title: Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis.
abstract: BACKGROUND
  It has been determined that the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1) regulate several key processes in a wide variety of cancers. However, the function and mechanism of the SDF-1/CXCR4 system in the metastasis of colorectal cancer remain controversial.
  
  
  METHODS
  Immunohistochemistry was performed to examine quantitatively the expression of CXCR4 in 40 human samples of colorectal cancer and liver metastasis. The functions of SDF-1 on HCT116 colon cancer cells were investigated in vitro. We subcutaneously inoculated HCT116 cells with hepatic stellate cells (HSCs) expressing SDF-1. The CXCR4 inhibitor AMD3100 was tested in vitro and in vivo.
  
  
  RESULTS
  By quantitatively counting the number of cells, it was shown that there are more CXCR4-positive cells at the metastatic site in the liver compared with the primary sites. We demonstrated the effect of SDF-1 on the invasion and antiapoptosis of HCT116 cells in vitro. In mouse experiment of liver metastasis, intraperitoneal administration of AMD3100 blocked the metastatic potential of HCT116 cells. Furthermore, we found that alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts derived from HSCs, surrounding the liver metastasis foci, secreted SDF-1. The subcutaneous inoculation of HCT116 cells with HSCs promoted the tumor initiation in nude mice, indicating the importance of the direct interaction between these cells in vivo.
  
  
  CONCLUSIONS
  These results suggest that HSCs play important role in liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis and provide preclinical evidence that blockade of the axis is a target for antimetastasis therapy.
authors: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. tphrd840@ybb.ne.jp
authors: Ryo
authors: R
authors: Matsusue
authors: Hajime
authors: H
authors: Kubo
authors: Shigeo
authors: S
authors: Hisamori
authors: Kae
authors: K
authors: Okoshi
authors: Hidekazu
authors: H
authors: Takagi
authors: Koya
authors: K
authors: Hida
authors: Keiko
authors: K
authors: Nakano
authors: Atsushi
authors: A
authors: Itami
authors: Kenji
authors: K
authors: Kawada
authors: Satoshi
authors: S
authors: Nagayama
authors: Yoshiharu
authors: Y
authors: Sakai
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D004797:Enzyme-Linked Immunosorbent Assay; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4