Taija M Af Hällström1, Hongjuan Zhao2, Junqiang Tian3, Ville Rantanen4, Stephen W Reese2, Rosalie Nolley2, Marikki Laiho5, Donna M Peehl6. 1. Department of Urology, Stanford University School of Medicine, Stanford, California; Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland. 2. Department of Urology, Stanford University School of Medicine, Stanford, California. 3. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California. 4. Department of Virology, Haartman Institute and Molecular Imaging Unit and Computational Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Program, University of Helsinki, Finland. 5. Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Department of Urology, Stanford University School of Medicine, Stanford, California. Electronic address: dpeehl@stanford.edu.
Abstract
PURPOSE: DNA damage responses are relevant to prostate cancer initiation, progression and treatment. Few models of the normal and malignant human prostate that maintain stromal-epithelial interactions in vivo exist in which to study DNA damage responses. We evaluated the feasibility of maintaining tissue slice grafts at subcutaneous vs subrenal capsular sites in RAG2(-/-)γC(-/-) mice to study the DNA damage responses of normal and malignant glands. MATERIALS AND METHODS: We compared the take rate and histology of tissue slice grafts from fresh, precision cut surgical specimens that were maintained for 1 to 4 weeks in subcutaneous vs subrenal capsular sites. Induction of γH2AX, p53, ATM and apoptosis was evaluated as a measure of the DNA damage response after irradiation. RESULTS: The take rate of subcutaneous tissue slice grafts was higher than typically reported but lower than at the subrenal capsular site. Subcutaneous tissue slice grafts frequently showed basal cell hyperplasia, squamous metaplasia and cystic atrophy, and cancer did not survive. In contrast, normal and malignant histology was well maintained in subrenal capsular tissue slice grafts. Regardless of implantation site the induction of γH2AX and ATM occurred in tissue slice graft epithelium 1 hour after irradiation and decreased to basal level by 24 hours, indicating DNA damage recognition and repair. As observed previously in prostatic ex vivo models, p53 was not activated. Notably, tumor but not normal cells responded to irradiation by undergoing apoptosis. CONCLUSIONS: To our knowledge this is the first study of DNA damage responses in a patient derived prostate tissue graft model. The subrenal capsular site of RAG2(-/-)γC(-/-) mice optimally maintains normal and malignant histology and function, permitting novel studies of DNA damage responses in a physiological context.
PURPOSE: DNA damage responses are relevant to prostate cancer initiation, progression and treatment. Few models of the normal and malignant human prostate that maintain stromal-epithelial interactions in vivo exist in which to study DNA damage responses. We evaluated the feasibility of maintaining tissue slice grafts at subcutaneous vs subrenal capsular sites in RAG2(-/-)γC(-/-) mice to study the DNA damage responses of normal and malignant glands. MATERIALS AND METHODS: We compared the take rate and histology of tissue slice grafts from fresh, precision cut surgical specimens that were maintained for 1 to 4 weeks in subcutaneous vs subrenal capsular sites. Induction of γH2AX, p53, ATM and apoptosis was evaluated as a measure of the DNA damage response after irradiation. RESULTS: The take rate of subcutaneous tissue slice grafts was higher than typically reported but lower than at the subrenal capsular site. Subcutaneous tissue slice grafts frequently showed basal cell hyperplasia, squamous metaplasia and cystic atrophy, and cancer did not survive. In contrast, normal and malignant histology was well maintained in subrenal capsular tissue slice grafts. Regardless of implantation site the induction of γH2AX and ATM occurred in tissue slice graft epithelium 1 hour after irradiation and decreased to basal level by 24 hours, indicating DNA damage recognition and repair. As observed previously in prostatic ex vivo models, p53 was not activated. Notably, tumor but not normal cells responded to irradiation by undergoing apoptosis. CONCLUSIONS: To our knowledge this is the first study of DNA damage responses in a patient derived prostate tissue graft model. The subrenal capsular site of RAG2(-/-)γC(-/-) mice optimally maintains normal and malignant histology and function, permitting novel studies of DNA damage responses in a physiological context.
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