van der Bilt JD, Soeters ME, Duyverman AM, Nijkamp MW, Witteveen PO, van Diest PJ, Kranenburg O, Borel Rinkes IH.

Department of Surgery (G04.228), PO Box 85500, 3508 GA Utrecht, The Netherlands. 

Ischemia/reperfusion (I/R) is often inevitable during hepatic surgery and may stimulate the outgrowth of colorectal micrometastases. Postischemic microcirculatory disturbances contribute to I/R damage and may induce prolonged tissue hypoxia and consequent stabilization of hypoxia-inducible factor (HIF)-1alpha. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1alpha to I/R-accelerated tumor growth. Partial hepatic I/R attributable to temporary clamping of the left liver lobe induced microcirculatory failure for up to 5 days. This was accompanied by profound and prolonged perinecrotic tissue hypoxia, stabilization of HIF-1alpha, and massive perinecrotic outgrowth of pre-established micrometastases.

Restoration of the microcirculation by treatment with Atrasentan and L-arginine minimized hypoxia and HIF-1alpha stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1alpha by the HSP90 inhibitor 17-DMAG caused an increase in tissue necrosis but reduced I/R-stimulated tumor growth by more than 70%. In conclusion, prevention of postischemic microcirculatory disturbances and perinecrotic hypoxia reduces the accelerated outgrowth of colorectal liver metastases after I/R. This may, at least in part, be attributed to the prevention of HIF-1alpha stabilization. Prevention of tissue hypoxia or inhibition of HIF-1alpha may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery. 

American Journal of Pathology. 2007 Apr;170(4):1379-88.