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Cell Death, Inflammation, and Liver Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 33507

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Special Issue Editors

Dr. Vangelis Kondylis

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Guest Editor

Institute for Pathology and Centre for Molecular Medicine, University Hospital of Cologne, 50937 Cologne, Germany
Interests: cell death; RIP kinases; NF-κB signaling; autophagy; inflammatory liver disease; hepatocarcinogenesis; mouse genetics

Prof. Dr. Mathias Heikenwälder

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Guest Editor

Department Chronic inflammation and Cancer, German Cancer research Center (DKFZ), 69120 Heidelberg, Germany
Interests: HCC; iCC; metabolic reprogramming; immunotherapy; NASH; ASH

Special Issue Information

Dear Colleagues,

Liver cancer typically arises in the presence of inflammatory liver diseases and has been intrinsically linked to chronic inflammation-induced cell death (necro-inflammation). While apoptosis is a well-established driver of hepatocarcinogenesis, other types of programmed cell death, including necroptosis, pyroptosis, and ferroptosis, have been recently associated with liver disease progression, cancer development, and cancer plasticity. How each form of cell death shapes quantitative and qualitative aspects of inflammatory responses and eventually leads to liver cancer has just started to be unraveled. Necroptosis, for instance, may induce a distinct cytokine microenvironment that favors development of intrahepatic cholangiocarcinoma, instead of hepatocellular carcinoma. The release of specific cytokines or danger associated molecular patterns (DAMPs), such as HMGB1, from immune or dying cells can fuel inflammation-driven activation of hepatic stellate cells and hepatic progenitors. Moreover, distinct metabolic environments might affect the type of cell death, tumor surveillance, and treatment response. Along this line, triggering immunogenic cell death and anti-tumor immune responses in established liver tumors are currently considered as promising therapeutic options.

This Special Issue will highlight basic and more (pre)clinical aspects of the role of cell death and inflammation in liver cancer that will advance our understanding of the underlying molecular complexity. We therefore invite colleagues to submit their contributions and exciting findings on the topic.

Dr. Vangelis Kondylis
Prof. Dr. Mathias Heikenwälder
Guest Editors

Manuscript Submission Information

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Keywords

hepatocarcinogenesis
hepatitis
inflammatory microenviroment
liver damage
programmed cell death
HCC
iCC
cancer immunotherapy
mouse models

Published Papers (10 papers)

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Research

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25 pages, 8865 KiB

Open AccessArticle

p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation

by Vangelis Kondylis, Farina Schneider, Fabian Schorn, Nikos Oikonomou, Beate Katharina Straub, Sabine Werner, Philip Rosenstiel and Manolis Pasparakis

Cancers 2022, 14(10), 2436; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102436 - 15 May 2022

Viewed by 2599

Abstract

SQSTM1/p62 is a multitasking protein that functions as an autophagy receptor, but also as a signaling hub regulating diverse cellular pathways. p62 accumulation in mice with autophagy-deficient hepatocytes mediates liver damage and hepatocarcinogenesis through Nrf2 overactivation, yet the role of the p62-Keap1-Nrf2 axis in cell death and hepatocarcinogenesis in the absence of underlying autophagy defects is less clear. Here, we addressed the role of p62 and Nrf2 activation in a chronic liver disease model, namely mice with liver parenchymal cell-specific knockout of NEMO (NEMO^LPC-KO), in which we demonstrate that they show no inherent autophagy impairment. Unexpectedly, systemic p62 ablation aggravated the phenotype and caused early postnatal lethality in NEMO^LPC-KO mice. Expression of a p62 mutant (p62ΔEx2-5), which retains the ability to form aggregates and activate Nrf2 signaling, did not cause early lethality, but exacerbated hepatocarcinogenesis in these mice. Our immunohistological and molecular analyses showed that the increased tumor burden was only consistent with increased expression/stability of p62ΔEx2-5 driving Nrf2 hyperactivation, but not with other protumorigenic functions of p62, such as mTOR activation, cMYC upregulation or increased fibrosis. Surprisingly, forced activation of Nrf2 per se did not increase liver injury or tumor burden in NEMO^LPC-KO mice, suggesting that autophagy impairment is a necessary prerequisite to unleash the Nrf2 oncogenic potential in mice with autophagy-competent hepatocytes. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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20 pages, 3632 KiB

