PROSTATE CANCER STEM CELLS
123
mature
androgen ablation
transit
stem normal
malignant
FIGURE 7.5 Stem cell model of normal tissue renewal and prostate cancer. The malignant stem cell arises from transformation of the normal stem cell and gives rise to more differentiated progeny. Androgen ablation induces apoptosis of the androgen-dependent mature cells, and the resulting overproduction of malignant stem cells and their progenitors imparts an undifferentiated appearance to the tumor unless androgen-receptor signaling in these cells is reactivated via alternative pathways. (From refs. 92 to 94.)
colony-forming efficiency compared to an unselected population, demonstrating the increased proliferative capacity of this fraction. There is no significant difference between the primary and secondary colony-forming efficiency of the stem cell fraction, which emphasizes its high self-renewal ability. CD44C /α2 β1 hi /CD133 cells, the putative transit-amplifying population, in contrast, exhibit a significantly lower capacity for self-renewal. CD44C /α2 β1 hi /CD133C cells selected from prostate tumors are considerably more invasive in vitro than stem cells selected from benign prostate, which complies with a cancer stem cell phenotype. Similar to stem cells from normal prostate, they express HMW keratins 5 and 14 as well as cytokeratin 19. Expression of the differentiation markers’ androgen receptor and prostatic acid phosphatase can, however, be induced by incubation in the presence of serum and androgen in vitro, indicating that prostate cancer stem cells can differentiate to a luminal phenotype and therefore recapitulate the differentiation program that is seen in the original tumor. CD44C /α2 β1 hi /CD133C cells have proven highly tumorigenic in preliminary experiments with NOD/SCID mice (A. Collins; unpublished observations). Serial transplantation studies are currently under way to demonstrate the ability of the putative prostate cancer stem cells to give rise repeatedly to phenocopies of the original tumor.