Hepatocyte–Stellate Cell Cross-Talk in the Liver Engenders a Permissive Inflammatory Microenvironment That Drives Progression in Hepatocellular Carcinoma

Abstract

Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features which are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the crosstalk between hepatocytes (human hepatoma cells) and activated human HSC. Unsupervised genome-wide expression profiling demonstrated that hepatocyte-HSC crosstalk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of pro-inflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte-HSC crosstalk also generated a permissive pro-angiogenic microenvironment, particularly by inducing VEGFA and MMP9 expression in HSC. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte-HSC crosstalk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCC. Interestingly, the effects of crosstalk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings therefore indicate that the crosstalk between hepatoma cells and activated HSC is an important feature of HCC progression, which may be targeted by epigenetic modulation.

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

“…Several studies have shown that activated HSCs may also contribute to liver carcinogenesis, owing to their capacity to generate a permissive environment that facilitates liver tumor cell growth. Coculture experiments have demonstrated that activated HSCs promote migration, growth, invasion, and survival of hepatocarcinoma and cholangiocarcinoma cells (11,13). In addition, hepatic myofibroblasts secrete proinflammatory and proangiogenic factors essential for tumor growth, and in parallel inhibit immune surveillance by natural killer (NK) and natural killer T (NKT) cells (13,53,97).…”

Myristoylated Alanine-Rich protein Kinase C Substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo

“…This choice was based on previous published evidence indicating that activated HSC produce and secrete soluble factors and chemokines that promote a pro-inflammatory microenvironment, tissue angiogenesis and tumour progression. Therefore, activated hHSC favour the ''homing'' of tumour cells in the liver microenvironment [20][21][22]. Hence, the conditioned medium of activated hHSC is as an excellent and specific tool to investigate the possible cross-talk between cancer cells and hHSC during chemotaxis.…”

Hepatitis C Virus Induces Interleukin-1β (IL-1β)/IL-18 in Circulatory and Resident Liver Macrophages

“…Hepatocellular injury followed by inflammation and activation of the innate immune system may lead to early-stage liver fibrosis, resulting in hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition (12). Gene expression analyses also highlighted the role of proinflammatory cytokines (e.g., IL-1␤ and IL-6) and chemokines (e.g., IL-8 and CCL2) as key orchestrators of the cross talk between hepatocytes and activated HSCs (13). The invasive capacity of malignant cells increases in the presence of IL-1␤ and IL-6 (14).…”