Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Autor: Fan W; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Adebowale K; Department of Chemical Engineering, Stanford University, Stanford, CA, USA.; Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA., Váncza L; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Li Y; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Rabbi MF; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA., Kunimoto K; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Chen D; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Mozes G; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Chiu DK; Department of Pathology, Stanford University, Stanford, CA, USA.; Division of Immunology, Stanford University, Stanford, CA, USA., Li Y; Department of Automation, Tsinghua University, Beijing, China., Tao J; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Wei Y; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Adeniji N; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Brunsing RL; Department of Radiology, Stanford University, Stanford, CA, USA., Dhanasekaran R; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.; VA, Palo Alto, CA, USA., Singhi A; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Geller D; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Lo SH; Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA, USA., Hodgson L; Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY, USA., Engleman EG; Department of Pathology, Stanford University, Stanford, CA, USA.; Division of Immunology, Stanford University, Stanford, CA, USA., Charville GW; Department of Pathology, Stanford University, Stanford, CA, USA., Charu V; Department of Pathology, Stanford University, Stanford, CA, USA.; Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Monga SP; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Kim T; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.; Faculty of Science and Technology, Keio University, Yokohama, Japan., Wells RG; Departments of Medicine and Bioengineering, University of Pennsylvania, Philadelphia, PA, USA., Chaudhuri O; Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.; Department of Mechanical Engineering, Stanford University, Stanford, CA, USA., Török NJ; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. ntorok@stanford.edu.; VA, Palo Alto, CA, USA. ntorok@stanford.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Feb; Vol. 626 (7999), pp. 635-642. Date of Electronic Publication: 2024 Jan 31.
DOI: 10.1038/s41586-023-06991-9
Abstrakt: Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development 1,2 , and increased stiffness is known to promote HCC progression in cirrhotic conditions 3,4 . Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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