title: Urothelial carcinogen resistance driven by stronger Toll-like receptor 2 (TLR2) and Uroplakin III (UP III) defense mechanisms: a new model.
abstract: OBJECTIVE
  The objective of the study was to illustrate the applicability and significance of the novel Lewis urothelial cancer model compared to the classic Fisher 344.
  
  
  METHODS
  Fischer 344 and Lewis females rats, 7 weeks old, were intravesical instilled N-methyl-N-nitrosourea 1.5 mg/kg every other week for a total of four doses. After 15 weeks, animals were sacrificed and bladders analyzed: histopathology (tumor grade and stage), immunohistochemistry (apoptotic and proliferative indices) and blotting (Toll-like receptor 2-TLR2, Uroplakin III-UP III and C-Myc). Control groups received placebo.
  
  
  RESULTS
  There were macroscopic neoplastic lesions in 20 % of Lewis strain and 70 % of Fischer 344 strain. Lewis showed hyperplasia in 50 % of animals, normal bladders in 50 %. All Fischer 344 had lesions, 20 % papillary hyperplasia, 30 % dysplasia, 40 % neoplasia and 10 % squamous metaplasia. Proliferative and apoptotic indices were significantly lower in the Lewis strain (p < 0.01). The TLR2 and UP III protein levels were significantly higher in Lewis compared to Fischer 344 strain (70.8 and 46.5 % vs. 49.5 and 16.9 %, respectively). In contrast, C-Myc protein levels were significantly higher in Fischer 344 (22.5 %) compared to Lewis strain (13.7 %).
  
  
  CONCLUSIONS
  The innovative Lewis carcinogen resistance urothelial model represents a new strategy for translational research. Preservation of TLR2 and UP III defense mechanisms might drive diverse urothelial phenotypes during carcinogenesis in differently susceptible individuals.
authors.affiliation: School of Medical Sciences, University of Campinas, Unicamp, Rua: Tessália Vieira de Camargo, 1262, Cidade Universitária "Zeferino Vaz", Campinas, São Paulo, CEP: 13083-887, Brazil, reisleo.l@gmail.com.
authors.forename: Leonardo Oliveira
authors.initials: LO
authors.lastname: Reis
authors.forename: Karen
authors.initials: K
authors.lastname: Ferrari
authors.forename: Marina
authors.initials: M
authors.lastname: Zamuner
authors.forename: Guilherme Zweig
authors.initials: GZ
authors.lastname: Rocha
authors.forename: Athanase
authors.initials: A
authors.lastname: Billis
authors.forename: Wagner José
authors.initials: WJ
authors.lastname: Fávaro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000502:physiology*; D005260:Female; D008770:Methylnitrosourea / Q000009:adverse effects; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D060171:Uroplakin III / Q000502:physiology*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; C495343:Tlr2 protein, rat; D051195:Toll-Like Receptor 2; D060171:Uroplakin III; D008770:Methylnitrosourea