The Role of CD133 in Normal Human Prostate Stem Cells and Malignant Cancer-Initiating Cells

Abstract

Resolving the specific cell of origin for prostate cancer is critical to define rational targets for therapeutic intervention and requires the isolation and characterization of both normal human prostate stem cells and prostate cancer-initiating cells (CIC). Single epithelial cells from fresh normal human prostate tissue and prostate epithelial cell (PrEC) cultures derived from them were evaluated for the presence of subpopulations expressing stem cell markers and exhibiting stem-like growth characteristics. When epithelial cell suspensions containing cells expressing the stem cell marker CD133+ are inoculated in vivo, regeneration of stratified human prostate glands requires inductive prostate stromal cells. PrEC cultures contain a small subpopulation of CD133+ cells, and fluorescence-activated cell sorting–purified CD133+ PrECs self-renewand regenerate cell populations expressing markers of transit-amplifying cells (ΔNp63), intermediate cells (prostate stem cell antigen), and neuroendocrine cells (CD56). Using a series of CD133 monoclonal antibodies, attachment and growth of CD133+ PrECs requires surface expression of full-length glycosylated CD133 protein. Within a series of androgen receptor–positive (AR+) human prostate cancer cell lines, CD133+ cells are present at a low frequency, self-renew, express AR, generate phenotypically heterogeneous progeny negative for CD133, and possess an unlimited proliferative capacity, consistent with CD133+ cells being CICs. Unlike normal adult prostate stem cells, prostate CICs are AR+ and do not require functional CD133. This suggests that (a) AR-expressing prostate CICs are derived from a malignantly transformed intermediate cell that acquires “stem-like activity” and not from a malignantly transformed normal stem cell and (b) AR signaling pathways are a therapeutic target for prostate CICs.

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

“…The fact that CD133 À cells are more susceptible to malignancy does not negate the proof that CD133 þ identifies normal prostatic stem cells that are responsible for normal tissue replenishment [10,27] (Fig. 4B).…”

“…CD133 þ stem cells in human prostate tissues are growth quiescent, with longterm proliferative capacity and a high efficiency of establishing colonies in vitro and in vivo [10,12,27]. Primary human CD133 À basal cells are proliferative and also have the ability to form colonies, but they form fewer colonies over a shorter time period [10].…”

“…Nor does it disagree with the fact that CD133 þ isolates cancer repopulating cells within the tumor itself [12,27,31]. It does, however, raise the possibility that normal stem cells and cells of origin of cancer, within the basal compartment, are not necessarily the same cells, and the latter may involve rapidly proliferating or transient-amplifying cells within the basal cell fraction, as was originally postulated by Vander Griend et al [27]. Such phenotypic plasticity was also documented in leukemia, where a reserve of stem cells could be derived from an oncogenetically activated transient-amplifying cell [32].…”

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

“…Multi-drug resistance-ATP binding cassette (MDR-ABC) transporters potentially regulate prostate epithelial differentiation by mediating efflux of steroids [11,12]. In low-calcium, serum-free media, human prostate cells expressing stem cell markers CD133 and ABCG2 generate CD133 -/ABCG2 -transit amplifying and neuroendocrine cells, indicating that CD133 and ABCG2 expressing cells can differentiate into multiple lineages [13]. Moreover, transcriptome profiling of human prostate ABCG2 + cells showed stem cell gene expression pattern [14].…”

The complexities of identifying a cell of origin for human prostate cancer

“…6 Since the absence of p63 is used by pathologists to distinguished human tumours in specimen, 7 a compelling case has been made to exclude the basal cell type as being a cell of origin of prostatic carcinomas, until now.…”