FGF9 from cancer-associated fibroblasts is a possible mediator of invasion and anti-apoptosis of gastric cancer cells

Abstract

BackgroundCancer-associated fibroblasts (CAFs), which reside around tumor cells, are suggested to play a pivotal role in tumor progression. Here we performed microarray analyses to compare gene expression profiles between CAFs and non-cancerous gastric fibroblasts (NGFs) from a patient with gastric cancer and found that fibroblast growth factor 9 (FGF9) was a novel growth factor overexpressed in CAFs. We then examined the biological effects of FGF9 during progression of gastric cancer.MethodsExpression of FGF9 in CAFs and NGFs, and their secreted products, were examined by Western blotting. The effects of FGF9 on AGS and MKN28 gastric cancer cells in terms of proliferation, invasion and anti-apoptosis were assessed by WST-1 assay, invasion chamber assay and FACS, respectively. Furthermore, the intracellular signaling by which FGF9 exerts its biological roles was examined in vitro.ResultsFGF9 was strongly expressed in CAFs in comparison with NGFs, being compatible with microarray data indicating that FGF9 was a novel growth factor overexpressed in CAFs. Treatment with FGF9 promoted invasion and anti-apoptosis through activation of the ERK and Akt signaling pathways in AGS and MKN28 cells, whereas these effects were attenuated by treatment with anti-FGF9 neutralizing antibody. In addition, FGF9 treatment significantly enhanced the expression of matrix metalloproteinase 7 (MMP7) in both cell lines.ConclusionsFGF9 is a possible mediator secreted by CAFs that promotes the anti-apoptosis and invasive capability of gastric cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1353-3) contains supplementary material, which is available to authorized users.

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

“…In addition to the previously reported overexpression of Fgf2 and Fgfr2 , we also found that CAFs tended to overexpress Tgfb , Mmp7 , and Fgf9 (Figure A–E). When secreted, these CAF‐secreted factors have previously been shown to support the growth of various tumour types . As lung cancer and alveolar cells in our model both overexpress Fgf9 (and eGfp), we confirmed the absence of any contaminating epithelial cells within our CAF samples using flow cytometry (0% EpCAM + or GFP + cells) and thus confirmed that the CAFs in our model overexpress Fgf9 .…”

The anti-apoptotic and prognostic value of fibroblast growth factor 9 in gastric cancer

“…A previous study showed that FGF9 from cancer-associated fibroblasts may activate invasion ability of GC cells [28]. In our study, we found that knockdown of FGF9 resulted in reduced cell growth and induced apoptosis in GC.…”

FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells

“…Many reports have illustrated that FGF9 is essential for steroidogenesis and sex determination . However, abnormal expression of FGF9 is involved in different types of cancers . Studies have also shown that endogenous overexpression of FGF9 might cause lung adenocarcinoma, and microRNA‐140‐5p and microRNA‐26a could suppress FGF9 expression to reduce hepatocellular carcinoma and gastric cancer, respectively .…”

“…35 Studies have reported that FGF9 participates in palate formation, sex determination and lung development in the embryonic stage and has low expression levels under normal conditions in few adult organs. [36][37][38] However, abnormal expression of FGF9 might cause various cancer formations, [39][40][41][42] and the mechanisms remain elusive.…”