title: A tissue graft model of DNA damage response in the normal and malignant human prostate.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California; Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland.
authors.forename: Taija M
authors.initials: TM
authors.lastname: Af Hällström
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Ville
authors.initials: V
authors.lastname: Rantanen
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Reese
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Nolley
authors.affiliation: Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California. Electronic address: dpeehl@stanford.edu.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D060787:Neoplasm Grading; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016378:Tissue Transplantation / Q000379:methods*
keywords: DNA damage; H2AFX protein; human; prostate; prostatic neoplasms; transplants
references.citation: J Natl Cancer Inst. 2001 Jan 17;93(2):128-33
references.pmid: 11208882
references.citation: Nature. 2012 Jan 18;481(7381):287-94
references.pmid: 22258607
references.citation: Cancer Res. 2004 Mar 1;64(5):1712-21
references.pmid: 14996731
references.citation: Cancer Res. 2010 May 15;70(10):3925-34
references.pmid: 20442295
references.citation: Am J Pathol. 2010 Jul;177(1):229-39
references.pmid: 20472887
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7211-6
references.pmid: 17431037
references.citation: Radiother Oncol. 2010 Jan;94(1):90-101
references.pmid: 19931928
references.citation: Radiother Oncol. 2008 Sep;88(3):388-97
references.pmid: 18524402
references.citation: Prostate. 2005 Jul 1;64(2):149-59
references.pmid: 15678503
references.citation: Nat Cell Biol. 2004 Oct;6(10):923-8
references.pmid: 15459720
references.citation: Cancer Res. 2010 Nov 1;70(21):8630-41
references.pmid: 20978201
references.citation: Blood. 2003 Oct 1;102(7):2522-31
references.pmid: 12791667
references.citation: Clin Cancer Res. 2012 Aug 1;18(15):4019-25
references.pmid: 22619305
references.citation: Cancer Cell. 2002 Aug;2(2):113-6
references.pmid: 12204531
references.citation: Prostate. 2008 Jun 1;68(8):902-18
references.pmid: 18324675
references.citation: Mol Cell Biol. 2004 Jul;24(14):6350-61
references.pmid: 15226436
references.citation: J Clin Oncol. 2008 May 20;26(15):2497-504
references.pmid: 18413638
references.citation: Cell Cycle. 2011 Oct 15;10(20):3545-53
references.pmid: 22030624
references.citation: Nature. 2009 Oct 22;461(7267):1071-8
references.pmid: 19847258
references.citation: DNA Repair (Amst). 2007 Jan 4;6(1):128-34
references.pmid: 17178256
references.citation: Prostate. 2005 Feb 15;62(3):260-6
references.pmid: 15389778
references.citation: Mol Cell. 2010 Oct 22;40(2):179-204
references.pmid: 20965415
references.citation: Mol Cancer Ther. 2011 Jul;10(7):1185-93
references.pmid: 21571912
references.citation: Nucleic Acids Res. 1989 Nov 25;17(22):9113-26
references.pmid: 2587254
references.citation: Am J Pathol. 2010 Apr;176(4):1901-13
references.pmid: 20167861
references.citation: Cancer Res. 2010 Dec 1;70(23):9808-15
references.pmid: 21084272
references.citation: Asian J Androl. 2010 Jul;12(4):509-18
references.pmid: 20364154