Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma—Nature's Guide for Successful Cancer Immunotherapy

Heikenwälder, Mathias; Pikarsky, Eli

doi:10.1055/s-0037-1606255

Cited by 4 publications

(4 citation statements)

References 82 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the recent interest in the immune microenviroment (48,49) with focus on T cells in NASH (37,50), mainly the AlbLTab model seems to have the potential for consecutive subtyping of lymphocytes and PD-L1 expression analysis. A response rate of 20% for PD-1 (anti-programmed cell death-1 antibody) monotherapy in phase I/II trials has been attributed to the refractory immune-suppressive status in liver cancer patients (51), which needs further investigation.…”

mentioning

confidence: 99%

Characterization of HCC Mouse Models: Towards an Etiology-Oriented Subtyping Approach

Friemel

Frick

Unger

et al. 2019

Molecular Cancer Research

View full text Add to dashboard Cite

Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTab transgenic mice as well as TAK1 LPC-KO and Mcl-1 Dhep mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/ 19, glutamine synthetase) in mouse and n ¼ 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLTab transgenic mice and TAK1 LPC-KO models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTab murine livers. CGH profiles from the Mcl-1 Dhep model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity). Implications: Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.

show abstract

mentioning

confidence: 99%

Characterization of HCC Mouse Models: Towards an Etiology-Oriented Subtyping Approach

Friemel

Frick

Unger

et al. 2019

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…During the chronic infection phase, inflammation can damage the hepatic tissue, triggering regeneration and scarring (fibrosis); this process can eventually develop into cirrhosis or HCC, although these last outcomes are not necessarily preceded by fibrosis (Guo et al., 2015; Mesri et al., 2014). HCC oncogenesis can result from a combination of direct and indirect mechanisms involved in HCV infection, including chronic oxidative damage, interactions with viral proteins (NS5A and NS3) and the immune system‐mediated inflammation (Heikenwälder & Pikarsky, 2017; Mesri et al., 2014). Of note, HCC is the fifth most common cancer and the third leading cause of death worldwide (Akram et al., 2017; Heikenwälder & Pikarsky, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…HCC oncogenesis can result from a combination of direct and indirect mechanisms involved in HCV infection, including chronic oxidative damage, interactions with viral proteins (NS5A and NS3) and the immune system‐mediated inflammation (Heikenwälder & Pikarsky, 2017; Mesri et al., 2014). Of note, HCC is the fifth most common cancer and the third leading cause of death worldwide (Akram et al., 2017; Heikenwälder & Pikarsky, 2017).…”

Section: Introductionmentioning

confidence: 99%

HLA‐G 3′UTR haplotype analyses in HCV infection and HCV‐derived cirrhosis, hepatocellular carcinoma and fibrosis

Oliveira Correa,

Zambra,

Michita

et al. 2023

Int J Immunogenetics

View full text Add to dashboard Cite

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune‐related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA‐G) gene codes for an immunomodulatory protein known to be expressed in the maternal–foetal interface and in immune‐privileged tissues. The HLA‐G 3′ untranslated region (3′UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA‐G 3′UTR with susceptibility to viral infections, but other polymorphic variants in the HLA‐G 3′UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA‐G 3′UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR‐1, UTR‐2 and UTR‐3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA‐G expression can be involved in HCV infection susceptibility.

show abstract

“…Approximately 90% of hepatocellular carcinomas (HCC) arise from chronic inflammation associated with continuous hepatic injury and hepatocyte regeneration [2]. During primary liver cancer development, the inflammation leads to the production of many cytokines, chemokines and growth factors which then enhance cell proliferation, migration and metastasis [3,4]. Moreover, in recent years, hepatic carcinoma tumorigenesis and development have been strongly associated with genetic mutations, epigenetic modifications and alterations to key signaling pathways [5][6][7].…”

mentioning

confidence: 99%

The AT1/Raf/ERK1/2 signaling pathway is involved in Angiotensin II-enhanced proliferation of hepatic carcinoma cells

Bai

Tang

et al. 2019

neo

View full text Add to dashboard Cite

Angiotensin II (Ang II) has been strongly associated with biological behavior in human malignant tumors; nevertheless, its function in hepatic carcinoma growth and progression is still not well understood. This study investigates the effect and mechanism of Ang II on the HepG2 and Hep3B hepatic carcinoma cell lines in vitro. The effect of Ang II on HepG2 and Hep3B cell viability was examined by cell counting kit-8 assay (CCK-8). Quantitative real-time PCR and Western blot analysis detected the expression of angiotensin type 1 and type 2 receptors (AT1 and AT2), total extra-cellular signalregulated kinases 1/2 (ERK1/2), phospho-ERK1/2 (p-ERK1/2) and Bcl-2 and c-Myc. Ang II significantly promoted HepG2 cell proliferation by affecting AT1 and AT2 expression and induced ERK1/2 pathway activation. This was reversed by treating HepG2 and Hep3B cells with AT1 blockers; candesartan, Raf inhibitor sorafenib, and ERK1/2 inhibitor PD98059. Ang II also up-regulated the expression of Bcl-2 and c-Myc in HepG2 cells, and our results suggest that Ang II has a positive role in HepG2 and Hep3B cell proliferation through the AT1/Raf/ERK1/2 signaling pathway.

show abstract

Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma—Nature's Guide for Successful Cancer Immunotherapy

Cited by 4 publications

References 82 publications

Characterization of HCC Mouse Models: Towards an Etiology-Oriented Subtyping Approach

Characterization of HCC Mouse Models: Towards an Etiology-Oriented Subtyping Approach

HLA‐G 3′UTR haplotype analyses in HCV infection and HCV‐derived cirrhosis, hepatocellular carcinoma and fibrosis

The AT1/Raf/ERK1/2 signaling pathway is involved in Angiotensin II-enhanced proliferation of hepatic carcinoma cells

Contact Info

Product

Resources

About