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Int J Biol Sci 2015; 11(8):948-960. doi:10.7150/ijbs.12468 This issue Cite

Research Paper

Overexpression of FGF9 in Prostate Epithelial Cells Augments Reactive Stroma Formation and Promotes Prostate Cancer Progression

Yanqing Huang¹, Chengliu Jin^1#, Tomoaki Hamana¹, Junchen Liu¹, Cong Wang², Lei An¹, Wallace L. McKeehan¹, Fen Wang^1,2,3✉

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.
^# Current address: Transgenic and Gene Targeting Core, Georgia State University, Atlanta, GA, USA

✉ Corresponding author: Fen Wang, Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030-3303. E-mail: fwangtamhsc.edu

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.

Keywords: fibroblast growth factor, receptor tyrosine kinase, conditional gene knockout, prostate cancer progression, EMT, reactive stroma.

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