a-three-dimensional-spheroid-model-to-investigate-tumor-stromal

A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma

The aggressiveness and lack of well-tolerated and widely effective treatments for advanced hepatocellular carcinoma (HCC), the predominant form of liver ...

Minia University

University of Birmingham

We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD).

Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease.

NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc.

cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis.

TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms.

Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in Rel mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.

c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

Author Correction: c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver ( rs738409;  rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes ( rs2596542;  rs187115;  rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored.  and  SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while  SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis.  rs7421861 was independently associated with NAFLD-HCC development, while  rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.

A  Role in the Genetic Predisposition to NAFLD-HCC?

Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.

Article	Year
Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease. The American journal of gastroenterology\| PubMed ID: 32453041	2020
cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis. Rheumatology (Oxford, England)\| PubMed ID: 32725139	2020
TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms. Gut\| PubMed ID: 32907830	2021
c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nature metabolism\| PubMed ID: 33168981	2020
Author Correction: c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nature metabolism\| PubMed ID: 33303984	2021
Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach? Gut\| PubMed ID: 33541866	2021
A Role in the Genetic Predisposition to NAFLD-HCC? Cancers\| PubMed ID: 33808740	2021
Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease. Journal of hepatology\| PubMed ID: 34090928	2021

Marco Y. W. Zaki

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