Key features of the environment promoting liver cancer in the absence of cirrhosis

Zaki, Marco Y.W.; Mahdi, Ahmed Khairallah; Patman, Gillian; Whitehead, Anna; Maurício, João; McCain, Misti; Televantou, Despina; Abou-Beih, Sameh; Ramon‐Gil, Erik; Watson, Robyn; Cox, Charlotte V.; Leslie, Jack; Wilson, Caroline; Govaere, Olivier; Lunec, John; Mann, Derek A.; Nakjang, Sirintra; Oakley, Fiona; Shukla, Ruchi; Anstee, Quentin M.; Tiniakos, Dina; Reeves, Helen L.

doi:10.1038/s41598-021-96076-2

Cited by 14 publications

(11 citation statements)

References 39 publications

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“…Tumor development in this murine model was closely associated with the release of different proinflammatory and protumorigenic cytokines such as TNFα and IL6 [ 175 ]. The activation of NF-kB and HCC development is likely to be etiology-independent with our team developing a new dietary-induced HCC experimental model that showed NF-kB activation in the non-tumor tissue of mice developing HCC [ 176 ]. IL6 has also been shown to contribute to hepatocarcinogenesis and a study in HCV patients suggested that this may be gender dependent.…”

Section: Viral Hepatitis Immune Imbalance and Hcc Developmentmentioning

confidence: 99%

Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma

Zaki

Fathi

Samir

et al. 2022

Cancers

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Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.

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Section: Viral Hepatitis Immune Imbalance and Hcc Developmentmentioning

confidence: 99%

Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma

Zaki

Fathi

Samir

et al. 2022

Cancers

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“…Mice fed a healthy rodent chow diet had many fewer tumors, but even these were not completely protected after 18 months. Hepatic tumor formation in the context of a high-fat diet and steatosis has been extensively studied and multiple contributing mechanisms are thought to be involved (3,11,16,17). Perhaps among them, the most important is lipotoxicity-driven oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Animals with severe genetic anomalies (14) or animals maintained on a toxic, nutrient-restricted diet such as the methionine-and choline-deficient diet (15) may develop severe liver anomalies more rapidly. When a high-fat or high-fat and -sugar diet alone is utilized in "genetically normal" strains, overt liver damage (beyond steatosis) is not routinely observed before 36 weeks of age (16) and a year or more is required for terminal damage -including hepatocellular carcinoma -to be widely manifested (17,18).…”

Section: Introductionmentioning

confidence: 99%

Liver Protein Expression in Nash Mice on a High-Fat Diet

Varani

McClintock

Knibbs

et al. 2022

Preprint

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Male MS-NASH mice were maintained on a high-fat diet for 16 weeks with and without red algae-derived minerals. Obeticholic acid (OCA) was used as a comparator in the same strain and diet. C57BL/6 mice maintained on a standard (low-fat) rodent chow diet were used as a control. At the end of the in-life portion of the study, body weight, liver weight, liver enzyme levels and liver histology were assessed. Samples obtained from individual livers were subjected to Tandem Mass Tag labeling/mass spectroscopy for protein profile determination. As compared to mice maintained on the low-fat diet, all high-fat-fed mice had increased whole body and liver weight, increased liver enzyme (aminotransferases) levels and widespread steatosis/ballooning hepatocyte degeneration. Histological evidence for liver inflammation and collagen deposition was also present, but changes were to a lesser extent. A moderate reduction in ballooning degeneration and collagen deposition was observed with mineral supplementation. Control mice on the high-fat diet alone demonstrated multiple protein changes associated with dysregulated fat and carbohydrate metabolism, lipotoxicity and oxidative stress. Cholesterol metabolism and bile acid formation were especially sensitive to diet. In mice receiving multi-mineral supplementation along with the high-fat diet, there was reduced liver toxicity as evidenced by a decrease in levels of several cytochrome P450 enzymes and other oxidant-generating moieties. Additionally, elevated expression of several keratins was also detected in mineral-supplemented mice. The protein changes observed with mineral supplementation were not seen with OCA. Our previous studies have shown that mice maintained on a high-fat diet for up to 18 months develop end-stage liver injury including hepatocellular carcinoma. Mineral-supplemented mice were substantially protected against tumor formation and other end-state consequences of high-fat feeding. The present study identifies early (16-week) protein changes occurring in the livers of the high-fat diet-fed mice, and how the expression of these proteins is influenced by mineral supplementation. These findings help elucidate early protein changes that contribute to end-stage liver injury and potential mechanisms by which dietary minerals may mitigate such damage.

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“…The copyright holder for this this version posted February 25, 2022. ; https://doi.org/10.1101/2022.02. 24.481779 doi: bioRxiv preprint alone or in combination with the American lifestyle induced obesity syndrome diet (DEN/ALIOS), the latter to establish HCC on a background of NASH 15,16 (Supplementary Data Fig. 1l-o).…”

Section: Pro-tumour Cxcr2 + Neutrophils Associate With Nash-hcc Resis...mentioning

confidence: 99%

“…1h-k ). For an additional autochthonous model, we employed either Diethylnitrosamine (DEN) alone or in combination with the American lifestyle induced obesity syndrome diet (DEN/ALIOS), the latter to establish HCC on a background of NASH 15,16 ( Supplementary Data Fig. 1l-o ).…”

Section: Introductionmentioning

confidence: 99%

CXCR2 inhibition enables NASH-HCC immunotherapy

Leslie

Mackey

Jamieson

et al. 2022

Preprint

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Objective: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design: Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results: Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoral XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoral immunity, this was confirmed by loss of therapeutic effect upon genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a pro-tumor to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.

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Key features of the environment promoting liver cancer in the absence of cirrhosis

Cited by 14 publications

References 39 publications

Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma

Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma

Liver Protein Expression in Nash Mice on a High-Fat Diet

CXCR2 inhibition enables NASH-HCC immunotherapy

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