Research Focus

Inside Stanford Digestive Health - Winter/Spring 2024

Diabetes and Liver Cancer: Connecting the Dots and Unveiling New Mechanisms

Clinical studies indicate that approximately 30% of hepatocellular carcinomas (HCC) associated with metabolic dysfunction associated steatohepatitis (MASH) manifest before cirrhosis, during a stage when the liver cell matrix remains "soft”.  As current HCC screening guidelines include only cirrhotic patients many of these patients are not receiving any surveillance.

Type 2 diabetes (T2DM) has been clinically associated with an increased risk for HCC.  A recent study published by the Torok lab in Nature unveiled how diabetes transforms the liver into a favorable environment for cancer cell proliferation and invasion.  The lead author of this paper is postdoctoral scholar Weiguo Fan, PhD.

The team of researchers elucidated that advance glycation end products (AGEs) that are generated during poor glycemic control or could be consumed by food prepared at high temperatures, accumulate in liver the extracellular matrix (ECM).  This results in structural alterations in collagen architecture and connectivity that enhances the viscoelasticity of the matrix, independent of stiffness.

Analyses of liver samples from individuals with type 2 diabetes and MASH revealed higher levels of liver AGEs and increased viscoelasticity compared to healthy individuals, or those without T2DM.  Feeding mice a high-AGE diet resulted in MASH with elevated liver AGEs, as well as increased liver viscoelasticity.  This viscoelastic liver environment led to accelerated hepatocarcinogenesis, with tumor growth reduced by inhibitors targeting AGE-collagen cross-linking.

Studies of the collagen networks in human and mouse liver samples showed that AGEs reduced network interconnectivity, shortened collagen fiber lengths, and increased heterogeneity, contributing to tissue viscoelasticity that was confirmed by computer modeling.

Mechanistically, increased tissue viscoelasticity activated the YAP/TAZ pathway, promoting cell proliferation and liver cancer invasion through the integrin β1-TNS1-YAP molecular pathway, and inhibiting either YAP activation or Tensin 1 in vivo reduced cancer formation.

This study underscores the importance of liver cancer screening for patients with type 2 diabetes, as high viscoelasticity is closely associated with liver cancer even in the absence of cirrhosis. The findings suggest updating guidelines to include recommendations for liver cancer screening in this population, given the significant risk posed by type 2 diabetes.

Researchers from Purdue University; the University of Pittsburgh; the University of California, Davis; Albert Einstein College of Medicine; and the University of Pennsylvania contributed to the work.

The study was supported by Stanford Medicine's SPARK Program in Translational Research and its Innovative Medicines Accelerator, as well as funding from the National Institutes of Health (grants R01DK083283, RO1CA277710, 1RO1AG060726, R37 CA214136, 1R01CA251155, 1R01CA204586 and 1R01GM126256).

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