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Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression.

Huang Y, Jin C, Hamana T, Liu J, Wang C, An L, McKeehan WL, Wang F - Int. J. Biol. Sci. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Overexpression of FGF9 promotes PCa metastasis in mice. A. Kaplan-Meier analysis of metastasis-free time in TRAMP and F9TRAMP mice. B. In situ hybridization showing Fgf9 expression in lymph node metastases of F9TRAMP and TRAMP tumors. C. Immunostaining of the indicated proteins in lymph node metastases of F9TRAMP and TRAMP tumors. Scale bars, 50 µm.
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Figure 4: Overexpression of FGF9 promotes PCa metastasis in mice. A. Kaplan-Meier analysis of metastasis-free time in TRAMP and F9TRAMP mice. B. In situ hybridization showing Fgf9 expression in lymph node metastases of F9TRAMP and TRAMP tumors. C. Immunostaining of the indicated proteins in lymph node metastases of F9TRAMP and TRAMP tumors. Scale bars, 50 µm.

Mentions: To determine whether F9TRAMP tumors were more metastatic, we then examined the metastatic tumors in F9TRAMP and TRAMP mice at the times of sacrifice. Most of the metastatic loci were located in lymph node, liver, and kidney. The metastasis-free curve and log-rank test (P<0.05) showed that F9TRAMP mice (n=54) developed metastases earlier than TRAMP mice (n=39) (Fig. 4A). Moreover, the frequency of metastasis was higher in F9TRAMP mice than in TRAMP mice at all inspection times. In situ hybridization showed that Fgf9 mRNA was expressed in metastatic PCa cells in both F9TRAMP and TRAMP mice but not adjacent non-cancerous tissues (Fig. 4Ba,b). The metastatic PCa cells in both strains expressed AR and T-antigens (Fig. 4Bc-f). Intriguingly, most of the metastatic tumors were synaptophysin positive and P63 negative (Fig. 4Bg-j). This indicates the presence of neuroendocrine differentiation in metastatic tumors, which is frequently observed in advance human PCa.


Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression.

Huang Y, Jin C, Hamana T, Liu J, Wang C, An L, McKeehan WL, Wang F - Int. J. Biol. Sci. (2015)

Overexpression of FGF9 promotes PCa metastasis in mice. A. Kaplan-Meier analysis of metastasis-free time in TRAMP and F9TRAMP mice. B. In situ hybridization showing Fgf9 expression in lymph node metastases of F9TRAMP and TRAMP tumors. C. Immunostaining of the indicated proteins in lymph node metastases of F9TRAMP and TRAMP tumors. Scale bars, 50 µm.
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Related In: Results  -  Collection

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Figure 4: Overexpression of FGF9 promotes PCa metastasis in mice. A. Kaplan-Meier analysis of metastasis-free time in TRAMP and F9TRAMP mice. B. In situ hybridization showing Fgf9 expression in lymph node metastases of F9TRAMP and TRAMP tumors. C. Immunostaining of the indicated proteins in lymph node metastases of F9TRAMP and TRAMP tumors. Scale bars, 50 µm.
Mentions: To determine whether F9TRAMP tumors were more metastatic, we then examined the metastatic tumors in F9TRAMP and TRAMP mice at the times of sacrifice. Most of the metastatic loci were located in lymph node, liver, and kidney. The metastasis-free curve and log-rank test (P<0.05) showed that F9TRAMP mice (n=54) developed metastases earlier than TRAMP mice (n=39) (Fig. 4A). Moreover, the frequency of metastasis was higher in F9TRAMP mice than in TRAMP mice at all inspection times. In situ hybridization showed that Fgf9 mRNA was expressed in metastatic PCa cells in both F9TRAMP and TRAMP mice but not adjacent non-cancerous tissues (Fig. 4Ba,b). The metastatic PCa cells in both strains expressed AR and T-antigens (Fig. 4Bc-f). Intriguingly, most of the metastatic tumors were synaptophysin positive and P63 negative (Fig. 4Bg-j). This indicates the presence of neuroendocrine differentiation in metastatic tumors, which is frequently observed in advance human PCa.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.

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.

No MeSH data available.


Related in: MedlinePlus