title: Diffuse-type gastric cancer cells switch their driver pathways from FGFR2 signaling to SDF1/CXCR4 axis in hypoxic tumor microenvironments.
abstract: Cancer-associated fibroblasts (CAFs) have been considered to play an important role for tumor progression of cancer. Solid tumors contain heterogeneous distribution of oxygen in their microenvironments. This study investigated the growth signaling of gastric cancer (GC) cells in focus on the interaction with CAFs and GC cells under normoxia and hypoxia. Four diffuse-type GC cell lines, two intestinal-type GC cell lines and three CAF cell lines were used. Cells were examined for expression of C-X-C chemokine receptor 4 (CXCR4), fibroblast growth factor receptor 2 (FGFR2) and stromal-derived factor 1 (SDF1) by RT-PCR, western blot, ELISA and immunohistochemical staining of xenografted tumors. GC cell proliferation was examined under hypoxia in the presence or absence of CAFs, a FGFR2 inhibitor, a CXCR4 inhibitor and HIF1α siRNA. Proliferation of diffuse-type GC cells, but not intestinal-type GC cells, was significantly increased by CAFs. CXCR4 expression by diffuse-type GC cells was significantly increased in hypoxia, while FGFR2 expression was decreased. CXCR4 expression was correlated with hypoxic microenvironment of xenografted tumor, but FGFR2 expression was not. FGFR2 inhibition significantly decreased the growth-stimulating activity of CAFs for diffuse-type GC cells in normoxia. In contrast, CXCR4 inhibition significantly decreased the growth-stimulating activity of CAFs in hypoxia. SDF1 production by CAFs was increased in hypoxia, while cancer cells did not produce SDF1. HIF1 siRNA significantly decreased both CXCR4 expression by diffuse-type GC cells and SDF1 production by CAFs. These findings suggest that diffuse-type GC cells might switch their driver pathways from FGFR2 signaling to SDF1/CXCR4 axis through HIF1 in hypoxic tumor microenvironments.
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Haruhito
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Surgical Oncology and Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan m9312510@med.osaka-cu.ac.jp.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Tatsunari
authors.initials: T
authors.lastname: Fukuoka
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Tamami
authors.initials: T
authors.lastname: Morisaki
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kasashima
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Go
authors.initials: G
authors.lastname: Masuda
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noda
authors.affiliation: Department of Surgical Oncology and.
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: C527276:CXCR4 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D017978:Receptors, Growth Factor; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2