, Galvez JJ. The Tumor Pathology of Genetically Engineered Mice: A New Approach to Molecular Pathology. In: Fox JG, Davisson MT, Quimby FW, Barthold SW, Newcomer CE, Smith AL, eds. The Mouse in Biomedical Research: Experimental Biology and Oncology Second ed. New York: Elsevier, Inc; 2006:581-622.
- Cardiff RD, Anver MR, Boivin GP, et al. Precancer in mice: animal models used to understand, prevent, and treat human precancers. Toxicol Pathol 2006;34:699-707.
- Borowsky AD, Dingley KH, Ubick E, Turteltaub KW, Cardiff RD, Devere-White R. Inflammation and atrophy precede prostatic neoplasia in a PhIP-induced rat model. Neoplasia 2006;8:708-15.
- Hill R, Song Y, Cardiff RD, Van Dyke T. Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell 2005;123:1001-11.
- Hill R, Song Y, Cardiff RD, Van Dyke T. Heterogeneous Tumor Evolution Initiated by Loss of pRb Function in a Preclinical Prostate Cancer Model. Cancer Res 2005;65:10243-54.
- Shappell SB, Thomas GV, Roberts RL, et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res 2004;64:2270-305.
- Scherl A, Li JF, Cardiff RD, Schreiber-Agus N. Prostatic intraepithelial neoplasia and intestinal metaplasia in prostates of probasin-RAS transgenic mice. Prostate 2004;59:448-59.
- Gum JR, Jr., Hicks JW, Crawley SC, et al. Mice Expressing SV40 T Antigen Directed by the Intestinal Trefoil Factor Promoter Develop Tumors Resembling Human Small Cell Carcinoma of the Colon. Mol Cancer Res 2004;2:504-13.
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