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


METHODS
Expression 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.


RESULTS
FGF9 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.


CONCLUSIONS
FGF9 is a possible mediator secreted by CAFs that promotes the anti-apoptosis and invasive capability of gastric cancer cells.
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. tianjinsunchao@hotmail.com.|Department of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, China. tianjinsunchao@hotmail.com.
Chao
C
Sun
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. hfukui@hyo-med.ac.jp.
Hirokazu
H
Fukui
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. k-hara@hyo-med.ac.jp.
Ken
K
Hara
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. 24167653@qq.com.|Department of Geriatric Digestive Internal Medicine, Sichuan Academy of Medical Science & Sichuan People's Hospital, Chengdu, China. 24167653@qq.com.
Xinxing
X
Zhang
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. yoshi-77@hcm-mail.hyo-med.ac.jp.
Yoshitaka
Y
Kitayama
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. eda@hyo-med.ac.jp.
Hirotsugu
H
Eda
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. tomita@hyo-med.ac.jp.
Toshihiko
T
Tomita
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. t-oshima@hyo-med.ac.jp.
Tadayuki
T
Oshima
Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan. skikuchi@hyo-med.ac.jp.
Shojiro
S
Kikuchi
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. watarij@hyo-med.ac.jp.
Jiro
J
Watari
Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan. msasako@hyo-med.ac.jp.
Mitsuru
M
Sasako
Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan. miwahgi@hyo-med.ac.jp.
Hiroto
H
Miwa
D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D051525:Fibroblast Growth Factor 9 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D057134:Antibodies, Neutralizing; D014408:Biomarkers, Tumor; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7