Cancer Stem Cells

Stem-Like Cells with Luminal Progenitor Phenotype Survive Castration in Human Prostate Cancer†‡§

  1. Markus Germann1,2,
  2. Antoinette Wetterwald1,2,
  3. Natalia Guzmán-Ramirez1,2,
  4. Gabri van der Pluijm3,
  5. Zoran Culig4,
  6. Marco G. Cecchini1,2,¶,*,
  7. Elizabeth D. Williams5,
  8. George N. Thalmann1,2

Article first published online: 15 MAY 2012

DOI: 10.1002/stem.1087

Issue

STEM CELLS

STEM CELLS

Volume 30, Issue 6, pages 1076–1086, June 2012

Additional Information

How to Cite

Germann, M., Wetterwald, A., Guzmán-Ramirez, N., van der Pluijm, G., Culig, Z., Cecchini, M. G., Williams, E. D. and Thalmann, G. N. (2012), Stem-Like Cells with Luminal Progenitor Phenotype Survive Castration in Human Prostate Cancer. STEM CELLS, 30: 1076–1086. doi: 10.1002/stem.1087

Author Information

  1. 1

    Department of Urology, University of Bern, Bern, Switzerland

  2. 2

    Department of Clinical Research, University of Bern, Bern, Switzerland

  3. 3

    Department of Urology, Leiden University Medical Center, Leiden, The Netherlands

  4. 4

    Department of Urology, Innsbruck Medical University, Innsbruck, Austria

  5. 5

    Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia

  1. Telephone: +41-31-632-2259; Fax: +41-31-632-0551

*Urology Research Laboratory, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland

  1. †

    Author contributions: M.G.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; A.W.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; N.G.-R.: collection and/or assembly of data; G.v.d.P.: conception and design and final approval of manuscript; Z.C.: revision and approval of manuscript; M.G.C.: conception and design, provision of study material, data analysis and interpretation, manuscript writing, and final approval of manuscript; E.D.W.: conception and design, provision of study material, and final approval of manuscript; G.N.T.: conception and design, provision of study material, data analysis and interpretation, and final approval of manuscript.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLSEXPRESS March 21, 2012.

  4. Telephone: +41-31-632-2259; Fax: +41-31-632-0551

Publication History

  1. Issue published online: 15 MAY 2012
  2. Article first published online: 15 MAY 2012
  3. Accepted manuscript online: 21 MAR 2012 02:36PM EST
  4. Manuscript Accepted: 26 FEB 2012
  5. Manuscript Revised: 21 FEB 2012
  6. Manuscript Received: 14 JUL 2011

Funded by

  • Oncosuisse
  • Grant identifier OCS-01752-08-2005
  • Sixth Framework Program of the European Community. Grant Number: identifier: PROMET-018858)
  • Swiss National Science Foundation. Grant Number: identifier: 31003A-116237
  • Australian National Health and Medical Research Council Career Development Award. Grant Number: NHMRC ID#519539
  • Victorian Government's Operational Infrastructure Support Program

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Keywords:

  • Ageing;
  • Prostate cancer;
  • Castration resistant;
  • Cancer stem cells;
  • Tumor-reinitiating cells;
  • Cancer cell dormancy;
  • Neuroendocrine cells

Abstract

Castration is the standard therapy for advanced prostate cancer (PC). Although this treatment is initially effective, tumors invariably relapse as incurable, castration-resistant PC (CRPC). Adaptation of androgen-dependent PC cells to an androgen-depleted environment or selection of pre-existing, CRPC cells have been proposed as mechanisms of CRPC development. Stem cell (SC)-like PC cells have been implicated not only as tumor initiating/maintaining in PC but also as tumor-reinitiating cells in CRPC. Recently, castration-resistant cells expressing the NK3 homeobox 1 (Nkx3-1) (CARNs), the other luminal markers cytokeratin 18 (CK18) and androgen receptor (AR), and possessing SC properties, have been found in castrated mouse prostate and proposed as the cell-of-origin of CRPC. However, the human counterpart of CARNs has not been identified yet. Here, we demonstrate that in the human PC xenograft BM18, pre-existing SC-like and neuroendocrine (NE) PC cells are selected by castration and survive as totally quiescent. SC-like BM18 cells, displaying the SC markers aldehyde dehydrogenase 1A1 or NANOG, coexpress the luminal markers NKX3-1, CK18, and a low level of AR (ARlow) but not basal or NE markers. These CR luminal SC-like cells, but not NE cells, reinitiate BM18 tumor growth after androgen replacement. The ARlow seems to mediate directly both castration survival and tumor reinitiation. This study identifies for the first time in human PC SC-/CARN-like cells that may represent the cell-of-origin of tumor reinitiation as CRPC. This finding will be fundamental for refining the hierarchy among human PC cancer cells and may have important clinical implications. STEM CELLS2012;30:1076–1086

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