Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases.
BACKGROUND
Ischemia/reperfusion (I/R) injury is frequently encountered during hepatic surgery. We recently showed that I/R accelerates the outgrowth of pre-established colorectal micrometastases. The aim of this study was to assess the influence of ischemia time, gender, age, and liver steatosis on the accelerated outgrowth of colorectal metastases following I/R.


METHODS
Five days after tumor cell inoculation, mice were subjected to 20, 30 or 45 min of left lobar I/R. To assess the influence of age, gender, and liver steatosis on I/R-accelerated tumor growth, we compared old with young mice, male with female mice, and mice with healthy livers with mice with steatotic livers. Endpoints were extent of tissue necrosis and tumor growth.


RESULTS
With increasing ischemia times, tissue necrosis and I/R-accelerated tumor growth increased, with a significant stimulatory effect at 30 and 45 min of ischemia. I/R-stimulated outgrowth of micrometastases was further increased by 33% in aged mice and by 42% in steatotic livers and was associated with increased tissue necrosis. In female mice tissue necrosis had decreased by 47% and tumor growth was reduced in both control and clamped liver lobes. The stimulatory effect of I/R on metastasis outgrowth was similar in male and female mice.


CONCLUSIONS
I/R-accelerated outgrowth of colorectal micrometastases largely depends on the duration of the ischemic period, with a safe upper limit of 20 min in mice. The stimulatory effects of I/R on tumor growth are exacerbated in aged mice and in steatotic livers.
van der Bilt
Jarmila D W
JD
Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
Kranenburg
Onno
O
Borren
Alie
A
van Hillegersberg
Richard
R
Borel Rinkes
Inne H M
IH
D000375:Aging / Q000502:physiology*; D000818:Animals; D015179:Colorectal Neoplasms / Q000209:etiology*; D005234:Fatty Liver / Q000150:complications*; D005260:Female; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D015427:Reperfusion Injury / Q000209:etiology*