Open AccessArticle

HELLS Is Negatively Regulated by Wild-Type P53 in Liver Cancer by a Mechanism Involving P21 and FOXM1

by Stefanie Schuller, Jan Sieker, Philip Riemenschneider, Bianca Köhler, Elisabeth Drucker, Sofia M. E. Weiler, Daniel Dauch, Carsten Sticht, Benjamin Goeppert, Stephanie Roessler, Silvia Ribback, Kai Breuhahn, Falko Fend, Frank Dombrowski, Kerstin Singer and Stephan Singer

Cancers 2022, 14(2), 459; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020459 - 17 Jan 2022

Cited by 5 | Viewed by 3033

Abstract

The major tumor suppressor P53 (TP53) acts primarily as a transcription factor by activating or repressing subsets of its numerous target genes, resulting in different cellular outcomes (e.g., cell cycle arrest, apoptosis and senescence). P53-dependent gene regulation is linked to several aspects of chromatin remodeling; however, regulation of chromatin-modifying enzymes by P53 is poorly understood in hepatocarcinogenesis. Herein, we identified Helicase, lymphoid specific (HELLS), a major epigenetic regulator in liver cancer, as a strong and selective P53 repression target within the SNF2-like helicase family. The underlying regulatory mechanism involved P53-dependent induction of P21 (CDKN1A), leading to repression of Forkhead Box Protein M1 (FOXM1) that in turn resulted in downregulation of HELLS expression. Supporting our in vitro data, we found higher expression of HELLS in murine HCCs arising in a Trp53−/− background compared to Trp53+/+ HCCs as well as a strong and highly significant correlation between HELLS and FOXM1 expression in different HCC patient cohorts. Our data suggest that functional or mutational inactivation of P53 substantially contributes to overexpression of HELLS in HCC patients and indicates a previously unstudied aspect of P53′s ability to suppress liver cancer formation. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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21 pages, 5841 KiB

Open AccessArticle

Transforming Growth Factor-β Activated Kinase 1 (Tak1) Is Activated in Hepatocellular Carcinoma, Mediates Tumor Progression, and Predicts Unfavorable Outcome

by Dirk Andreas Ridder, Lana Louisa Urbansky, Hagen Roland Witzel, Mario Schindeldecker, Arndt Weinmann, Kristina Berndt, Tiemo Sven Gerber, Bruno Christian Köhler, Federico Nichetti, Annekathrin Ludt, Nadine Gehrke, Jörn Markus Schattenberg, Stefan Heinrich, Wilfried Roth and Beate Katharina Straub

Cancers 2022, 14(2), 430; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020430 - 15 Jan 2022

Cited by 9 | Viewed by 2324

Abstract

Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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15 pages, 48604 KiB

Open AccessArticle

DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma

by Keerthi Kurma, Olivier Manches, Florent Chuffart, Nathalie Sturm, Khaldoun Gharzeddine, Jianhui Zhang, Marion Mercey-Ressejac, Sophie Rousseaux, Arnaud Millet, Herve Lerat, Patrice N. Marche, Zuzana Macek Jilkova and Thomas Decaens

Cancers 2021, 13(19), 4981; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194981 - 04 Oct 2021

Cited by 30 | Viewed by 4227

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The majority of HCC cases are associated with liver fibrosis or cirrhosis developing from chronic liver injuries. The immune system of the liver contributes to the severity of tissue damage, the establishment of fibrosis and the disease’s progression towards HCC. Herein, we provide a detailed characterization of the DEN-induced HCC rat model during fibrosis progression and HCC development with a special focus on the liver’s inflammatory microenvironment. Fischer 344 male rats were treated weekly for 14 weeks with intra-peritoneal injections of 50 mg/kg DEN. The rats were sacrificed before starting DEN-injections at 0 weeks, after 8 weeks, 14 weeks and 20 weeks after the start of DEN-injections. We performed histopathological, immunohistochemical, RT-qPCR, RNA-seq and flow cytometry analysis. Data were compared between tumor and non-tumor samples from the DEN-treated versus untreated rats, as well as versus human HCCs. Chronic DEN injections lead to liver damage, hepatocytes proliferation, liver fibrosis and cirrhosis, disorganized vasculature, and a modulated immune microenvironment that mimics the usual events observed during human HCC development. The RNA-seq results showed that DEN-induced liver tumors in the rat model shared remarkable molecular characteristics with human HCC, especially with HCC associated with high proliferation. In conclusion, our study provides detailed insight into hepatocarcinogenesis in a commonly used model of HCC, facilitating the future use of this model for preclinical testing. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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Review

