title: Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression.
abstract: Bone metastasis is the major cause of morbidity and mortality of prostate cancer (PCa). Fibroblast growth factor 9 (FGF9) has been reported to promote PCa bone metastasis. However, the mechanism by which overexpression of FGF9 promotes PCa progression and metastasis is still unknown. Herein, we report that transgenic mice forced to express FGF9 in prostate epithelial cells (F9TG) developed high grade prostatic intraepithelial neoplasia (PIN) in an expression level- and time-dependent manner. Moreover, FGF9/TRAMP bigenic mice (F9TRAMP) grew advanced PCa earlier and had higher frequencies of metastasis than TRAMP littermates. We observed tumor microenvironmental changes including hypercellularity and hyperproliferation in the stromal compartment of F9TG and F9TRAMP mice. Expression of TGFβ1, a key signaling molecule overexpressed in reactive stroma, was increased in F9TG and F9TRAMP prostates. Both in vivo and in vitro data indicated that FGF9 promoted TGFβ1 expression via increasing cJun-mediated signaling. Moreover, in silico analyses showed that the expression level of FGF9 was positively associated with expression of TGFβ1 and its downstream signaling molecules in human prostate cancers. Collectively, our data demonstrated that overexpressing FGF9 in PCa cells augmented the formation of reactive stroma and promoted PCa initiation and progression.
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Chengliu
authors.initials: C
authors.lastname: Jin
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hamana
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Junchen
authors.initials: J
authors.lastname: Liu
authors.affiliation: 2. Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Wallace L
authors.initials: WL
authors.lastname: McKeehan
authors.affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA ; 2. Wenzhou Medical College, Wenzhou, Zhejiang, China ; 3. Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M, Health Science Center, College Station, TX, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology*
chemical_list: C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse
keywords: EMT; conditional gene knockout; fibroblast growth factor; prostate cancer progression; reactive stroma.; receptor tyrosine kinase