title: Bone marrow derived "fibrocytes" contribute to tumor proliferation and fibrosis in gastric cancer.
abstract: BACKGROUND
  Cancer-associated fibroblasts (CAFs) in the stroma are considered to play important roles for gastric cancer proliferation, invasion, and fibrosis, but the source of CAFs and their interaction with cancer cells in the microenvironment have not been fully determined. Here we elucidated the role of bone marrow-derived cells, fibrocytes, in development of gastric cancers, as represented by scirrhous gastric cancer.
  
  
  METHODS
  In co-culturing MKN45 gastric cancer cells and purified fibrocytes from healthy volunteers, migration and endothelial mesenchymal transition associated gene expression were evaluated using western blot analysis. Also, mouse xenograft models of MKN45 with or without fibrocytes were conducted to investigate their tumorigenicity and immunohistological differences of tumors.
  
  
  RESULTS
  Co-culture of fibrocytes with MKN45 resulted in morphological changes from cobblestone-shape to spindle-shape and enhanced expression of α-SMA and collagen type I in fibrocytes, suggesting that co-culture with gastric cancer cells may have induced the differentiation of fibrocytes to myofibroblasts. Furthermore, enhanced expression of SDF-1 in MKN45 and CXCR4 in fibrocytes were also determined. Mouse xenograft models inoculated with MKN45 and fibrocytes revealed significantly larger tumors than those inoculated with MKN45 cells alone, and the stroma in co-inoculated tumors consisted of myofibroblasts and fibrosis. Mouse-derived cells expressing both CD45 and type I collagen were also observed in co-inoculated tumors.
  
  
  CONCLUSIONS
  Fibrocytes derived from bone marrow may migrate into the microenvironment of gastric cancer by SDF-1/CXCR4 system, and enhance the tumor proliferation and fibrosis as CAFs.
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Terai
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tsukada
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Isamu
authors.initials: I
authors.lastname: Makino
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000503:physiopathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4