Lorenzo A Orci1, Stéphanie Lacotte2, Vaihere Delaune3, Florence Slits2, Graziano Oldani3, Vladimir Lazarevic4, Carlo Rossetti5, Laura Rubbia-Brandt6, Philippe Morel3, Christian Toso3. 1. Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: lorenzo.orci@hcuge.ch. 2. Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 3. Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4. Genomic Research Laboratory, Geneva University Hospitals, Geneva, University of Geneva, Switzerland. 5. Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese, Italy. 6. Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Abstract
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 & 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.
Authors: Hui Liu; Chang Chun Ling; Wai Ho Oscar Yeung; Li Pang; Jiang Liu; Jie Zhou; Wei Yi Zhang; Xiao Bing Liu; Tak Pan Kevin Ng; Xin Xiang Yang; Chung Mau Lo; Kwan Man Journal: Cell Death Dis Date: 2021-05-14 Impact factor: 8.469
Authors: Kevin Tak-Pan Ng; Oscar Wai-Ho Yeung; Yin Fan Lam; Jiang Liu; Hui Liu; Li Pang; Xin Xiang Yang; Jiye Zhu; Weiyi Zhang; Matthew Y H Lau; Wen Qi Qiu; Hoi Chung Shiu; Man Kit Lai; Chung Mau Lo; Kwan Man Journal: Cell Death Discov Date: 2021-07-21