Bladder cancers arise from distinct urothelial sub-populations

• Published in: Nature cell biology Vol. 16; no. 10; pp. 982 - 991
• Main Authors: Van Batavia, Jason, Yamany, Tammer, Molotkov, Andrei, Dan, Hanbin, Mansukhani, Mahesh, Batourina, Ekaterina, Schneider, Kerry, Oyon, Daniel, Dunlop, Mark, Wu, Xue-Ru, Cordon-Cardo, Carlos, Mendelsohn, Cathy
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2014
• Subjects: Animals; Bladder cancer; Butylhydroxybutylnitrosamine; Cancer cells; Carcinoma in Situ - chemically induced; Carcinoma in Situ - genetics; Carcinoma in Situ - metabolism; Carcinoma, Papillary - chemically induced; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Transitional Cell - chemically induced; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Cell Lineage; Development and progression; Female; Genetic aspects; Humans; Identification and classification; Keratin; Keratin-5 - genetics; Keratin-5 - metabolism; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Mice, 129 Strain; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Mutation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Pathology; Urinary Bladder Neoplasms - chemically induced; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urology; New York; United States > US
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3038

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.