by Krista Conger, Stanford University Medical Center
Collagen fibers in a three-dimensional hydrogel (left panel). When advanced glycation end products—a byproduct of poorly controlled diabetes—are added (right), the fibers are shorter and more cross-linked, creating conditions that favor cancer progression. Credit: Weiguo Fan
For centuries, doctors have used their hands as essential diagnostic tools—exploring joints and palpating abdomens to assess a patient’s health. Often a cancer will reveal itself as a lump or unusual stiffness in a normally bouncy tissue or organ.
More recently, the relationship between stiffness and cancer has been documented through biophysical studies and clinical trials, particularly in liver and breast cancer. For example, stiffness is a primary hallmark of liver cirrhosis, which can progress to liver cancer.
Now researchers at Stanford University have shown that another biophysical characteristic known as viscoelasticity—think of how stretching a ball of Silly Putty or a clump of bread dough is met at first with resistance, and then with release—is even more tightly correlated with liver cancer than stiffness, particularly in people with type 2 diabetes.
The distinction matters because people with type 2 diabetes are two to three times as likely as 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 growing worldwide, particularly in marginalized communities where healthy food choices and opportunities for regular exercise are scarce.
“This is the first time that the dogma of matrix stiffness as a primary predictor of liver cancer is being challenged,” said professor of gastroenterology and hepatology Natalie Torok, MD. “Current guidelines recommend routine liver cancer screening only for people with cirrhosis. As a result, many people with type 2 diabetes are not screened at all. These new findings have major implications not just for liver cancer, but also other cancers for which diabetes is a risk factor, including breast cancers.”
Torok is the senior author of the study, which was published online Jan. 31 in Nature. Postdoctoral scholar Weiguo Fan, Ph.D., is the lead author.
Torok and her colleagues collaborated with researchers in the laboratory of associate professor of mechanical engineering Ovijit Chaudhuri, Ph.D., to investigate the role of viscoelasticity in liver cancer in patient samples, animal models and cells grown in the laboratory in a Jell-O-like tissue scaffolding called a hydrogel.
“This study is the first on the role of viscoelasticity in cancer with data that spans from humans and mouse models to in vitro 3D culture studies and computational simulations,” Chaudhuri said. “It definitively establishes the role of viscoelasticity in liver cancer progression.”
Stiffness test
Liver stiffness is measured non-invasively with 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 wave of vibration moving through a stiff medium differs from one moving through something more malleable. People with a liver stiffness that exceeds 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 such as stiffness arise from what’s called the extracellular matrix—the space between and around an organ’s cells that is chock-a-block with proteins, sugars and minerals.
“Our organs are not just clumps of cells,” Chaudhuri said. “The cells exist in a scaffolding called the extracellular matrix that gives them physical support but also affects their maturation, specialization and functioning.”
Like a grade-school teacher, the matrix provides a physical framework that supports and organizes the cells, gentling and channeling them to harmoniously create a functional tissue. When the matrix is disrupted, any bad-apple cancerous or pre-cancerous cells more readily lose their way, spreading to places they shouldn’t; dividing uncontrollably; or morphing in to other, more dangerous versions of themselves.
More information: Weiguo Fan et al, Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver, Nature (2024). DOI: 10.1038/s41586-023-06991-9
Journal information: Nature
Provided by Stanford University Medical Center
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