hepatocellular carcinoma
Credit: Nephron, CC BY-SA 3.0 , via Wikimedia Commons

A new study reveals that the mechanical property of elevated viscoelasticity correlates with increased risk of liver cancer, particularly in people with type 2 diabetes. These results suggest that this easily measured biophysical property can identify type 2 diabetics at increased risk for liver cancer who do not meet current screening guidelines.

The relationship between stiffness and cancer has been documented through biophysical studies and clinical trials. For example, stiffness is a primary hallmark of liver cirrhosis, which can progress to liver cancer. But the new study suggests that higher liver viscoelasticity may be an early sign of progressive disease and may be a possible additional screening tool for type 2 diabetics, who are two to three times as likely as people without diabetes to develop liver cancer, which often occurs in the absence of cirrhosis. The study is published in Nature.

“Viscoelasticity is a mechanical property of a tissue,” explains study co-author, Lóránd Váncza, PhD, a postdoctoral researcher in the laboratory of senior author Natalie Török, MD at Stanford University. “The main feature is energy dissipation, how energy disappears within the tissue and makes room for cellular invasion.”

In this study, the Stanford team measured viscoelasticity with atomic force microscopy, or AFM. With AFM, researchers apply a force on the tissue and measure the resulting stiffness and energy dissipation of that tissue.

To probe the potential relationship between viscoelasticity and risk of liver cancer, the study included patients with type 2 diabetes and those with non-alcoholic steatohepatitis (NASH) with or without type 2 diabetes whose livers were pre-cirrhotic—still considered in the healthy stage. In the pre-cirrhotic stage, no difference was observed in the stiffness of their livers. But researchers know that 30% of patients with NASH and type 2 diabetes go on to develop liver cancer.

“A paradigm exists in the liver field that stiffness drives cancer,” explains Váncza. “So our question was that if the stiffness is the same, then why do 30% of these patients develop liver cancer before their liver stiffens?”

Finding an answer to this question has clinical implications because there currently are no effective therapies for NASH patients. They are monitored regularly, asked to eat healthy, to move, but slowly they progress to cirrhosis and then to liver cancer and liver failure.

“Before this, we did not have any markers or risk factors to filter this 30% of the patients who are at risk to develop earlier cancer,” says Váncza. “So if we can identify this cohort of the patients, we can monitor them closely before cancer develops. It is a better screening tool for people with NASH and type 2 diabetes.”

The Stanford team has already begun a clinical study evaluating the mechanical properties of these patients with Magnetic Resonance Elastography (MRE) to determine if they can identify patients at risk of liver cancer.

Digging deeper into the nature of the extracellular liver matrix, the researchers observed that increased viscoelasticity was related to the presence of advanced glycation end products (AGEs). Type 2 diabetes is known to be characterized by an accumulation of AGEs in the extracellular liver matrix. However, how this affects liver cancer in non-cirrhotic conditions is unclear.

“In this study, we found that AGEs promote changes in collagen architecture and enhance ECM viscoelasticity but not changes in stiffness,” says Váncza. The AGE-related changes in the matrix alter the collagen architecture from a crosslinked mesh type to star shapes. “You see lower interconnectivity of the matrix with shorter fibers bound together and these are weaker connections. It creates a niche with high viscoelasticity that promotes cancer cells to proliferate, invade, and migrate,” he adds.

The team also examined a series of cellular signals that promote liver cancer progression in viscoelastic conditions including a cancer-associated protein called YAP. “We’ve already known that Yap has an important role in liver cancer and can be activated by stiffness, but we did not know it was related to viscoelasticity,” adds Váncza. “In this study, we found that AGEs in the liver matrix creates a viscoelastic niche leading to the activation of mechanosignalling via Yap that in turn promotes liver cancer cell proliferation and invasion.”

“This is the first time that changes in collagen structure have been proven to promote viscoelasticity and liver cancer progression independent of stiffness,” says Török, Stanford professor of gastroenterology and hepatology. “It’s a complete change in paradigm that could explain the greater risk of liver cancer in people with type 2 diabetes and may help select people should undergo regular liver cancer screening.”

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