title: 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 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.
authors.affiliation: Department of Urology, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792, USA; Paul Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. Electronic address: shi@urology.wisc.edu.
authors.forename: Xudong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Urology, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792, USA; Paul Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Gipp
authors.affiliation: Paul Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dries
authors.affiliation: Department of Urology, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792, USA; Paul Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. Electronic address: bushman@urology.wisc.edu.
authors.forename: Wade
authors.initials: W
authors.lastname: Bushman
mesh_terms: D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011247:Pregnancy; D011467:Prostate / Q000166:cytology* / Q000601:surgery; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D013234:Stem Cells / Q000166:cytology*