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12 pages, 729 KiB

Open AccessReview

Modulation of the Gut Microbiome to Improve Clinical Outcomes in Hepatocellular Carcinoma

by Sj Shen, Saroj Khatiwada, Jason Behary, Rachel Kim and Amany Zekry

Cancers 2022, 14(9), 2099; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092099 - 23 Apr 2022

Cited by 8 | Viewed by 3216

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recently, the gut microbiota has been shown to be closely linked to modulation of the immune and inflammatory responses, hence its potential as a therapeutic target. Although still under intense investigation, there exists a ‘gut–liver axis’ that links changes in the gut to the liver. In this regard, composition of gut microbiota and related metabolites, such as bile acids and short-chain fatty acids, have been shown to orchestrate key immune–metabolic events in liver disease and liver cancer. As hepatic immune cells are important determinants of antitumor responses, it is now increasingly recognized that the gut–liver axis plays a key role in influencing the intrahepatic immune response in HCC to favor a pro- or antitumor immune milieu. Hence, modulation of gut microbiota is potentially an attractive option to reinvigorate the antitumor responses. In this regard, promising evidence from melanoma preclinical and clinical studies has demonstrated the efficacy of gut-based intervention in reinvigorating the antitumor responses and improving responses to immunotherapy. However, the role of gut-based interventions as a therapeutic option in HCC remains to be elucidated. This review details how the gut microbiota and bacterial metabolites affect gut barrier function and ultimately immune response in HCC and raises the question of the potential of gut-based interventions as an adjunct therapy for patients with HCC receiving immunotherapy. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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16 pages, 729 KiB

Open AccessReview

The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma

by Anastasia D. Karampa, Anna C. Goussia, Georgios K. Glantzounis, Eleftheria M. Mastoridou, Nikolaos-Andreas T. Anastasopoulos and Antonia V. Charchanti

Cancers 2022, 14(3), 760; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030760 - 01 Feb 2022

Cited by 11 | Viewed by 2686

Abstract

Hepatocarcinogenesis is a long process with a complex pathophysiology. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10–14 months. Autophagy acts as a double-edged sword during this process. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism; however, it has been also implicated in later stages promoting survival of cancer cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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27 pages, 2098 KiB

Open AccessReview

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

by Ester García-Pras, Anabel Fernández-Iglesias, Jordi Gracia-Sancho and Sofía Pérez-del-Pulgar

Cancers 2022, 14(1), 48; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010048 - 23 Dec 2021

Cited by 25 | Viewed by 5190

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the contribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorigenesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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26 pages, 1129 KiB

Open AccessReview

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

by Chaofan Fan, Shing Kam and Pierluigi Ramadori

Cancers 2021, 13(20), 5250; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205250 - 19 Oct 2021

Cited by 6 | Viewed by 3197

Abstract

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. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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20 pages, 1068 KiB

Open AccessReview

Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes

by Yijun Wang, Tongyue Zhang, Mengyu Sun, Xiaoyu Ji, Meng Xie, Wenjie Huang and Limin Xia

Cancers 2021, 13(20), 5127; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205127 - 13 Oct 2021

Cited by 15 | Viewed by 2379

Abstract

One of the major challenges in hepatocellular carcinoma (HCC) treatment is drug resistance and low responsiveness to systemic therapies, partly due to insufficient T cell infiltration. Myeloid-derived suppressor cells (MDSCs) are immature marrow-derived cell populations with heterogeneity and immunosuppression characteristics and are essential components of the suppressive tumor immune microenvironment (TIME). Increasing evidence has demonstrated that MDSCs are indispensable contributing factors to HCC development in a T cell-dependent or non-dependent manner. Clinically, the frequency of MDSCs is firmly linked to HCC clinical outcomes and the effectiveness of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Furthermore, MDSCs can also be used as prognostic and predictive biomarkers for patients with HCC. Therefore, treatments reprograming MDSCs may offer potential therapeutic opportunities in HCC. Here, we recapitulated the dynamic relevance of MDSCs in the initiation and development of HCC and paid special attention to the effect of MDSCs on T cells infiltration in HCC. Finally, we pointed out the potential therapeutic effect of targeting MDSCs alone or in combination, hoping to provide new insights into HCC treatment. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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13 pages, 875 KiB

Open AccessReview

Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development

by Paula Sánchez Sánchez, María del Mar Rigual and Nabil Djouder

Cancers 2021, 13(20), 5045; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205045 - 09 Oct 2021

Cited by 8 | Viewed by 3374

Abstract

Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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