Hepatocyte - Stellate Cell Crosstalk in the Liver Engenders a Permissive Inflammatory Microenvironment that Drives Progression in Hepatocellular Carcinoma

摘要

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.