Perspective: The Mechanobiology of Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a deadly primary liver cancer that most often develops in a cirrhotic (highly scarred) liver. Cirrhosis is associated with large-scale mechanical changes in the liver, with increases in stiffness to levels that alter liver cell behavior. Importantly, recent research has yielded two key observations: that mechanical changes in the microenvironment can promote the development and progression of a variety of cancers, and that nuclear deformation can increase genetic instability and the accumulation of DNA damage in some contexts. HCC is a unique cancer given that it occurs in an environment that is already very stiff and that liver cells in cirrhosis have highly deformed nuclei. This suggests that mechanical changes in the liver could be a source of genetic instability that leads to cancer development. ABSTRACT: Hepatocellular carcinoma (HCC) is the second most deadly primary cancer in the world and is thus a major global health challenge. HCC primarily develops in patients with an underlying chronic liver disease, the vast majority with advanced cirrhosis, characterized by increased matrix deposition and liver stiffness. Liver stiffness is highly associated with cancer development and poor patient outcome and is measured clinically to assess cancer risk; cirrhotic livers greatly exceed the threshold stiffness shown to alter hepatocyte cell behavior and to increase the malignancy of cancer cells. Recent studies have shown that cirrhotic liver cells have highly irregular nuclear morphologies and that nuclear deformation mediates mechanosensitive signaling. Separate research has shown that nuclear deformation can increase genetic instability and the accumulation of DNA damage in migrating cancer cells. We hypothesize that the mechanical changes associated with chronic liver disease are drivers of oncogenesis, activating mechanosensitive signaling pathways, increasing rates of DNA damage, and ultimately inducing malignant transformation.