title: Hepatic ischemia-reperfusion increases vascular endothelial growth factor and cancer growth in rats.
abstract: BACKGROUND
  In liver surgery, the hepatic pedicle often is clamped to reduce blood loss, and later unclamped, representing hepatic ischemia and reperfusion (I/R) with induction of hypoxia. Vascular endothelial growth factor (VEGF) expression reportedly is induced by hypoxia; further, some cancer cells express the VEGF receptor (flt-1, flk-1/KDR). We hypothesized that I/R-induced VEGF expression could enhance growth of microscopic tumor via VEGF receptors on tumor cells, thus promoting liver metastasis in a rat model.
  
  
  METHODS
  Time-dependent VEGF expression in liver and plasma was determined by enzyme-linked immunosorbent assay in rats subjected to 60 min of 70% hepatic I/R (I/R group). Other rats given an intrasplenic inoculation of a rat colon adenocarcinoma cell line (RCH-H4) were divided 3 days later into three groups: group A, untreated; group B, sham operation; group C, 70% I/R for 60 min. Liver metastasis was evaluated on day 14. Expression of flt-1 and flk-1/KDR was examined in RCN-H4 cells, and effects of exogenous VEGF on RCN-H4 cell proliferation were determined by MTT assays.
  
  
  RESULTS
  Hepatic VEGF expression increased significantly in the I/R group compared to the control group. Liver metastasis was more extensive in group C than in groups A and B. RCN-H4 cells expressed flt-1 and flk-1/KDR, while exogenous VEGF increased RCN-H4 cell proliferation.
  
  
  CONCLUSIONS
  Hepatic ischemia reperfusion leads to induction of VEGF and this is associated with increased tumor burden in an animal model of colon cancer metastasis.
authors.affiliation: Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. hanil@ommc-hp.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Tamagawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Masaru
authors.initials: M
authors.lastname: Uchinami
authors.forename: Koji
authors.initials: K
authors.lastname: Doi
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Masanobu
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000503:physiopathology* / Q000556:secondary*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2