Cancer Stem Cells

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Differentiation of a Highly Tumorigenic Basal Cell Compartment in Urothelial Carcinoma†‡

  1. Xiaobing He1,
  2. Luigi Marchionni2,
  3. Donna E. Hansel3,
  4. Wayne Yu2,
  5. Akshay Sood1,
  6. Jie Yang2,
  7. Giovanni Parmigiani1,2,4,
  8. William Matsui2,
  9. David M. Berman1,2,5,§,*

Article first published online: 9 APR 2009

DOI: 10.1002/stem.92

Issue

STEM CELLS

STEM CELLS

Volume 27, Issue 7, pages 1487–1495, July 2009

Additional Information

How to Cite

He, X., Marchionni, L., Hansel, D. E., Yu, W., Sood, A., Yang, J., Parmigiani, G., Matsui, W. and Berman, D. M. (2009), Differentiation of a Highly Tumorigenic Basal Cell Compartment in Urothelial Carcinoma. STEM CELLS, 27: 1487–1495. doi: 10.1002/stem.92

Author Information

  1. 1

    Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland USA

  2. 2

    Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland USA

  3. 3

    Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA

  4. 4

    Department of Biostatistics, The Johns Hopkins Medical Institutions, Baltimore, Maryland USA

  5. 5

    Departments of Urology, The Johns Hopkins Medical Institutions, Baltimore, Maryland USA

  1. §

    Telephone: 443-287-0878

*Department of Pathology, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Room 545, Baltimore, Maryland 21231, USA

  1. †

    Author contributions: X.H., L.M., D.M.B.: conception and design, data collection, data analysis and interpretation, manuscript writing, final approval of manuscript; D.E.H.: data collection, data analysis and interpretation, provision of study material; W.Y., A.K.: data collection, data analysis; J.Y.: provision of study material; G.P.: conception and design; W.M.: conception and design, data analysis and interpretation, final approval of manuscript.

  2. ‡

    First published online in STEM CELLS EXPRESS April 9, 2009.

Publication History

  1. Issue published online: 6 JUL 2009
  2. Article first published online: 9 APR 2009
  3. Accepted manuscript online: 9 APR 2009 12:00AM EST
  4. Manuscript Accepted: 1 APR 2009
  5. Manuscript Received: 10 FEB 2009

Funded by

  • NIH. Grant Numbers: R01DK072000, P01CA077664, K08DK059375
  • The Bladder Cancer Research Center at Johns Hopkins University
  • Stemline Therapeutics
  • NSF. Grant Number: DMS0342111
  • NIH/NCRR. Grant Numbers: 1U54RR023561-01A1, P50CA088843

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Keywords:

  • Differentiation;
  • Malignancy;
  • Stem cell microenvironment interactions;
  • Stromal cells

Abstract

Highly tumorigenic cancer cell (HTC) populations have been identified for a variety of solid tumors and assigned stem cell properties. Strategies for identifying HTCs in solid tumors have been primarily empirical rather than rational, particularly in epithelial tumors, which are responsible for 80% of cancer deaths. We report evidence for a spatially restricted bladder epithelial (urothelial) differentiation program in primary urothelial cancers (UCs) and in UC xenografts. We identified a highly tumorigenic UC cell compartment that resembles benign urothelial stem cells (basal cells), co-expresses the 67-kDa laminin receptor and the basal cell-specific cytokeratin CK17, and lacks the carcinoembryonic antigen family member CEACAM6 (CD66c). This multipotent compartment resides at the tumor-stroma interface, is easily identified on histologic sections, and possesses most, if not all, of the engraftable tumor-forming ability in the parental xenograft. We analyzed differential expression of genes and pathways in basal-like cells versus more differentiated cells. Among these, we found significant enrichment of pathways comprising “hallmarks” of cancer, and pharmacologically targetable signaling pathways, including Janus kinase-signal transducer and activator of transcription, Notch, focal adhesion, mammalian target of rapamycin, epidermal growth factor receptor (erythroblastic leukemia viral oncogene homolog [ErbB]), and wingless-type MMTV integration site family (Wnt). The basal/HTC gene expression signature was essentially invisible within the context of nontumorigenic cell gene expression and overlapped significantly with genes driving progression and death in primary human UC. The spatially restricted epithelial differentiation program described here represents a conceptual advance in understanding cellular heterogeneity of carcinomas and identifies basal-like HTCs as attractive targets for cancer therapy. STEM CELLS 2009;27:1487–1495

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