Warm hepatic ischemia-reperfusion promotes growth of colorectal carcinoma micrometastases in mouse liver via matrix metalloproteinase-9 induction.
Surgical resection remains the best treatment for colorectal metastases isolated to the liver; however, 5-year survival rates following liver resection are only 40% to 50%, with liver recurrence being a significant reason for treatment failure. The ischemia-reperfusion (I/R) injury incurred during liver surgery can lead to cellular dysfunction and elevations in proinflammatory cytokines and matrix metalloproteinases (MMP). In rodents, I/R injury to the liver has been shown to accelerate the outgrowth of implanted tumors. The mechanism for increased tumor growth in the setting of liver I/R injury is unknown. To investigate the effect of I/R on tumor growth, an experimental model was used whereby small hepatic metastases form after 28 days. Mice subjected to 30 min of 70% liver ischemia at the time of tumor inoculation had significantly larger tumor number and volume, and had elevated MMP9 serum and liver tissue MMP9 as evidenced by zymography and quantitative real-time PCR. Mice treated with doxycycline, a broad-spectrum MMP inhibitor, had reduced MMP9 levels and significantly smaller tumor number and volume in the liver. MMP9-null mice were used to determine if the effects of doxycycline were due to the absence of stromal-derived MMP9. The MMP9-null mice, with or without doxycycline treatment, had reduced tumor number and volume that was equivalent to wild-type mice treated with doxycycline. These findings indicate that hepatic I/R-induced elevations in MMP9 contribute to the growth of metastatic colorectal carcinoma in the liver and that postresection MMP9 inhibition may be clinically beneficial in preventing recurrence following hepatic surgery.
Nicoud
Ian B
IB
Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4753, USA.
Jones
Christopher M
CM
Pierce
Janene M
JM
Earl
T Mark
TM
Matrisian
Lynn M
LM
Chari
Ravi S
RS
Gorden
D Lee
DL
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D004318:Doxycycline / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015424:Reperfusion / Q000009:adverse effects / Q000379:methods; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline