title: Site-specific fibroblasts regulate site-specific inflammatory niche formation in gastric cancer.
abstract: BACKGROUND
  Fibroblasts are the commonest type of cancer stromal cells. Inflammation occurs in cancer tissue, and the inflammatory process has been suggested to be caused by interactions between immune cells and cancer cells. In this study, we clarified that site-specific fibroblasts regulate the formation of a site-specific inflammatory niche according to the depth of gastric cancer cell invasion.
  
  
  METHODS
  Immunohistochemistry was performed with paraffin-embedded tissues. The numbers of immune cells and the fibroblast area were calculated according to the cancer depth. The gene expression patterns of submucosal fibroblasts and subperitoneal fibroblasts stimulated with HSC44PE-conditioned medium were analyzed with a microarray. To examine the effects on the cancer microenvironment of differences in gene expressions between HSC44PE-stimulated submucosal fibroblasts and subperitoneal fibroblasts, assays of HSC44PE proliferation, T cell migration, and M2-like macrophage differentiation were performed.
  
  
  RESULTS
  The distributions of immune cells differed between the submucosal layer and the subserosal layer. The number of M2 macrophages was significantly higher and the fibroblast area was significantly larger in the subserosal layer compared with the submucosal layer. High expression levels of IL1B, TNFSF15, and CCL13 were observed in HSC44PE-stimulated submucosal fibroblasts, and higher expression levels of TGFB2, CSF1, CCL8, and CXCL5 were found in HSC44PE-stimulated subperitoneal fibroblasts. HSC44PE-stimulated subperitoneal fibroblast medium promoted the differentiation of monocytes into M2-like macrophages, whereas HSC44PE-stimulated submucosal fibroblasts significantly induced the migration of Jurkat cells and the growth of HSC44PE cells.
  
  
  CONCLUSIONS
  The dynamic states of immune cells differ between the submucosal and subserosal layers in cancer tissues. Site-specific fibroblasts regulate site-specific inflammatory niche formation according to the depth of cancer cell invasion.
authors.affiliation: Laboratory of Cancer Biology, Department of Integrated Bioscience, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba, Japan.|Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Abe
authors.affiliation: Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Akiko Kawano
authors.initials: AK
authors.lastname: Nagatsuma
authors.affiliation: Laboratory of Cancer Biology, Department of Integrated Bioscience, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba, Japan.|Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Laboratory of Cancer Biology, Department of Integrated Bioscience, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba, Japan. aochiai@east.ncc.go.jp.|Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. aochiai@east.ncc.go.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005347:Fibroblasts / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: Fibroblasts; Gastric cancer; Immune cells; Inflammation; Inflammatory niche