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Background & Aims There is growing evidence that liver graft ischemia-reperfusion (I/R) is a risk factor for hepatocellular carcinoma (HCC) recurrence, but the mechanisms involved are unclear. Herein, we tested the hypothesis that mesenteric congestion resulting from portal blood flow interruption induces endotoxin-mediated Toll-like receptor 4 (Tlr4) engagement, resulting in elevated liver cancer burden. We also assessed the role of remote ischemic preconditioning (RIPC) in this context. Methods C57Bl/6j mice were exposed to standardized models of liver I/R injury and RIPC, induced by occluding the hepatic and femoral blood vessels. HCC was induced by injecting RIL-175 cells into the portal vein. We further evaluated the impact of the gut–liver axis (lipopolysaccharide (LPS)-Tlr4 pathway) in this context by studying mice with enhanced (lipopolysaccharide infusion) or defective (Tlr4−/− mice, gut sterilization, and Tlr4 antagonist) Tlr4 responses. Results Portal triad clamping provoked upstream mesenteric venous engorgement and increased bacterial translocation, resulting in aggravated tumor burden. RIPC prevented this mechanism by preserving intestinal integrity and reducing bacterial translocation, thereby mitigating HCC recurrence. These observations were linked to the LPS-Tlr4 pathway, as supported by the high and low tumor burden displayed by mice with enhanced or defective Tlr4 responses, respectively. Conclusions Modulation of the gut–liver axis and the LPS-Tlr4 response by RIPC, gut sterilization, and Tlr4 antagonism represents a potential therapeutic target to prevent I/R lesions, and to alleviate HCC recurrence after liver transplantation and resection. Lay summary Cancer recurrence can occur after liver resection or liver transplantation for hepatocellular carcinoma (HCC). This study suggests that intestinal venous congestion, which often occurs during liver surgery, favors the translocation of gut-derived bacterial products in the portal vein, thereby facilitating cancer recurrence by enhancing the signaling of Toll-like receptor 4 in the liver. Using a mouse model of HCC recurrence, we show that strategies that (i) reduce bacterial translocation (by gut decontamination, or by protecting the intestine from venous ischemia damage) or (ii) inhibit Tlr4 signaling in the liver, could reduce cancer recurrence.

Background and Aims: Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in 10–15% of patients. To date, studies assessing the risk of post-transplant HCC recurrence have focused on recipients’ characteristics. Here, we investigate the impact of donor characteristics and liver graft quality on the risk of post-liver transplantation HCC recurrence. Methods: Using the Scientific Registry of Transplant Recipients (SRTR), we included adult patients granted with an exception for HCC diagnosis and receiving a liver transplant between 2004 and 2011. Post-transplant HCC recurrence was determined by using malignancy follow-up data and scrutinizing causes of death files (as validated by Samoylova ML et al. Liver Transplant 2013). A multivariate Cox proportional-hazards regression was fitted, evaluating the role of donor characteristics on the risk of posttransplant HCC recurrence, after adjusting for confounding factors such as tumour size and number, AFP and transplant centre. Results: 9724 recipients were included. The 5-year cumulative recurrence rate was 7.8% (95%CI: 7.2–8.5). After adjusting for confounders, patients receiving a graft from a donor older than 60 years (hazard ratio (HR) 1.42, 95%CI: 1.16–1.74, p = 0.001), a donor with a history of diabetes (HR 1.48, 95%CI: 1.18–1.86, p = 0.001) and a donor with obesity class II (body mass index >35kg/m) or more (HR 1.32, 95%CI: 1.03–1.70, p = 0.027), had significantly higher post-transplant HCC recurrence rates. The proportionalhazards Shoenfeld’s residuals test P value was 0.619. Conclusions: In addition to tumour characteristics, donor-related factors such as elevated donor age, increasing body mass index, and diabetes should be taken into account when predicting the risk of post-liver transplant HCC recurrence.