Perinecrotic hypoxia contributes to ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases.
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.
van der Bilt
Jarmila D W
JD
Department of Surgery (G04.228), PO Box 85500, 3508 GA Utrecht, The Netherlands.
Soeters
Marije E
ME
Duyverman
Annique M M J
AM
Nijkamp
Maarten W
MW
Witteveen
Petronella O
PO
van Diest
Paul J
PJ
Kranenburg
Onno
O
Borel Rinkes
Inne H M
IH
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D000077868:Atrasentan; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000187:drug effects; D009336:Necrosis; D009368:Neoplasm Transplantation; D011759:Pyrrolidines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D016227:Benzoquinones; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D011759:Pyrrolidines; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D001120:Arginine; D000077868:Atrasentan