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

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, CR...

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Published in:	Stem cells (Dayton, Ohio) Vol. 30; no. 6; pp. 1076 - 1086
Main Authors:	Germann, Markus, Wetterwald, Antoinette, Guzmán-Ramirez, Natalia, van der Pluijm, Gabri, Culig, Zoran, Cecchini, Marco G., Williams, Elizabeth D., Thalmann, George N.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-06-2012 Oxford University Press
Subjects:	Ageing Androgens Androgens - genetics Animals Cancer cell dormancy Cancer stem cells Castration Castration resistant Cell Line, Tumor Cell Survival - physiology Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - pathology Gene Expression Regulation, Neoplastic Genotype & phenotype Humans Immunohistochemistry Male Mice Mice, SCID Neoplastic Stem Cells - pathology Neuroendocrine cells Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms - surgery Survival Analysis Transplantation, Heterologous Tumor-reinitiating cells
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Summary:	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
Bibliography:	Oncosuisse Australian National Health and Medical Research Council Career Development Award - No. NHMRC ID#519539 ArticleID:STEM1087 First published online in STEM CELLSEXPRESS March 21, 2012. Sixth Framework Program of the European Community - No. identifier: PROMET-018858 Disclosure of potential conflicts of interest is found at the end of this article. Grant identifier OCS-01752-08-2005 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. Victorian Government's Operational Infrastructure Support Program Swiss National Science Foundation - No. identifier: 31003A-116237 istex:436C80EE3D4DF56083CC675A2EA8A2150501B7E1 ark:/67375/WNG-2J411Q6G-H First published online in S 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. C EXPRESS March 21, 2012. TEM Telephone: +41‐31‐632‐2259; Fax: +41‐31‐632‐0551 ELLS ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1066-5099 1549-4918
DOI:	10.1002/stem.1087