Article | Published:

Bladder cancers arise from distinct urothelial sub-populations

Nature Cell Biology volume 16, pages 982991 (2014) | Download Citation

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.

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Acknowledgements

We thank W. Finstad for help with data collection, D. Metzger and P. Chambon for the Krt5CreERT2 line, F. H. Li for technical assistance, the Herbert Irving Comprehensive Cancer Center Histology Core facility for paraffin embedding and the Herbert Irving Comprehensive Cancer Center Microscopy Core for help with confocal microscopy. We thank C. Abate-Shen for critical reading of the manuscript and M. Benson, T. Owczarek and J. Mckiernan for helpful discussions. This work was funded by The TJ Martell Foundation (C.M.) and a Dean’s Research Fellowship from Columbia University (T.Y.).

Author information

Author notes

    • Jason Van Batavia
    • , Tammer Yamany
    •  & Andrei Molotkov

    These authors contributed equally to this work.

    • Andrei Molotkov

    Present address: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Affiliations

  1. Departments of Urology, Genetics & Development, Columbia University, New York, New York 10032, USA

    • Jason Van Batavia
    • , Tammer Yamany
    • , Andrei Molotkov
    • , Hanbin Dan
    • , Ekaterina Batourina
    • , Kerry Schneider
    • , Daniel Oyon
    • , Mark Dunlop
    •  & Cathy Mendelsohn
  2. Department of Pathology, Columbia University, New York, New York 10032, USA

    • Mahesh Mansukhani
  3. Departments of Urology & Pathology, New York University School of Medicine, New York, New York 10016, USA

    • Xue-Ru Wu
  4. Veterans Affairs New York Harbour Healthcare System Manhattan Campus, New York, New York 10010, USA

    • Xue-Ru Wu
  5. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Carlos Cordon-Cardo

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Contributions

J.V.B., T.Y. and A.M. contributed equally to this work. A.M. and C.M. conceived ideas and experimental design. J.V.B., T.Y., H.D., E.B., D.O. and K.S. collected data. J.V.B., T.Y. and M.M. performed histopathological analysis. J.V.B. and T.Y. interpreted the data. J.V.B., T.Y. and C.M. wrote the manuscript. X-R.W., M.D. and C.C-C. provided technical support and conceptual advice.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jason Van Batavia or Tammer Yamany or Andrei Molotkov or Cathy Mendelsohn.

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https://doi.org/10.1038/ncb3038

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