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2014 ; 13
(1
): 154-63
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Prostate progenitor cells proliferate in response to castration
#MMPMID24905440
Shi X
; Gipp J
; Dries M
; Bushman W
Stem Cell Res
2014[Jul]; 13
(1
): 154-63
PMID24905440
show ga
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 in the adult prostate 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 cells 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.