title: Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.
abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/-)) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/-) mice, compared with WT mice. Impaired tumor development in IL-6(-/-) mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
authors.affiliation: Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Ryota
authors.initials: R
authors.lastname: Takahashi
authors.forename: Wachiko
authors.initials: W
authors.lastname: Nakata
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakitani
authors.forename: Takako
authors.initials: T
authors.lastname: Serizawa
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Masao
authors.initials: M
authors.lastname: Akanuma
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000378:metabolism*; D008770:Methylnitrosourea; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D017077:Culture Media, Conditioned; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D008770:Methylnitrosourea