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(American Journal of Pathology. 2007;170:1379-1388.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061028

Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

Jarmila D.W. van der Bilt*, Marije E. Soeters*, Annique M.M.J. Duyverman*, Maarten W. Nijkamp*, Petronella O. Witteveen{dagger}, Paul J. van Diest{ddagger}, Onno Kranenburg* and Inne H.M. Borel Rinkes*

From the Departments of Surgery,* Medical Oncology,{dagger} and Pathology,{ddagger} University Medical Center Utrecht, 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)-1{alpha}. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1{alpha} 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-1{alpha}, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and L-arginine minimized hypoxia and HIF-1{alpha} stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1{alpha} 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-1{alpha} stabilization. Prevention of tissue hypoxia or inhibition of HIF-1{alpha} may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery.




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