title: Suppressed prostate epithelial development with impaired branching morphogenesis in mice lacking stromal fibromuscular androgen receptor.
abstract: Using the cre-loxP system, we generated a new mouse model [double stromal androgen receptor knockout (dARKO)] with selectively deleted androgen receptor (AR) in both stromal fibroblasts and smooth muscle cells, and found the size of the anterior prostate (AP) lobes was significantly reduced as compared with those from wild-type littermate controls. The reduction in prostate size of the dARKO mouse was accompanied by impaired branching morphogenesis and partial loss of the infolding glandular structure. Further dissection found decreased proliferation and increased apoptosis of the prostate epithelium in the dARKO mouse AP. These phenotype changes were further confirmed with newly established immortalized prostate stromal cells (PrSC) from wild-type and dARKO mice. Mechanistically, IGF-1, placental growth factor, and secreted phosphoprotein-1 controlled by stromal AR were differentially expressed in PrSC-wt and PrSC-ARKO. Moreover, the conditioned media (CM) from PrSC-wt promoted prostate epithelium growth significantly as compared with CM from PrSC-dARKO. Finally, adding IGF-1/placental growth factor recombinant proteins into PrSC-dARKO CM was able to partially rescue epithelium growth. Together, our data concluded that stromal fibromuscular AR could modulate epithelium growth and maintain cellular homeostasis through identified growth factors.
authors.affiliation: George H Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Kuo-Pao
authors.initials: KP
authors.lastname: Lai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Spencer
authors.initials: S
authors.lastname: Vitkus
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D004848:Epithelium / Q000254:growth & development*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D009929:Organ Size; D019899:Paracrine Communication; D010750:Phosphoproteins / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D011467:Prostate / Q000033:anatomy & histology / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; C000608037:Pgf protein, mouse; D010750:Phosphoproteins; D011257:Pregnancy Proteins; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D000072483:Placenta Growth Factor; D007334:Insulin-Like Growth Factor I