Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases--activation of cell invasion and migration pathways.
Elucidating the mechanism of liver tumor growth and metastasis after hepatic ischemia-reperfusion (I/R) injury of a small liver remnant will lay the foundation for the development of therapeutic strategies to target small liver remnant injury, and will reduce the likelihood of tumor recurrence after major hepatectomy or liver transplantation for liver cancer patients. In the current study, we aimed to investigate the effect of hepatic I/R injury of a small liver remnant on liver tumor development and metastases, and to explore the precise molecular mechanisms. A rat liver tumor model that underwent partial hepatic I/R injury with or without major hepatectomy was investigated. Liver tumor growth and metastases were compared among the groups with different surgical stress. An orthotopic liver tumor nude mice model was used to further confirm the invasiveness of the tumor cells from the above rat liver tumor model. Significant tumor growth and intrahepatic metastasis (5 of 6 vs. 0 of 6, P=0.015), and lung metastasis (5 of 6 vs. 0 of 6, P=0.015) were found in rats undergoing I/R and major hepatectomy compared with the control group, and was accompanied by upregulation of mRNA levels for Cdc42, ROCK (Rho kinase), and vascular endothelial growth factor, as well as activation of hepatic stellate cells. Most of the nude mice implanted with liver tumor from rats under I/R injury and major hepatectomy developed intrahepatic and lung metastases. In conclusion, hepatic I/R injury of a small liver remnant exacerbated liver tumor growth and metastasis by marked activation of cell adhesion, invasion, and angiogenesis pathways.
Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China. kwanman@hkucc.hku.hk
Kwan
K
Man
Kevin T
KT
Ng
Chung Mau
CM
Lo
Joanna W
JW
Ho
Bai Shun
BS
Sun
Chris K
CK
Sun
Terence K
TK
Lee
Ronnie T P
RT
Poon
Sheung Tat
ST
Fan
D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006498:Hepatectomy / Q000009:adverse effects*; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011915:Rats, Inbred BUF; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054460:rho-Associated Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein