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Cancer and Metastasis Reviews

, 28:291 | Cite as

Urothelial carcinoma: Stem cells on the edge

  • William D. Brandt
  • William Matsui
  • Jonathan E. Rosenberg
  • Xiaobing He
  • Shizhang Ling
  • Edward M. Schaeffer
  • David M. Berman
Article

Abstract

Tumors are heterogeneous collections of cells with highly variable abilities to survive, grow, and metastasize. This variability likely stems from epigenetic and genetic influences, either stochastic or hardwired by cell type-specific lineage programs. That differentiation underlies tumor cell heterogeneity was elegantly demonstrated in hematopoietic tumors, in which rare primitive cells (cancer stem cells (CSCs)) resembling normal hematopoietic stem cells are ultimately responsible for tumor growth and viability. Because of the compelling clinical implications CSCs pose—across the entire spectrum of cancers—investigators applied the CSC model to cancers arising in tissues with crudely understood differentiation programs. Instead of relying on differentiation, these studies used empirically selected markers and statistical arguments to identify CSCs. The empirical approach has stimulated important questions about “stemness” in cancer cells as well as the validity and stoichiometry of CSC assays. The recent identification of urothelial differentiation programs in urothelial carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs. Importantly, CSCs from invasive UroCas (UroCSCs) appear well situated to exchange important signals with adjacent stroma, to escape immune surveillance, and to survive cytotoxic therapy. These signals have potential roles in treatment resistance and many participate in druggable cellular pathways. In this review, we discuss the implications of these findings in understanding CSCs and in better understanding how UroCas form, progress, and should be treated.

Keywords

Differentiation Cancer stem cell Stroma Bladder Wnt Carcinoma in situ 

Notes

Acknowledgments

Our work is supported by NIH Grant Numbers R01DK072000, P01CA077664; The Bladder Cancer Research Center at Johns Hopkins University, and Stemline Therapeutics.

Disclosure

UroCSC research in DMB's laboratory was partially supported by Stemline Therapeutics which licenses associated inventions from the Johns Hopkins University. DMB and the University are entitled to royalty payments from this arrangement. DMB is also a paid consultant to Stemline Therapeutics and owns Stemline Therapeutics stock options. The terms of this arrangement are managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • William D. Brandt
    • 1
  • William Matsui
    • 2
  • Jonathan E. Rosenberg
    • 4
  • Xiaobing He
    • 1
  • Shizhang Ling
    • 1
  • Edward M. Schaeffer
    • 3
  • David M. Berman
    • 1
    • 2
    • 3
  1. 1.Department of PathologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  4. 4.Lank Center for Genitourinary CancerDana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA

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