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, Paul J. Van Diest, Onno Kranenburg, Inne H.M.Borel Rinkes

Research output: Contribution to journalArticle

Abstract

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)-1α. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1α 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-1α, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and L-arginine minimized hypoxia and HIF-1α stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1α 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-1α stabilization. Prevention of tissue hypoxia or inhibition of HIF-1α may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery.

Original languageEnglish (US)
Pages (from-to)1379-1388
Number of pages10
JournalAmerican Journal of Pathology
Volume170
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Van Der Bilt, J. D. W., Soeters, M. E., Duyverman, A. M. M. J., Nijkamp, M. W., Witteveen, P. O., Van Diest, P. J., Kranenburg, O., & Rinkes, I. H. M. B. (2007). Perinecrotic hypoxia contributes to ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. American Journal of Pathology, 170(4), 1379-1388. https://doi.org/10.2353/ajpath.2007.061028