Hepatic ischemia-reperfusion increases vascular endothelial growth factor and cancer growth in rats.
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.
Tamagawa
Koji
K
Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. hanil@ommc-hp.jp
Horiuchi
Tetsuya
T
Uchinami
Masaru
M
Doi
Koji
K
Yoshida
Makoto
M
Nakamura
Tomoaki
T
Sasaki
Hisashi
H
Taniguchi
Masanobu
M
Tanaka
Kuniyoshi
K
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
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