People with type 2 diabetes are two to three times more likely than people without diabetes to develop the liver cancer, which often occurs in the absence of cirrhosis. Liver cancer rates are rising 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.
Researchers at Stanford University have shown that another biophysical characteristic known as viscoelasticity – think of how stretching a ball of Silly Putty or a lump of bread dough first encounters resistance and then release – is even more closely related to cancer to the liver. compared to stiffness, particularly in people with type 2 diabetes.
“This is the first time that the dogma of matrix stiffness as a primary predictor of liver cancer has been 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 important implications not only for liver cancer, but also for other cancers for which diabetes is a risk factor, including breast cancer.”
Torok is the senior author of the study, which was published online in Nature . Postdoctoral scholar Weiguo Fan, Ph.D., is the lead author.
Liver cancer and diabetes: here are the new guidelines
Torok and his 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 cells grown in the laboratory in a gelatin a similar tissue scaffold called a hydrogel.
“This study is the first on the role of viscoelasticity in cancer with data ranging from human and mouse models to 3D in vitro culture studies and computational simulations,” Chaudhuri said. “It definitively establishes the role of viscoelasticity in liver cancer progression.”
Liver stiffness is measured noninvasively with imaging techniques called transient elastography or MR elastography that involve a vibrating pad placed on the abdomen. Vibrations are transmitted from the imaging probe to the organ; the vibration wave moving through a rigid medium differs from one moving through something more malleable.
People with liver stiffness that exceeds a certain threshold are diagnosed with liver cirrhosis; Current guidelines recommend getting 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 is chock-full of proteins, sugars, and minerals.
“Our organs are not just clumps of cells,” Chaudhuri said. “Cells exist in a scaffold called the extracellular matrix that provides them with physical support but also influences their maturation, specialization and functioning.”
Like an elementary school teacher, the matrix provides a physical structure that supports and organizes cells, softening and channeling them to harmoniously create functional tissue. When the matrix is destroyed, the cancerous or precancerous cells of the rotten apple more easily lose their way, spreading to places where they shouldn't; split uncontrollably; or transform into other, more dangerous versions of themselves.
People with diabetes have elevated levels of what are called advanced glycation end products, or AGEs. AGEs occur when blood sugar is poorly controlled and high levels of sugar molecules known as glucose begin to deposit on nearby proteins, including collagen, a key structural component of the extracellular matrix. (AGEs are also present in foods rich in protein or fat or in foods prepared over high heat such as frying or grilling.)
The researchers found that liver samples from people with type 2 diabetes had higher levels of AGEs and were more viscoelastic, but not stiffer, than liver samples from people without type 2 diabetes. A closer look at the laboratory mice showed that animals fed an AGE-rich diet had shorter and 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 they were 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 evaluate the effect of various changes in their growth and behavior.
“In our engineered hydrogels, we can fine-tune one biophysical property such as viscoelasticity or stiffness at a time to understand how each property affects 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 the natural barriers meant to keep the cells in place.
Finally, Torok and his colleagues went a step further, analyzing a series of cellular signals that promote liver cancer progression under viscoelastic conditions that include a cancer-associated protein called YAP.
“This is the first time that changes in collagen structure have been shown to 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 a
nd may help select people who should undergo regular liver cancer screening.”
Fortunately, like stiffness, viscoelasticity can be assessed noninvasively with MR elastography by changing some parameters in the frequency and vibration measurement. Torok is planning 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 address this problem,” Torok said. “Our research suggests that many more people, particularly those with diabetes, should be screened for cancer. If we did, perhaps we could act sooner and save lives.”
Researchers from Purdue University; Beijing Tsinghua University; the University of Pittsburgh; the University of California, Davis; Albert Einstein Higher Institute of Medicine; Keio University in Yokohama; and the University of Pennsylvania contributed to the work.
According to the American Cancer Society, more than 41,000 new cases of liver cancer and intrahepatic bile duct cancer will be diagnosed in the United States this year, and nearly 30,000 people will die from these diseases.
Liver cancer is cancer that begins in the cells of the liver, which is a soccer ball-sized organ in the upper right part of the abdomen. The liver is essential for digesting food and ridding the body of toxic substances.
Intrahepatic bile duct cancer, which is sometimes classified as a type of liver cancer, occurs in parts of the bile ducts inside the liver. The bile ducts carry bile, a digestive fluid, and connect the liver to the gallbladder and small intestine.
Factors that increase the risk of primary liver cancer include:
Chronic HBV or HCV infection. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) increases the risk of liver cancer.
Cirrhosis. This progressive and irreversible condition causes scar tissue to form in the liver and increases your chances of developing liver cancer.
Some hereditary liver diseases. Liver diseases that can increase the risk of liver cancer include hemochromatosis and Wilson's disease.
Diabetes. People with this blood sugar disorder have a higher risk of liver cancer than those who do not have diabetes.
Non-alcoholic fatty liver disease. A buildup of fat in the liver increases the risk of liver cancer.
Exposure to aflatoxins. Aflatoxins are poisons produced by molds that grow on improperly stored crops. Grains and nuts can be contaminated with aflatoxins and end up in foods made from these products.
Excessive alcohol consumption.
Consuming more than a moderate amount of alcohol every day for many years can lead to irreversible liver damage and increase the risk of liver cancer.
Strategies to prevent liver cancer include:
Reduce the risk of cirrhosis. Cirrhosis is scarring of the liver and increases the risk of liver cancer.
You can reduce your risk of cirrhosis by drinking alcohol in moderation, if at all, and maintaining a healthy weight.
Get vaccinated against hepatitis B. You can reduce your risk of getting hepatitis B by getting the hepatitis B vaccine. The vaccine can be given to almost anyone, including newborns, older adults, and people with compromised immune systems .
Take steps to prevent hepatitis C. There is no vaccine against hepatitis C, but you can reduce the risk of infection by being careful to avoid unprotected sex with a partner infected with HBV, HCV, or any other sexually transmitted infection . Do not inject illegal drugs. If you do, make sure the needle you use is sterile and don't share it.
And before you get a piercing or tattoo, check out the shops in your area and ask the staff what their safety practices are. Improperly sterilized needles can spread the hepatitis C virus.
Seek treatment for hepatitis B or hepatitis C.
Treatments are available for hepatitis B and hepatitis C infections. Research shows that treatment can reduce the risk of c. to the liver. Ask your doctor about screening for c. to the liver.
For the general population, screening for c. to the liver reduces the risk of death from liver cancer and is generally not recommended. People with conditions that increase the risk of c. liver disease, including hepatitis B, hepatitis C, and liver cirrhosis, may consider screening.
Discuss the pros and cons of screening with your healthcare team. Together you can decide whether screening is right for you based on your risk. Screening typically involves a blood test and an abdominal ultrasound exam every six months.
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