Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), is one of the most frequent human cancer and is characterized by a high mortality rate. The aggressiveness appears strictly related to the liver pathological background on which cancer develops. Inflammation and the consequent fibro/cirrhosis, derived from chronic injuries of several origins (viral, toxic and metabolic) and observable in almost all oncological patients, represents the most powerful risk factor for HCC and, at the same time, an important obstacle to the efficacy of systemic therapy. Multiple microenvironmental cues, indeed, play a pivotal role in the pathogenesis, evolution and recurrence of HCC as well as in the resistance to standard therapies observed in most of patients. The identification of altered pathways in cancer cells and of microenvironmental changes, strictly connected in pathogenic feedback loop, may permit to plan new therapeutic approaches targeting tumor cells and their permissive microenvironment, simultaneously.

Keywords: Hepatitis; hepatocyte nuclear factor 4 alpha (HNF4α); liver fibrosis; transforming growth factor beta (TGFβ); yes-associated protein (YAP).

Figure 1

Cell-cell and cell-stroma interplay sustaining fibrosis and inducing hepatocyte transformation. HSC, hepatic stellate cell; CAF, cancer activated fibroblast; EMT, epithelial-to-mesenchymal transition.

Figure 2

Deregulation of HNF4α in hepatocytes during HCC pathogenesis. Signals from microenvironment responsible for a reduced/loss of HNF4α expression/activity were shown and correlated to tumor-associated outcomes. See text for references. HNF4α, hepatocyte nuclear factor 4α; HSC, hepatic stellate cells; HCC, hepatocellular carcinoma; EMT, epithelial-to-mesenchymal transition; IL-6, interleukin 6; HBV, hepatitis B virus; HCV, hepatitis C virus; ECM, extracellular matrix; TGFβ, transforming growth factor β.

Figure 3

Potential tumor suppressor effects of HNF4α restoration/delivery in HCC. See text for references. HNF4α, hepatocyte nuclear factor 4α; HCC, hepatocellular carcinoma; HSC, hepatic stellate cells; EMT, epithelial-to-mesenchymal transition; ECM, extracellular matrix; CSC, cancer stem cells.