title: The niche component periostin is produced by cancer-associated fibroblasts, supporting growth of gastric cancer through ERK activation.
abstract: Overexpression of periostin (POSTN), an extracellular matrix protein, has been observed in several cancers. We investigated the importance of POSTN in gastric cancer. Genome-wide gene expression analysis using publicly available microarray data sets revealed significantly high POSTN expression in cancer tissues from stage II-IV gastric cancer, compared with background normal tissues. The POSTN/vimentin mRNA expression ratio was highly associated with gene groups that regulate the cell cycle and cell proliferation. IHC showed that periglandular POSTN deposition, comprising linear deposition abutting the glandular epithelial cells in normal mucosa, disappeared during intestinal gastric cancer progression. Stromal POSTN deposition was also detected at the invasive front of intestinal-type and diffuse-type cancers. In situ hybridization confirmed POSTN mRNA in cancer-associated fibroblasts, but not in tumor cells themselves. POSTN enhanced the in vitro growth of OCUM-2MLN and OCUM-12 diffuse-type gastric cancer cell lines, accompanied by the activation of ERK. Furthermore, coinoculation of gastric cancer cells with POSTN-expressing NIH3T3 mouse fibroblast cells facilitated tumor formation. The OCUM-2MLN orthotopic inoculation model demonstrated that tumors of the gastric wall in Postn(-/-) mice were significantly smaller than those in wild-type mice. Ki-67 and p-ERK positive rates were both lower in Postn(-/-) mice. These findings suggest that POSTN produced by cancer-associated fibroblasts constitutes a growth-supportive microenvironment for gastric cancer.
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kunita
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Caname
authors.initials: C
authors.lastname: Iwata
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Komura
authors.affiliation: Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishiyama
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimazu
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Shibahara
authors.affiliation: Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Morishita
authors.affiliation: Department of Surgical Oncology, Medical School, Osaka City University, Osaka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Surgical Oncology, Medical School, Osaka City University, Osaka, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.affiliation: Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kudo
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: mfukayama-tky@umin.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi G
authors.initials: TG
authors.lastname: Kashima
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; C082838:Postn protein, mouse; D016212:Transforming Growth Factor beta; D014746:Vimentin