Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

Pinyol, Roser; Torrecilla, Sara; Wang, Huan; Montironi, Carla; Piqué-Gili, Marta; Torres‐Martín, Miguel; Leow, Wei Qiang; Willoughby, Catherine E.; Ramadori, Pierluigi; Andreu-Oller, Carmen; Taik, Patricia; Lee, Youngmin A.; Moeini, Agrin; Peix, Judit; Faure-Dupuy, Suzanne; Riedl, Tobias; Schuehle, Svenja; Oliveira, Cláudia Pinto Marques Souza de; Alves, Venâncio Avancini Ferreira; Boffetta, Paolo; Lachenmayer, Anja; Roessler, Stephanie; Mínguez, Beatriz; Schirmacher, Peter; Dufour, Jean‐François; Thung, Swan N.; Reeves, Helen L.; Carrilho, Flair José; Chang, Charissa; Uzilov, Andrew; Heikenwälder, Mathias; Sanyal, Arun J.; Friedman, Scott L.; Sia, Daniela; Llovet, Josep M.

doi:10.1016/j.jhep.2021.04.049

Cited by 153 publications

(135 citation statements)

References 46 publications

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“…In a diet-induced NASH-HCC murine model, CD8 T cells not only lacked effective immune surveillance functions but also promoted HCC development (48). In humans, whole-exome sequencing of NASH-driven HCC liver shows an increased hepatic T cell accumulation and an enrichment of gene signatures associated with T lymphocytes (112). In this study, the cirrhotic NASH-driven HCC cases displayed common features of immune exhaustion, a state of dysfunction commonly associated with chronic T cell stimulation by tumor antigens (112).…”

Section: T Cells In Nash-associated Hepatocellular Carcinomamentioning

confidence: 99%

“…In humans, whole-exome sequencing of NASH-driven HCC liver shows an increased hepatic T cell accumulation and an enrichment of gene signatures associated with T lymphocytes (112). In this study, the cirrhotic NASH-driven HCC cases displayed common features of immune exhaustion, a state of dysfunction commonly associated with chronic T cell stimulation by tumor antigens (112). Mechanistically, it has been shown that inactivation of T cell protein tyrosine phosphatase (TCPTP) in hepatocytes can drive STAT-1 and STAT-3-dependent gene expression of T cell chemoattractants such as CXCL9 that promote T cell recruitment (113).…”

Section: T Cells In Nash-associated Hepatocellular Carcinomamentioning

confidence: 99%

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Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.

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Section: T Cells In Nash-associated Hepatocellular Carcinomamentioning

confidence: 99%

Section: T Cells In Nash-associated Hepatocellular Carcinomamentioning

confidence: 99%

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

et al. 2021

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“…Moreover, these cells showed activated Hedgehog and Yap pathways, mainly involved in the control of energy expenditure and maintenance of myofibroblastic traits [ 21 ]. Finally, it has recently demonstrated that HSCs from carriers of the homozygous PNPLA3 I148M variant were characterized by signatures of defective DNA repair, reduced TP53 signaling and oxidative stress, contributing to the development of hepatic carcinogenesis [ 22 ].…”

Section: Common Genetic Variations Promote the Switch From Nash To Hccmentioning

confidence: 99%

“…ACVR2A gene encodes for a cytokine receptor involved in cell differentiation and proliferation whose downregulation has been associated with poorer outcome in colorectal cancers thus suggesting it may act as tumor suppressor also in HCC [ 70 ]. Finally, the authors found that the tumor mutational burden was higher in non-cirrhotic NASH-HCC than in cirrhotic ones [ 22 ]. Intriguingly, NASH-HCC showed a unique tumor signature characterized by bile and fatty acid signaling, oxidative stress, inflammation, and mitochondrial dysfunction and in patients who carried the PNPLA3 I148M variant it was enriched in defective pathways of DNA repair and reduced TP53 signaling, thus reinforcing the role of this polymorphism in HCC development.…”

Section: The Pathogenic Role Of Rare Genetic Variants In Nafld-hcc Developmentmentioning

confidence: 99%

Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC

2021

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Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.

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“…A list of the most frequent mutations influencing cellular metabolism is here reported in Table 1. However, in liver cancer, not only the genomic landscape but also the immune characteristics of transforming cells frequently define the microenvironment that dictates a distinct metabolic profile of the tumor as, for instance, in the case of NASH-related HCC [6]. In turn, metabolites produced by cancer cells generate a permissive immune-microenvironment for favorable growing conditions.…”

Section: Introductionmentioning

confidence: 99%

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Fan

Kam

Ramadori

2021

Cancers

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Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

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Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

Cited by 153 publications

References 46 publications

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

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