MP21-02 TRACING THE ORIGINS OF BLADDER CANCER USING FATE MAPPING TECHNIQUES

Field: Medicine (Health Sciences)

You have accessJournal of UrologyBladder Cancer: Basic Research I1 Apr 2014MP21-02 TRACING THE ORIGINS OF BLADDER CANCER USING FATE MAPPING TECHNIQUES Tammer Yamany, Jason Van Batavia, Ekatherina Batourina, Hanbin Dan, Kerry Schneider, Carmen Matos, and Cathy Mendelsohn Tammer YamanyTammer Yamany More articles by this author , Jason Van BataviaJason Van Batavia More articles by this author , Ekatherina BatourinaEkatherina Batourina More articles by this author , Hanbin DanHanbin Dan More articles by this author , Kerry SchneiderKerry Schneider More articles by this author , Carmen MatosCarmen Matos More articles by this author , and Cathy MendelsohnCathy Mendelsohn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.830AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bladder cancer is among the most common cancers in men and women. By far, the most common type of bladder cancer in the United States is urothelial carcinoma, which derives from the urothelium, the stratified epithelial layer lining the bladder. The urothelium consists of a basal layer of K5-expressing cells (K5-BCs), intermediate cells, and superficial cells, which are terminally differentiated. Historically, urothelial carcinoma has been thought to progress through two different pathways: a low-grade papillary variant and a high-grade pre-invasive carcinoma in situ (CIS). That both types of lesions can exist simultaneously in the same patient, together with the distinct morphology of papillary and CIS lesions, has led to the suggestion that they are derived from different urothelial subtypes. We used N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced carcinogenesis in P53 heterozygous mice in combination with fate mapping to indelibly label K5-BCs and intermediate cells respectively, then examined their potential to generate CIS, papillary and invasive lesions. METHODS Krt5CreERT2;Rosa26LacZ;P53+/- and Up2CreERT2;Rosa26LacZ;P53+/- mice were used to label K5-BCs and intermediate cells, respectively. Tamoxifen was administered to induce labeling of the specific cell types, then animals were treated with the carcinogen for 16, 20, or 24 weeks. Bladders were embedded in paraffin blocks for histopathological and immunohistochemical analysis. RESULTS LacZ expressing cells in Krt5CreERT2;LacZ mice are found predominantly in CIS lesions (9 CIS lesions vs 3 papillary lesions in 5 bladders). LacZ expressing cells in Up2CreERT2;LacZ mice contribute entirely to papillary carcinomas (14 papillary lesions vs 0 CIS lesions in 7 bladders). Both K5-BCs and UP2-expressing intermediate cells contribute to lamina propria invading lesions and muscle invading lesions. However, 47.8% of labeled lesions in the Krt5CreERT2;LacZ mice are invasive, while 26.3% of labeled lesions in the Up2CreERT2;LacZ mice are invasive. Immunohistochemical analysis reveals that keratin 5 expression is found in all papillary lesions, despite receiving more contribution from UP2-expressing intermediate cells. Ki-67 expression, a marker of proliferation, and keratin 20 (CK20) expression are increased in CIS lesions. CONCLUSIONS These results indicate that papillary urothelial carcinoma and CIS likely have different cells of origin in the urothelium. These observations have important implications for our basic understanding of the pathogenesis and prognosis of urothelial carcinoma. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e225 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Tammer Yamany More articles by this author Jason Van Batavia More articles by this author Ekatherina Batourina More articles by this author Hanbin Dan More articles by this author Kerry Schneider More articles by this author Carmen Matos More articles by this author Cathy Mendelsohn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...