A luminal epithelial stem cell that is a cell of origin for prostate cancer

Abstract

In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3.1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells which express Nkx3.1 in the absence of testicular androgens (castration-resistant Nkx3.1-expressing cells, CARNs) are bipotential and can self-renew in vivo, while single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3.1 mutant mice in serial prostate regeneration assays suggest that Nkx3.1 is required for stem cell maintenance. Finally, targeted deletion of the Pten tumor suppressor gene in CARNs results in rapid formation of carcinoma following androgen-mediated regeneration. These observations indicate that CARNs represent a novel luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

“…More surprisingly, murine and human basal epithelial stem cells expressing high Trop2 and CD49f were also susceptible to malignant transformation [3,4]. Altogether, these exemplary studies demonstrated that both basal and luminal cell types contain potential cells of origin of prostate cancer [1,3].…”

“…In addition to this, Wang et al showed luminal stem cells (CARNs) are also a cell of origin of prostate cancer in mouse prostate [1]. While the existence of CARNs and their susceptibility to malignancy in human prostate is yet to be discerned, it is plausible that prostate cancer may arise from multiple benign cell types.…”

“…Although prostate cancer can arise from luminal (stem) cells [1,2], the concept that basal-enriched stem cells can also be cells of origin of prostate cancer is new and controversial [3,4]. In order to confirm that benign basal cells can be malignantly transformed, we used cells from the initiated but nontumorigenic BPH-1 epithelial cell line [20] that form tumors in recombination with tumor stroma (CAFs) [13].…”

“…In prostate cancer, this arrangement is disrupted, with an associated loss of cells with a basal cell phenotype. A minor luminal stem cell population was shown to be an efficient target for oncogenic transformation in mice [1], although this was not surprising given that mouse models of prostate cancer are commonly induced by luminal-specific promoters, including probasin and/or prostate-specific antigen (PSA) [2]. More surprisingly, murine and human basal epithelial stem cells expressing high Trop2 and CD49f were also susceptible to malignant transformation [3,4].…”

A plethora of progenitors in the post‐natal prostate

“…As the predominant histological subtype of prostate cancer acinar-type adenocarcinoma has a luminal phenotype, any cell type capable of generating a luminal phenotype under normal conditions is a candidate for generating luminal tumours during transformation. Both basal and luminal cells have been previously demonstrated to differentiate into luminal cells and initiate murine prostate cancer [1,3,4]. The study from the Blanpain lab suggests that several progenitors are capable of differentiation into luminal cells.…”