title: Tissue slice grafts of human renal cell carcinoma: an authentic preclinical model with high engraftment rate and metastatic potential.
abstract: OBJECTIVE
  Discovery of curative therapies for renal cell carcinoma (RCC) is hampered by lack of authentic preclinical models. Tumorgrafts, generated by direct implantation of patient-derived tissues into mice, have demonstrated superior ability to predict therapeutic response. We evaluated "tissue slice grafts" (TSGs) as an improved tumorgraft model of RCC.
  
  
  METHODS
  Cores of fresh RCC were precision-cut at 300 µm and implanted under the renal capsule of RAG2(-/-)γC(-/-) mice. Engraftment rate, histology, biomarker expression, genetic fidelity, and metastatic potential were evaluated. Magnetic resonance imaging (MRI) was tested as a noninvasive method to measure tumor volume, and response to a targeted therapy was determined.
  
  
  RESULTS
  All 13 cases of RCC engrafted and displayed characteristic histology and biomarkers. TSG volume quantified noninvasively by MRI highly correlated with graft weights, providing a unique tool for monitoring orthotopic growth. Moreover, in 2 cases, cancer cells from TSGs metastasized to clinically relevant sites, including bone. Microarray analysis and DNA sequencing demonstrated a high degree of correlation of global gene expression and von Hippel-Lindau (VHL) status between TSGs and parental tumors. Treatment of TSGs with sunitinib significantly decreased graft weight and mean vessel density compared with controls.
  
  
  CONCLUSIONS
  The TSG model of RCC faithfully recapitulates tumor pathology, gene expression, genetic mutation, and drug response. The high engraftment rate and metastatic potential of this authentic model, in conjunction with the ability to generate large first-generation animal cohorts and to quantitate tumor volume at the orthotopic site by MRI, proffer significant advantages compared with other preclinical platforms.
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Thong
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA; Department of Urology, Centre Hospitalier Universitaire du Kremlin-Bicêtre, Kremlin-Bicêtre, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ingels
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA; Division of Medicine, Turku University Hospital and University of Turku, Turku, Finland.
authors.forename: Maija P
authors.initials: MP
authors.lastname: Valta
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Nolley
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Santos
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Young
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA. Electronic address: dpeehl@stanford.edu.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D000077210:Sunitinib; D014183:Transplantation, Heterologous / Q000379:methods*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000077210:Sunitinib
keywords: Metastases; Renal cancer; Tumorgrafts
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