Prostate progenitor cells proliferate in response to castration

Abstract

Androgen-deprivation is a mainstay of therapy for advanced prostate cancer but tumor regression is usually incomplete and temporary because of androgen-independent cells in the tumor. It has been speculated that these tumor cells resemble the stem/progenitor cells of the normal prostate. The purpose of this study was to examine the response of slow-cycling progenitor cells in the adult mouse prostate to castration. Proliferating cells in the E16 urogenital sinus were pulse labeled by BrdU administration or by doxycycline-controlled labeling of the histone-H2B GFP mouse. A small population of labeled epithelial cells localized at the junction of the prostatic ducts and urethra. Fluorescence-activated cell sorting (FACS) showed that GFP label-retaining cells were enriched for cells co-expressing stem cell markers Sca-1, CD133, CD44 and CD117 (4- marker cells; 60-fold enrichment). FACS showed, additionally, that 4-marker cells were androgen receptor positive. Castration induced proliferation and dispersal of E16 labeled cells into more distal ductal segments. When naïve adult mice were administered BrdU daily for 2 weeks after castration, 16% of 4-marker exhibited BrdU label in contrast to only 6% of all epithelial cells (P<0.01). In sham-castrated controls less than 4% of 4-marker cells were BrdU labeled (P<0.01). The unexpected and admittedly counter-intuitive finding that castration induced progenitor cell proliferation suggests that androgen deprivation therapy in men with advanced prostate cancer could not only exert pleiotrophic effects on tumor sub-populations but may induce inadvertent expansion of tumor stem cells.

Prostate cancer downregulated SIRP-α modulates apoptosis and proliferation through p38-MAPK/NF-κB/COX-2 signaling

“…The primary mechanisms for the conversion of ADPC into AIPC are variations in gene expression, signal pathway abnormity, dysregulation of proto-oncogenes, cancer suppressor genes and growth factors (4,5). Thus far, a number of relevant genes and signal pathways in CaP have been described (6).…”

Isolation and analysis of discreet human prostate cellular populations

“…To better understand the castration-resistant cell types capable of regenerating prostate epithelium, a number of cell surface markers have recently been discovered that enrich for prostate stem cell activity including α2β1 integrin, CD49f, CD44, TROP2, CD133, CD117, CD338, and Sca-1 (mice only) (Garraway et al, 2010, Goldstein et al, 2010, Goldstein et al, 2008, Guo et al, 2012, Lawson et al, 2007, Lawson et al, 2010, Leong et al, 2008, Lukacs et al, 2010, Mulholland et al, 2009, Richardson et al, 2004, Shi et al, 2014, Xin et al, 2005, Xin et al, 2007). Fractions with these markers are enriched for cells that display increased clonogenicity, serial passaging as spheroids, and tissue regenerative capacity as xenografted recombinants with inductive urogenital sinus mesenchyme.…”

Downregulated microRNA-26a modulates prostate cancer cell proliferation and apoptosis by targeting COX-2

“…The primary reasons for ADPC becoming AIPC are gene expression variation, signal pathway abnormity, and dysregulation of proto-oncogenes, cancer suppressor genes and growth factors (4). At present, studies have identified a large number of relevant genes and signal pathways of prostate cancer (5)(6)(7). However, since the biological behavior of prostate cancer is extremely complex, any of the aforementioned hypotheses cannot clarify the pathogenetic mechanism of AIPC (6).…”