Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer

Germann, Markus; Wetterwald, Antoinette; Guzmán-Ramirez, Natalia; van der Pluijm, Gabri; Culig, Zoran; Cecchini, Marco G; Williams, Elizabeth D; Thalmann, George N (2012). Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem cells, 30(6), pp. 1076-86. Durham: AlphaMed Press 10.1002/stem.1087

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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 (AR(low)) but not basal or NE markers. These CR luminal SC-like cells, but not NE cells, reinitiate BM18 tumor growth after androgen replacement. The AR(low) 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology

UniBE Contributor:

Thalmann, George

ISSN:

1066-5099

Publisher:

AlphaMed Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:38

Last Modified:

06 Dec 2013 13:37

Publisher DOI:

10.1002/stem.1087

PubMed ID:

22438320

Web of Science ID:

000304087300005

URI:

https://boris.unibe.ch/id/eprint/15434 (FactScience: 222779)

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