Amponsa Vasty Osei, Shuman Lauren, Ellis Justine, Wang Erica, Walter Vonn, Owens Russell G, Zaleski Michael, Warrick Joshua I, Raman Jay D, DeGraff David J
Department of Pathology, Pennsylvania State University College of Medicine Hershey, PA, USA.
Department of Public Health Sciences, Pennsylvania State University College of Medicine Hershey, PA, USA.
Am J Clin Exp Urol. 2019 Jun 15;7(3):139-152. eCollection 2019.
Creation of genetically engineered mouse models of bladder cancer often involves the use of several background strains in conjunction with the carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). However, carcinogen susceptibility in commonly used strains, as well as phenotypic differences is not well characterized.
To determine differences in susceptibility and phenotypic outcome following BBN exposure of C57BL/6 and FVB, two strains commonly used for model development.
Male C57BL/6 and FVB mice were exposed to BBN (0.05%) in drinking water for 12 and 16 weeks. Dissected bladders were characterized by histological and immunohistochemical analyses. Gene Ontology analysis was performed to identify differences in gene expression across strains following BBN exposure.
While the C57BL/6 strain developed non-invasive tumors, FVB mice developed muscle invasive bladder cancer with squamous and/or glandular differentiation. Glandular differentiation was exclusively observed in the FVB strain. FVB tumors were highly immunogenic and inflamed by the presence of high expression of Cd274 (Pdl-1), murine histocompatibility complex (H2) and pro-inflammatory cytokines (Il-5 and Il-17).
Following BBN exposure, FVB mice undergo rapid tumorigenesis and disease progression characterized by Pdl-1 expression and development of glandular differentiation. These studies identify a degree of tumor heterogeneity in the FVB tumors previously undescribed, and identify FVB mice as a potentially useful model for the study of bladder adenocarcinoma and the inflammatory tumor microenvironment.
创建膀胱癌基因工程小鼠模型通常涉及使用几种背景品系并结合致癌物N-丁基-N-(4-羟基丁基)亚硝胺（BBN）。然而，常用品系对致癌物的易感性以及表型差异尚未得到充分表征。
确定常用于模型开发的C57BL/6和FVB这两种品系在接触BBN后易感性和表型结果的差异。
将雄性C57BL/6和FVB小鼠暴露于含0.05%BBN的饮用水中12周和16周。对解剖后的膀胱进行组织学和免疫组织化学分析。进行基因本体分析以确定BBN暴露后各品系间基因表达的差异。
C57BL/6品系发展为非侵袭性肿瘤，而FVB小鼠发展为具有鳞状和/或腺性分化的肌肉侵袭性膀胱癌。仅在FVB品系中观察到腺性分化。FVB肿瘤具有高度免疫原性，且因Cd274（Pdl-1）、小鼠组织相容性复合体（H2）和促炎细胞因子（Il-5和Il-17）的高表达而发炎。
接触BBN后，FVB小鼠经历快速肿瘤发生和疾病进展，其特征为Pdl-1表达和腺性分化的发展。这些研究确定了FVB肿瘤中以前未描述的一定程度的肿瘤异质性，并确定FVB小鼠是研究膀胱腺癌和炎性肿瘤微环境的潜在有用模型。
