Stromal and Immune Drivers of Hepatocarcinogenesis

Excerpt

In the large majority of cases, hepatocellular carcinoma (HCC) develops on the background of chronic liver inflammation and fibrosis. Liver microenvironment plays a crucial role in hepatocarcinogenesis, HCC progression, response to treatment, and patients’ long-term prognosis. Chronic liver inflammation and hepatocyte damage recruit and activate immune and stromal cells that release cytokines stimulating cell proliferation and producing liver fibrosis, hepatocellular stress, DNA damage, and chromosomal alterations that finally drive hepatocyte degeneration. Moreover, immune and stromal cells, e.g., cancer-associated fibroblasts, promote HCC progression by reducing tumor immunosurveillance, stimulating angiogenesis, and recruiting cancer stem cells. Activation of stromal and immune cells leads finally to epithelial–mesenchymal transition that confers increased initiation and metastasis of cancer cells and a greater resistance to therapies. Tumor microenvironment is also a relevant target for HCC treatment. Indeed, compounds targeting exhausted immune cells infiltrating HCC (i.e., nivolumab and pembrolizumab) have recently been shown to increase survival of HCC patients after sorafenib failure and were FDA-approved as a second-line treatment for advanced HCC.