title: Patient-derived tissue slice grafts accurately depict response of high-risk primary prostate cancer to androgen deprivation therapy.
abstract: BACKGROUND
  Effective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. However, the discovery of curative therapies for HRPCa is hampered by the lack of authentic preclinical models.
  
  
  METHODS
  We improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated.
  
  
  RESULTS
  High-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans.
  
  
  CONCLUSIONS
  Our study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of therapeutics for HRPCa and primary CRPC.
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California, USA. dpeehl@stanford.edu.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.forename: Alan
authors.initials: A
authors.lastname: Thong
authors.forename: Rosalie
authors.initials: R
authors.lastname: Nolley
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Reese
authors.forename: Jennifer
authors.initials: J
authors.lastname: Santos
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ingels
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
mesh_terms: D000728:Androgens / Q000172:deficiency* / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011944:Receptors, Androgen / Q000378:metabolism; D012307:Risk Factors; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D014408:Biomarkers, Tumor; D015820:Cadherins; D011944:Receptors, Androgen; D014746:Vimentin