title: A role for CD95 signaling in ischemia/reperfusion-induced invasion and outgrowth of colorectal micrometastases in mouse liver.
abstract: BACKGROUND
  Ischemia/reperfusion (I/R) injury in the liver is associated with accelerated outgrowth of micrometastases. The aim of the study was to test the role of CD95 signaling in accelerated outgrowth of colorectal liver metastases following I/R.
  
  
  METHODS
  Mice underwent vascular clamping 5 days after induction of colorectal liver metastases. Invasion and outgrowth of micrometastases following I/R were analyzed by post-mortem confocal microscopy (36 hr post-I/R) and by morphometric assessment of tumor load (5 days post-I/R), respectively. Tumor cell CD95 was suppressed by lentiviral RNA interference. The contribution of host CD95L was assessed by using gld-mice lacking functional CD95L.
  
  
  RESULTS
  CD95-knockdown in tumor cells strongly reduced perinecrotic invasion (tumor diameter from ∼830 to ∼470 µm) and largely prevented outgrowth acceleration of perinecrotic liver metastases following I/R (from ∼8- to ∼4.5-fold). In gld-mice, the relative hepatic area with necrosis was markedly reduced. Perinecrotic tumor cell clusters still displayed an invasive phenotype (tumor diameter of ∼980 µm). However, I/R-induced acceleration of tumor outgrowth was reduced in gld-mice from ∼8- to ∼5-fold.
  
  
  CONCLUSIONS
  I/R induces invasion and accelerated outgrowth of preestablished metastases in a CD95-dependent manner. Activation of the CD95 system following I/R not only contributes to liver injury, but may also promote aggressive tumor recurrence.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Maarten W
authors.initials: MW
authors.lastname: Nijkamp
authors.forename: Frederik J H
authors.initials: FJ
authors.lastname: Hoogwater
authors.forename: Klaas M
authors.initials: KM
authors.lastname: Govaert
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.forename: Andre
authors.initials: A
authors.lastname: Verheem
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel Rinkes
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D019014:fas Receptor