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

Abstract

Normal prostatic epithelium is composed of basal and luminal cells. Prostate cancer can be initiated in both benign basal and luminal stem cells, but because basal cell markers are not expressed in patient tumors, the former result was unexpected. Since the cells of origin of prostate cancer are important therapeutic targets, we sought to provide further proof that basal stem cells have tumorigenic potential. Prostatic basal cells were enriched based on a2b1integrin hi expression and further enriched for stem cells using CD133 in nontumorigenic BPH-1 cells. Human embryonic stem cells (hESCs) were also used as a source of normal stem cells. To test their tumorigenicity, we used two alternate stromal-based approaches; (a) recombination with human cancer-associated fibroblasts (CAFs) or (b) recombination with embryonic stroma (urogenital mesenchyme) and treated host mice with testosterone and 17b-estradiol. Enriched a2b1integrin hi basal cells from BPH-1 cells resulted in malignant tumor formation using both assays of tumorigenicity. Surprisingly, the tumorigenic potential did not reside in the CD133 1 stem cells but was consistently observed in the CD133 2 population. CAFs also failed to induce prostatic tumors from hESCs. These data confirmed that benign human basal cells include cells of origin of prostate cancer and reinforced their importance as therapeutic targets. In addition, our data suggested that the more proliferative CD133 2 basal cells are more susceptible to tumorigenesis compared to the CD133 1 -enriched stem cells. These findings challenge the current dogma that normal stem cells and cells of origin of cancer are the same cell type(s).

Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells

“…Our findings that basal cells are efficient cells of origin for human prostate cancer are consistent with previous findings by our group and others (15,16). These studies on the human disease have all used a tissue-regeneration approach to model development concomitant with tumorigenesis.…”

“…Naïve human prostate basal cells can initiate acinar-type adenocarcinoma in response to oncogenic stimulation (15). Consistent with these findings, basal cells from the BPH-1 human prostate cell line can initiate human prostate cancer in response to combined estrogen and testosterone treatment (16). These collective data suggest that human prostate tumors may set aside a subset of basal cells within the tumor to ensure continuous production of malignant luminal-like cancer cells.…”

New insights into prostate cancer stem cells

“…8 94 A recent report has shown that recombination of cancer-associated fibroblasts with integrin α2β1 hi human prostate basal cells (from non-tumorigenic BPH-1 cells) regenerates tumor grafts. 95 In summation, these results suggest that both human and murine prostate basal cells can serve as cells-of-origin for PCa.…”

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

“…Downregulation and hypermethylation of DAH genes are not associated with tumourigenic induction of prostate epithelial cells. To understand whether the downregulation and hypermethylation of DAH genes are strictly associated with prostate tumour formation, BPH-1 cells were recombined with either normal prostate fibroblasts (NPF -inducing normal growth) or cancer-associated fibroblasts (CAFinducing tumour formation) and grafted in the renal capsule of NOD-SCID mice 41 ( Figure 6a). BPH-1 þ CAF tumours exhibit squamous-like differentiation and do not express AR in their epithelial component.…”