The immunological and metabolic landscape in primary and metastatic liver cancer

Li, Xin; Ramadori, Pierluigi; Pfister, Dominik; Seehawer, Marco; Zender, Lars; Heikenwälder, Mathias

doi:10.1038/s41568-021-00383-9

Cited by 324 publications

(212 citation statements)

References 221 publications

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“…In the surroundings, differentiation, polarization, and activation of immune cells, which frequently correlate with increased glycolytic fluxes and augmented oxidative phosphorylation, strongly depend on the availability of substrates catalyzing these metabolic reactions (Figure 1). The impact of the metabolic microenvironment on the progression from chronic liver disease to cancer was recently reviewed elsewhere [21]. However, here we shortly summarize the metabolic pathways majorly affected by reprogramming and directly implicated in the epigenetic changes described in the next sections.…”

Section: Metabolic Reprogramming In Liver Cancermentioning

confidence: 99%

“…In fact, this is the quickest way to provide ATP via glucose consumption in unfavorable conditions of growth at the expenses of a reduced mitochondrial oxidative phosphorylation. These conditions are typically characterized by decreased O 2 availability due to scarce intratumoral vascularization and increased substrates consumption from hyperproliferating cancer cells [21]. Thus hypoxia is a central determinant of changes affecting glucose metabolism, triggering a switch from oxidative to glycolytic metabolism [22].…”

Section: Glycolysismentioning

confidence: 99%

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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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Section: Metabolic Reprogramming In Liver Cancermentioning

confidence: 99%

Section: Glycolysismentioning

confidence: 99%

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Fan

Kam

Ramadori

2021

Cancers

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“…Drug resistance has also been associated with metabolic reprogramming in HCC, and more specifically, with the switch from oxidative phosphorylation to aerobic glycolysis [ 163 , 164 ]. As previously mentioned, PKM2 is a rate-limiting enzyme in the glycolytic pathway.…”

Section: Altered Splicing Of Genes Involved In the Resistance Of Liver Cancer To Anticancer Drugsmentioning

confidence: 99%

Impact of Alternative Splicing Variants on Liver Cancer Biology

Marin

Reviejo

Soto

et al. 2021

Cancers

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The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

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“…Meanwhile, metabolic risk factors, such as obesity, metabolic syndrome, diabetes mellitus, and non-alcoholic fatty liver disease are increasingly prevalent and have become important causes of HCC [ 2 ]. However, regardless of pathogenic factors, abnormal metabolism plays a critical role in hepatocellular carcinogenesis and HCC development because the liver is a metabolic organ [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Glutamine Metabolism Scoring Predicts Prognosis and Therapeutic Resistance in Hepatocellular Carcinoma

Ying¹,

Cheng²,

Lu³

et al. 2021

Pathol. Oncol. Res.

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Glutamine metabolism (GM) plays a critical role in hepatocellular carcinoma (HCC); however, a comprehensive methodology to quantify GM activity is still lacking. We developed a transcriptome-based GMScore to evaluate GM activity and investigated the association of GMScore with prognosis and therapeutic resistance. Two independent HCC cohorts with transcriptome data were selected from The Cancer Genome Atlas (TCGA, n = 365) and the International Cancer Genome Consortium (ICGC, n = 231). The expression of 41 GM-associated genes were used to construct and validate GMScore. Several genomic or transcriptomic biomarkers were also estimated. Tumor response to immune checkpoint inhibitors (ICIs) was predicted using the tumor immune dysfunction and exclusion algorithm. GMScore was closely correlated with patient characteristics, including stage, histology grade, alpha-fetoprotein level, and vascular invasion. High GMScore was an independent risk factor for overall survival (OS) in both cohorts (HR = 4.2 and 3.91, both p < 0.001), superior to clinical indices and other biomarkers. High GMScore presented transcriptome features to indicate cell growth advantages and genetic stability, which was associated with poor OS of patients who received transcatheter arterial chemoembolization (TACE). High GMScore was also related to high expression of immune checkpoint genes, increased infiltration of regulatory T cells, and decreased infiltration of M1 macrophages. More importantly, high GMScore indicated poor predicted responses to ICIs, which could be verified in an ICI-treated melanoma cohort. In conclusion, GMScore is a strong prognostic index that may be integrated into existing clinical algorithms. A high GMScore may indicate resistance to TACE and ICIs based on its transcriptome and immune features. Validations using other HCC cohorts, especially ICI-treated HCC cohorts, are necessary.

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The immunological and metabolic landscape in primary and metastatic liver cancer

Cited by 324 publications

References 221 publications

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Impact of Alternative Splicing Variants on Liver Cancer Biology

Glutamine Metabolism Scoring Predicts Prognosis and Therapeutic Resistance in Hepatocellular Carcinoma

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