Stem cells in prostate cancer: treating the root of the problem

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   Figure 1

   Cellular identity of prostate stem cells. The prostate in composed of stromal and epithelial compartments that communicate through reciprocal communication. The epithelium consists of several identifiable cell types, including basal, intermediate, luminal, and neuroendocrine cells that have defining cytokeratin (CK) profiles and differing androgen receptor (AR) expression. Putative stem cells are identified in the AR⁻ basal compartment, based on sorting for cell surface markers including CD133, CD117, Sca-1, Trop2, and CD49f, or in the luminal compartment where AR⁺ castrate-resistant Nkx3-1-expressing cells (CARN) reside.
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   Figure 2

   Models of prostate stem cell hierarchies: based on functional and ontological studies, several different models of differentiation hierarchy for putative prostatic stem cells are proposed. (A) Linear hierarchical arrangement: prostatic stem cells are postulated to reside in the basal cell layer, based on functional studies using markers including CD117, Sca-1, Trop2, CD49f, and CD133. In this model, basal cells self-renew, give rise to progenitor (or transit amplifying cells; also basal phenotype), followed by intermediate cells and then terminally differentiated luminal or neuroendocrine cells in a linear manner. (B) Nonlinear hierarchical arrangement: a second differentiation model is proposed where a common stem cell gives rise to a lineage-specific progenitors, which then give rise to distinct cell lineages of basal, luminal, and neuroendocrine cells. This model is most similar to that proven for mammary stem cell differentiation. In the prostate, epithelial cells with an intermediate phenotype (i.e co-expressing markers of both basal and luminal cells) are proposed to house this common stem cell. (C) Independent arrangement: most recently, the identification of luminal stem cells (CARN; based on Nkx3-1 expression) was demonstrated using expression of Nkx3-1 in castrate-resistant prostate tissues. This discovery raises the possibility of multiple stem cells within the epithelium that independently gives rise to distinct cell lineages including basal, luminal, and neuroendocrine cells. This model does not exclude the possibility that basal and/or luminal stem cells can be multipotent and generate the opposing lineage as well.
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   Figure 3

   Prostate cancer-repopulating cells. In localized, androgen-dependent prostate cancer (left panel), cancer-repopulating cells (CRCs) are proposed to be a rare subpopulation distinguishable from the bulk of the tumor by their ability to survive treatment and regenerate tumor mass. The identity of these cells is less defined than that of in other solid tumors, but CD133 is postulated to enrich prostate cancer CRCs. The expression status of AR in human CD133⁺ CRCs remains under debate, but the tumor bulk is AR⁺ and is therefore androgen dependent. After failed front line therapies (i.e. radical prostatectomy or radiotherapy), patients commonly undergo androgen deprivation therapy (ADT). Recurrent disease after this treatment leads to castrate-resistant prostate cancer. In these tumors, the residual cancer cells gain the ability to adapt the androgen-depleted environment and synthesize their own androgens de novo in order to mediate and maintain cancer cell survival and growth. It is unknown whether the adaptive ability is common to all cancer cells or restricted to CRCs from the earlier stage tumor.

• © 2010 Society for Endocrinology