Pathogenesis from Inflammation to Cancer in NASH-Derived HCC

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. As opposed to the majority of patients with HCC, approximately 20–30% of cases of non-alcoholic steatohepatitis (NASH)-derived HCC develop malignant tumours in the absence of liver cirrhosis. NASH is characterized by metabolic dysregulation, chronic inflammation and cell death in the liver, which provide a favorable setting for the transformation of inflammation into cancer. This review aims to describe the pathogenesis and the underlying mechanism of the transition from inflammation to cancer in NASH.

Immunogenic Death of Hepatocellular Carcinoma Cells in Mice Expressing Caspase-Resistant ROCK1 Is Not Replicated by ROCK Inhibitors

“…A caveat to the DEN-induced mouse HCC model is that its etiology may differ from human HCC, which is associated with chronic inflammation in many patients. [ 49 ] Clinical studies in human HCC patients have previously determined that high CD8 + T cells and/or high CD8 + /Foxp3 + ratios are associated with increased overall and disease-free survival of HCC patients [ 36 , 37 , 38 ], suggesting that ICD in ROCK1nc tumours, which resulted in high CD8 + T cell numbers and CD8 + /Foxp3 + ratios, induced tumour-suppressive immunity. From a clinical perspective, the obvious question is whether pharmacological inhibition of ROCK activity would provoke similar phenotypes.…”

Pathogenesis of NAFLD-Related Hepatocellular Carcinoma: An Up-to-Date Review

“…In human liver, various immune cells constitute the unique immune microenvironment, including Kupffer cells (KCs), CD4 + T cells, CD8 + T cells, B lymphocytes, HSCs, natural killer cells (NK cells), dendritic cells (DCs), and other immune cells. 43 Under NASH conditions, some pathobiological factors, such as the insulin resistance, lipid accumulation and oxidative stress, could recruit and activate these immune cells, then release molecules that result in inflammation, fibrosis, and HCC (Figure 3). 44 KCs are the resident macrophages and one of the first lines of defense in the liver.…”

“…The resulting hepatocyte apoptosis, steatosis, hepatic damage and the activation of HSCs, which followed by the production of extracellular matrix and hepatic fibrosis formation. 43 In addition, the interaction between KCs and platelets induces the recruitment of the NKT cell and CD8 + T cell in the liver, and subsequent progression of NASH. Moreover, KCs can also cause the apoptosis-induced recruitment of Ly6C + monocyte, mediated by C-C motif chemokine ligand 2 (CCL2), and promote Th17 differentiation via the production of IL-23 or IL-6.…”

“…50 B cells are activated through TLR4 by PAMPs and can differentiate into plasma cells which produce anti-OSE immunoglobulins (IgG) or induce IFN-γ, IL-2, TNF, TGF-β production in CD4 + Th1 cells, then these cytokines induce immature macrophages to differentiate into the M1-like pro-inflammatory phenotype. 43 And Shalapour et al 51 reported that liver-resident immunoglobulin-A-producing (IgA + ) cells through expressing high levels of PD-L1 and IL-10 suppress the activation of cytotoxic CD8 + T lymphocytes (CTL), their IFN-γ production and cytotoxic response to the tumor. Another CD4 + T cell subtype exposed to the proinflammatory environment is CD4 + Th17, which expresses RORγt and secretes IL-17, increasing the levels of PTEN that inhibit the PI3K/AKT pathway.…”

“…Another CD4 + T cell subtype exposed to the proinflammatory environment is CD4 + Th17, which expresses RORγt and secretes IL-17, increasing the levels of PTEN that inhibit the PI3K/AKT pathway. 13,43 IL-17 also promotes the recruitment of neutrophils and macrophages, and induces the secretion of IL-6 aggravating insulin resistance, thereby promoting the inflammatory reactions and NAFLD progression. In contrast to the pro-inflammatory effects of Th17 cells, Treg cells have the opposite functions.…”