Fibrosis-dependent mechanisms of hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is a rising worldwide cause of cancer mortality, making the elucidation of its underlying mechanisms an urgent priority. The liver is unique in its response to injury, simultaneously undergoing regeneration and fibrosis. HCC occurs in the context of these two divergent responses, leading to distinctive pathways of carcinogenesis. In this review we highlight pathways of liver tumorigenesis that depend on, or are enhanced by, fibrosis. Activated hepatic stellate cells drive fibrogenesis, changing the composition of the extracellular matrix. Matrix quantity and stiffness also increase, providing a reservoir for bound growth factors. In addition to promoting angiogenesis, these factors may enhance the survival of both preneoplastic hepatocytes and activated hepatic stellate cells. Fibrotic changes also modulate the activity of inflammatory cells in the liver, reducing the activity of natural killer and natural killer T cells that normally contribute to tumor surveillance. These pathways synergize with inflammatory signals, including telomerase reactivation and reactive oxygen species release, ultimately resulting in cancer. Clarifying fibrosis-dependent tumorigenic mechanisms will help rationalize antifibrotic therapies as a strategy to prevent and treat HCC.

Figure 1

Fibrosis-dependent and inflammation-related links to HCC. In the liver, chronic infectious, metabolic, or toxic damage leads to persistent inflammation. Chronic damage and inflammation contribute to hepatocarcinogenesis by disrupting telomeres, releasing reactive oxygen species, and altering paracrine signaling in the cellular microenvironment. In addition, chronic inflammation leads to myofibroblast activation, resulting in liver fibrosis and cirrhosis. Fibrosis leads to reciprocal pathways of carcinogenesis: changes in ECM composition and nonparenchymal cell activity ultimately result in a growth-promoting, antiapoptotic environment for hepatocytes. Because fibrosis is intimately associated with chronic inflammation, an ongoing challenge is to experimentally isolate fibrosis-dependent carcinogenic pathways.

Figure 2

Pathways in liver fibrosis that promote HCC. Reciprocal signaling between stellate cells and precancerous hepatocytes creates a positive feedback loop, leading to increased hepatocyte growth and HSC activation. HSC activation can also contribute to carcinogenesis by promoting angiogenesis, and by altering the stromal environment. Changes in ECM composition simultaneously promote hepatocyte growth and inhibit NK function. Loss of NK function, in turn, promotes HSC survival and decreases tumor surveillance. Dotted lines indicate pathways suppressed in fibrosis.