For diabetes and liver cancer, study suggests new screening guidelines

For centuries, doctors have used their hands as essential diagnostic tools: exploring joints and palpating the abdomen to assess a patient’s health. Often, cancer shows up as an unusual lump or stiffness in a normally bouncy tissue or organ.

More recently, the relationship between stiffness and cancer has been documented by biophysical studies and clinical trials, particularly in liver and breast cancer. For example, stiffness is a key feature of liver cirrhosis, which can progress to liver cancer.

Researchers at Stanford University have shown that another biophysical characteristic known as viscoelasticity (think of how stretching a ball of Silly Putty or a piece of bread dough meets first resistance, then release) is even more closely correlated with liver cancer. as stiffness, especially in people with type 2 diabetes.

The distinction is important because people with type 2 diabetes are two to three times more likely than people without diabetes to develop liver cancer, which often occurs in the absence of cirrhosis. Liver cancer rates are increasing in part because the prevalence of diabetes is increasing worldwide, particularly in marginalized communities where healthy food choices and opportunities for regular exercise are rare.

“This is the first time that the dogma of matrix stiffness as the primary predictor of liver cancer has been called into question,” said professor of gastroenterology and hepatology Natalie Torok, MD. “Current guidelines recommend routine screening for liver cancer only in people with cirrhosis. As a result, many people with type 2 diabetes are not screened at all. These new findings have major implications not only for liver cancer, but also for other cancers for which diabetes is a risk factor, notably that of breast cancer.

Torok is the lead author of the study, published online Jan. 31 in Nature. Postdoctoral researcher Weiguo Fan, Ph.D., is the lead author.

Torok and colleagues collaborated with researchers in the laboratory of Associate Professor of Mechanical Engineering Ovijit Chaudhuri, Ph.D., to study the role of viscoelasticity in liver cancer in patient samples, animal models and cultured cells. in the laboratory in a Jell-O. -like a tissue scaffold called hydrogel.

“This study is the first on the role of viscoelasticity in cancer with data ranging from human and mouse models to in vitro 3D culture studies and computer simulations,” Chaudhuri said. “This definitively establishes the role of viscoelasticity in liver cancer progression.”

Rigidity test

Liver stiffness is measured non-invasively using imaging techniques called transient elastography or MR elastography involving a vibrating pad placed on the abdomen. The vibrations are transmitted from the imaging probe to the organ; the vibration wave moving through a rigid medium differs from that moving through something more malleable. People with liver stiffness above a certain threshold are diagnosed with liver cirrhosis; Current guidelines recommend that they be screened every six months for liver cancer with an abdominal ultrasound and blood tests.

Measurements like stiffness come from what’s called the extracellular matrix, the space between and around an organ’s cells that’s full of proteins, sugars and minerals.

“Our organs are not simple clumps of cells,” Chaudhuri said. “Cells exist in a scaffold called the extracellular matrix that provides them with physical support but also affects their maturation, specialization and function.”

Like an elementary school teacher, the matrix provides a physical framework that supports and organizes the cells, softening and channeling them to harmoniously create functional tissue. When the matrix is ​​disrupted, bad apple cancerous or precancerous cells become lost more easily, spreading where they shouldn’t; divide uncontrollably; or transform into other, more dangerous versions of themselves.

People with diabetes have high levels of what are called advanced glycation end products, or AGEs. AGEs occur when blood sugar levels are poorly controlled and high levels of sugar molecules called glucose begin to clump onto nearby proteins, including collagen, a key structural component of the extracellular matrix. (AGEs are also found in foods high in protein or fat or in foods prepared at high temperatures such as frying or grilling.)

The researchers found that liver samples from people with type 2 diabetes had higher AGE levels and were more viscoelastic, but not stiffer, than liver samples from people without type 2 diabetes. A review Further investigation of laboratory mice showed that animals fed a diet rich in EFAs had shorter, less interconnected collagen fibers in the extracellular matrix of the liver than those found in animals fed standard chow.

Next, the researchers studied how the cells behaved when grown in the laboratory in a three-dimensional gel to mimic the structure of the liver matrix. Tinkering with cells outside the body allowed them to assess the effect of various changes on their growth and behavior.

“In our engineered hydrogels, we can tune one biophysical property such as viscoelasticity or stiffness at a time to understand the impact of each property on cells,” Chaudhuri said. “We saw that a change in viscoelasticity alone is enough to drive more invasive behavior in cells.”

In particular, the researchers noted that a more viscoelastic matrix promotes changes in the shape of liver cells and allows the formation of invasive protrusions on their membranes that help them escape natural barriers meant to keep cells in their rightful place.

Paradigm shift

Finally, Torok and colleagues went further by dissecting a series of cellular signals that promote liver cancer progression under viscoelastic conditions, including a cancer-associated protein called YAP.

“This is the first time there has been evidence that changes in collagen structure promote viscoelasticity and liver cancer progression independent of stiffness,” Torok said. “This is a complete paradigm shift that could explain the higher risk of liver cancer in people with type 2 diabetes and could help select people who should undergo regular liver cancer screening.”

Fortunately, like stiffness, viscoelasticity can be assessed non-invasively by MRI elastography by changing a few vibration frequency and measurement parameters. Torok plans to launch a clinical trial to further study viscoelasticity, type 2 diabetes and liver cancer progression.

“One of the major questions in medicine today is why people with diabetes and fatty liver disease are so prone to liver cancer and how we can fix it,” Torok said. “Our research suggests that many more people, especially those with diabetes, should be screened for cancer. If we did, we might be able to act sooner and save lives.”

Purdue University researchers; Tsinghua University in Beijing; the University of Pittsburgh; the University of California, Davis; Albert Einstein College of Medicine; Keio University in Yokohama; and the University of Pennsylvania contributed to the work.