title: Bladder cancers arise from distinct urothelial sub-populations.
abstract: Bladder cancer is the sixth most common cancer in humans. This heterogeneous set of lesions including urothelial carcinoma (Uca) and squamous cell carcinoma (SCC) arise from the urothelium, a stratified epithelium composed of K5-expressing basal cells, intermediate cells and umbrella cells. Superficial Uca lesions are morphologically distinct and exhibit different clinical behaviours: carcinoma in situ (CIS) is a flat aggressive lesion, whereas papillary carcinomas are generally low-grade and non-invasive. Whether these distinct characteristics reflect different cell types of origin is unknown. Here we show using lineage tracing in a murine model of carcinogenesis that intermediate cells give rise primarily to papillary lesions, whereas K5-basal cells are likely progenitors of CIS, muscle-invasive lesions and SCC depending on the genetic background. Our results provide a cellular and genetic basis for the diversity in bladder cancer lesions and provide a possible explanation for their clinical and morphological differences.
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Van Batavia
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Tammer
authors.initials: T
authors.lastname: Yamany
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Molotkov
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Hanbin
authors.initials: H
authors.lastname: Dan
authors.affiliation: Department of Pathology, Columbia University, New York, New York 10032, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Mansukhani
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Batourina
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Schneider
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oyon
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Dunlop
authors.affiliation: 1] Departments of Urology &Pathology, New York University School of Medicine, New York, New York 10016, USA [2] Veterans Affairs New York Harbour Healthcare System Manhattan Campus, New York, New York 10010, USA.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Mendelsohn
mesh_terms: D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D002278:Carcinoma in Situ / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D005260:Female; D006801:Humans; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D053555:Keratin-5; D008164:Luminescent Proteins; D002085:Butylhydroxybutylnitrosamine