Prostate cancer stem cells 41 Origin of PCSCs

The origin of PCSCs continues to stay as a controversial issue. Different cells in origin may generate clinically relevant subtypes with different prognosis and outcome. There are two possible cell origin resources in PC: the basal and luminal cell-of-origin.

4.1.1. Basal cell-of-origin

Much stronger studies came from several independent laboratories that used different PC models to support the view that basal stem cells provide the cell-of-origin for PC. When CD49fhiTrop2hi cells were selected from the basal fraction, transfected with Akt/Erg vectors and transplanted to induce initiation of prostatic intraepithelial neoplasia [57]; these basal cells derived from primary benign human prostate tissue initiated PC in immunodeficient mice [24]. It was also reported that Lin'Sca-1+CD49fhi cells isolated from the basal fraction of murine prostate produced luminal-like disease characteristics of human PC after transplan tation [58]. Recently, Norman J. Maitland and colleagues reported that selected cells with basal phenotypes are tumor initiating and basal SCs are the source of a luminal progeny [23]. In addition, a small population of TRA-1-60+ CD151+ CD166+ tumor initiating cells (TICs) isolated from human prostate xenograft tumors exhibited stem-like cell characteristics and recapitulated the cellular hierarchy of the original tumor in serial xenotransplanta-tion experiments [59]. Moreover, these cells expressed basal cell markers and showed increased Nuclear factor-KB (NF-kB) signaling.

4.1.2. Luminal cell-of-origin

Luminal cells are believed to be the cells of origin for human PC, because the disease is characterized by AR+ luminal cell expansion. That is why pathologists diagnose PC based on the absence of basal cell markers. It is known, that rare luminal cells which express the homeo-box gene Nkx3.1 in the absence of testicular androgens (castration-resistant Nkx3.1-express-ing cells, CARNs) are bipotential with self-renewal capability in vivo [60]. Single-cell transplantation of CARNs can reconstitute prostate ducts in renal grafts. Besides, targeted deletion of PTEN in CARNs results in rapid formation of carcinoma following androgen-mediated regeneration. Hanneke Korsten and colleagues [61] showed that genetic alterations are first seen in a subset of luminal cells expressing the progenitor markers TROP2 and SCA-1, implying that the luminal cells are the cell-of-origin in this model.

The reason why the origin of PC and the cell type of origin remains a controversial issue is in part of the distinct functional assays that were employed. Furthermore, since PC is a very heterogeneous disease it is plausible that different PCs are derived from different originating cell types.

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