The strongest evidence for the clonal selection model of CRPC comes from the CSC hypothesis. CSCs are a minority of tumor cells capable of self-renewal and differentiation.[16, 92-97] The putative pre-existing castration-resistant cells alluded to by the clonal selection model share the same characteristics with prostate CSCs. The CSC model proposes that cells within a tumor are heterogeneous and exist in a hierarchical lineage relationship with different proliferative potentials. The concept was first described and became well established in acute myeloid leukemia, and to date it remains the prototype against which others are judged. However, CSCs, unlike normal stem cells, differentiate and self-renew in a dysregulated manner.
CSCs have been identified in solid tumors including prostate cancer. Collins et al. isolated from prostate cancer prostatectomy specimens and characterized putative prostate CSCs (CD44+, 2β1hi+, CD133+) with self-renewal properties for the first time. They estimated that approximately 0.1% of tumor cells showed this phenotype. Subsequent studies provided further evidence that tumorigenic stem cells are responsible for prostate cancer initiation, and progression to androgen-independence and resistance to cell death.[92, 96, 100] The putative prostate CSCs are thought to arise from multilineage stem cells, which either develop this capacity by accumulation of genetic alterations over time[93, 97, 101, 102] or as an alternative hypothesis, might be the result of an arrest of differentiation in stem cell development.[94, 103] These cells are thought to constitute a minority of the prostate cancer cells and remain so as the tumor progresses. Only after ADT are they selected for their growth and survival advantage (castration-resistance), and proliferate to predominate as CRPC. Facilitated by new tools, such as transgenic mouse and lineage tracing, a number of recent studies have provided further evidence that corroborates the clonal selection model. By lineage tracking, Wang et al. identified a small population of luminal cells in the mouse prostate known as CARN, which have survived androgen depletion and express NKX3-1. When androgen is restored in the mice, CARN can give rise to basal, luminal and neuroendocrine cells in prostate regeneration assay. Furthermore, when PTEN is deleted in these cells, they can form carcinomas. They thus concluded that CARN can serve as cells of origin of prostate cancer. That study provides direct evidence for the existence of castration resistant cell clones, but also raises the questions of whether CARN exist in the prostate before castration and whether the human prostate also contains CARN. To address these questions, Germann et al. took advantage of the human prostate cancer BM18 xenograft model which is highly castration-sensitive and identified CRSC with properties similar to CARN. CRSCs express luminal markers including NKX3-1, CK18 and a low level of AR, and can reinitiate tumor growth after androgen restoration. That study thus shows the existence of CARN in human prostate cancer cells, which might be responsible for the development of CRPC. We expect that future studies will provide additional proof for the existence of CARN in primary prostate cancer, and settle the debate once and for all.