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

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

Characterization and Clinical Relevance of ALDHbright Populations in Prostate Cancer

“…ALDH1A1þ cells have been proposed to be responsible for tumor re-initiation after castration (40,41). Our data, however, indicate that these cells are not likely associated with prognostic significance in CR prostate cancer, suggesting that ALDH1A1-negative cells might acquire a predominant clinical relevance following cancer progression to androgen independence.…”

Disseminated tumor cells and their prognostic significance in nonmetastatic prostate cancer patients

“…26 As suggested by Germann et al 27 stem-like cells in PCa have been implicated as tumor initiating and maintaining in men with PCa. In one of our future works, we will address this question with the help of a new capturing methods and a panel of markers covering EMT and stem cell-like features.…”

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…Additionally, in the BM18 xenograft model, preexisting CSCs, which are AR lo and co-express ALDH1A1 and/or NANOG, were selected by castration and could reinitiate CRPC tumor growth (Germann et al 2012). Most notably, Qin et al (2012) discovered a cell population with low expression of prostate specific antigen (PSA), a direct target gene of AR, within high-grade prostate tumors that exhibited a heightened self-renewal capacity.…”