Basal epithelial stem cells are efficient targets for prostate cancer initiation

Abstract

Prevailing theories suggest that luminal cells are the origin of prostate cancer because it is histologically defined by basal cell loss and malignant luminal cell expansion. We introduced a series of genetic alterations into prospectively identified populations of murine basal/stem and luminal cells in an in vivo prostate regeneration assay. Stromal induction of FGF signaling, increased expression of the ETS family transcription factor ERG1, and constitutive activation of PI3K signaling were evaluated. Combination of activated PI3K signaling and heightened androgen receptor signaling, which is associated with disease progression to androgen independence, was also performed. Even though luminal cells fail to respond, basal/stem cells demonstrate efficient capacity for cancer initiation and can produce luminal-like disease characteristic of human prostate cancer in multiple models. This finding provides evidence in support of basal epithelial stem cells as one target cell for prostate cancer initiation and demonstrates the propensity of primitive cells for tumorigenesis.

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

“…However, the ''initiation events'' were the basis for their selection as the epithelial source for these studies, since this instability facilitates induction of malignancy in response to CAFs and/or hormonal carcinogenesis; normal epithelial cells from primary specimens are not susceptible to carcinogenesis using these assays [13,38]. While there are key differences between BPH-1 cells and primary epithelial cells, including the methylation of the CD133, with silencing of up to 50% of BPH-1 cells [39], our data are supported by several previous studies in mice [4] and in primary human cells [3] showing that basal cells are a cell of origin of prostate cancer. In our study, we have extended these initial findings to further subfractionate the basal population and show the CD133 À cells are susceptible to tumorigenesis.…”

“…Most importantly, the finding that cells of origin of prostate cancer reside in the basal compartment is consistent with findings in human and murine tissues by Witte and coinvestigators who used high expression of Trop2 and CD49f to enrich for prostatic basal cells [3,4,33]. 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].…”

“…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].…”

“…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]. Altogether, these exemplary studies demonstrated that both basal and luminal cell types contain potential cells of origin of prostate cancer [1,3].…”

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

“…Generally, it is believed that basal cells are likely the cellular origin of prostate cancer 3,4,10,11 . However, it is also known that prostate cancer always displays a remarkable luminal phenotype including the amplification of luminal cells rather than basal cells and overproduction of luminal-derived prostate-specific protein (PSA) 12,13 .…”