Bladder cancers arise from distinct urothelial sub-populations

Jason Van Batavia; Tammer Yamany; Andrei Molotkov; Hanbin Dan; Mahesh Mansukhani; Ekaterina Batourina; Kerry Schneider; Daniel Oyon; Mark Dunlop; Xue-Ru Wu; Carlos Cordon-Cardo; Cathy Mendelsohn

doi:10.1038/ncb3038

Bladder cancers arise from distinct urothelial sub-populations

Nat Cell Biol. 2014 Oct;16(10):982-91, 1-5. doi: 10.1038/ncb3038. Epub 2014 Sep 14.

Affiliations

¹ Departments of Urology, Genetics &Development, Columbia University, New York, New York 10032, USA.
² Department of Pathology, Columbia University, New York, New York 10032, USA.
³ 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.
⁴ Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

PMID: 25218638
DOI: 10.1038/ncb3038

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Butylhydroxybutylnitrosamine
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
Female
Humans
Keratin-5 / genetics
Keratin-5 / metabolism
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Male
Mice, 129 Strain
Mice, Knockout
Mice, Transgenic
Microscopy, Confocal
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Urinary Bladder Neoplasms / chemically induced
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism*

Substances

Keratin-5
Luminescent Proteins
Butylhydroxybutylnitrosamine

Grants and funding

P30 CA016087/CA/NCI NIH HHS/United States