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.
Copyright © 2011 Wiley-Liss, Inc.