The Role of Hepatic Ischemia-Reperfusion Injury and Liver Parenchymal Quality on Cancer Recurrence

Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside” approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence

Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation

Background & Aims Liver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation – ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. Methods HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10min or 30min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping. Results I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10min and 30min ISC recipients ( p =0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs ( p =0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1 , Hif1a and Serpine1 . Conclusions This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval

Liver immune microenvironment from normal liver to hepatocellular carcinoma

Due to its specific location and functions, the liver is a primary target for blood alterations. In spite of its regenerative abilities allowing it to avoid major acute injury, chronic damages induce pathological changes. The incidence of non-alcoholic fatty liver disease (NAFLD) correlates with the increase in the worldwide obesity epidemic. NAFLD can worsen with the induction of inflammation, leading to the initiation of non-alcoholic steatohepatitis (NASH). These characteristic chronic liver diseases can promote the growth of hepatocellular carcinoma (HCC) for which the only available curative treatments are resection and transplantation

Comprendre, cibler et éliminer les lymphocytes B autoréactifs au cours du lupus (Vers une application thérapeutique des nanotubes de carbone comme vecteurs de peptides bioactifs)

Le lupus érythémateux disséminé est connu comme un syndrome impliquant les lymphocytes B. Nous avons donc imaginé une stratégie thérapeutique délétant spécifiquement les cellules B autoréactifs et basée sur l'utilisation des nanotubes de carbone servant à covectoriser deux types de molécules: l'une dérivée d'un autoantigène majeur de la réponse lupique permet le ciblage des cellules à éliminer via leur récepteur antigénique de surface, l'autre possédant une activité apoptogène induit la mort des cellules. J'ai validé l'utilisation de nanotubes de carbone fonctionnalisés comme vecteurs, car sans impact sur le système immunitaire in vitro. La région Nterminale de l'histone H2B est reconnue par les autoanticorps des souris lupiques et est impliquée dans la pathologie. Elle sera donc la molécule cible. Des plasmocytes exprimant le récepteur CXCR3 et produisant des IgG pathogènes ont été caractérisé et sont capables de migrer dans les reins pour contribuer à la destruction de l'organe.Systemic lupus erythematosus is considered as a B cells disease. Therefore, we decided to design an therapeutic strategy aiming at specifically suppressing pathogenic autoreactive B lymphocytes. This strategy is based on the use of carbon nanotubes in order to deliver two types of molecules: one is a peptide derived from a major lupus autoantigen and will allow us to target B cells to be eliminated via their antigen surface receptor; the other one will harbor a proapoptotic activity, leading to cell death. The use of functionalized carbon nanotube as carrier has been validated because of their absence of effect on immune cells in vitro. The Nterminal region of histone H2B represents a preferential target for autoantibodies in lupus mice and is implicated in the development of lupus pathology. It will be the target molecule. I could highlight CXCR3expressing, pathogen IgGproducing plasma cell population that can migrate in the inflamed kidneys where they can contribute to lesions.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Anti-CD122 antibody restores specific CD8+ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth

AbstractDOI: 10.1080/2162402X.2023.218499

Chimeric xenotransplantation

Organ transplantation is an effective treatment for selected patients with end-stage organ disease or specific cancer types. Its main limitations are the chronic lack of grafts and the lifetime need for immunosuppression. The advent of autologous organs generated into xenogeneic species has the potential to solve these issues

Portosystemic shunting prevents hepatocellular carcinoma in non-alcoholic fatty liver disease mouse models (2)

Abstractdata package

Portosystemic shunting prevents hepatocellular carcinoma in non-alcoholic fatty liver disease mouse models (3)

Abstractdata package