7th Annual Symposium
Physics of Cancer
October 4-6, 2016
|PoC - Physics of Cancer - Annual Symposium|
Liver Mechanics and Hepatocellular Carcinoma
University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
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Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer in the world. Approximately 90% of HCCs occur in cirrhotic (advanced fibrotic) livers, which are highly abnormal mechanically, and the risk of HCC increases dramatically in parallel with increased liver stiffness. HCC is the cancer most strongly associated with increased tissue stiffness. Our goal has been to determine the tissue mechanics of the normal and cirrhotic liver and to define the impact of these mechanical changes on hepatocytes, the major cells of the liver and the source cells for HCC. We have demonstrated in both rat models of liver fibrosis and in human livers that shear modulus increases significantly as fibrosis increases, although not linearly with increased matrix content. Livers demonstrated shear strain softening and compression stiffening, the latter of which increased significantly in advanced fibrosis and appeared to be secondary to a combination of proteoglycan content and cell-matrix interactions. Advanced fibrosis and cirrhosis are architectural definitions, and we show that the large-scale architectural arrangements associated with these stages of fibrosis are secondary to the mechanical properties of liver cells and matrix. Human HCCs were significantly stiffer than the cirrhotic tissue surrounding them and had increased proteoglycans and hyaluronic acid. Our data highlight the complex mechanics of the normal liver and the changes that occur in cirrhosis. Consistent with the hypothesis that these mechanical and matrix changes drive the development or progression of HCC, changes in the matrix and mechanical environment had a significant impact on hepatocyte phenotype in vitro.