Researchers from the University of California San Diego School of Medicine have uncovered groundbreaking insights into liver cancer, which is the sixth most frequently diagnosed cancer worldwide and the fourth leading cause of cancer-related deaths.
Their findings, recently published in the journal Nature, unveil a crucial link between cellular metabolism and DNA damage that may play a role in how fatty liver disease progresses to cancer.
This research opens new avenues for both preventing and treating liver cancer while deepening our understanding of its origins and the impact of dietary choices on our genetic makeup.
Liver Cancer Trends and Fatty Liver Disease
Hepatocellular carcinoma (HCC), the most common form of liver cancer, has seen a dramatic rise of 25-30% in the last two decades, a trend closely tied to increasing rates of fatty liver disease, which now affects about 25% of adults in the United States.
Within this group, approximately 20% develop a severe variant known as metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the likelihood of progressing to HCC.
Despite this alarming trend, the pathways through which MASH leads to liver cancer remain poorly understood.
Understanding Cellular Changes in MASH
Michael Karin, Ph.D., a distinguished professor in the Department of Pharmacology at UC San Diego, pointed out that the evolution from fatty liver disease to MASH, and ultimately to liver cancer, is both common and potentially lethal.
He stressed the urgent need to comprehend the subcellular changes occurring during this transition, as patients with MASH are at serious risk for dire outcomes, including liver failure and the often deadly progression to liver cancer.
To investigate this complex issue, the research team employed a combination of mouse models and analyses of human tissue samples and databases.
Their work demonstrated that diets high in fat and sugar—known triggers for MASH—induce DNA damage in liver cells.
This damage drives cells into a state called senescence, where they remain metabolically active but lose the ability to divide.
While senescence is normally a protective mechanism that allows for cellular repair or the removal of damaged cells, the behavior of liver cells is different.
Some of these damaged cells stubbornly survive, resembling “ticking time bombs” that may eventually restart their division and become cancerous.
Implications for Treatment and Prevention
Ludmil Alexandrov, Ph.D., an associate professor in cellular and molecular medicine and bioengineering at UC San Diego, highlighted that detailed genomic analyses of tumor DNA reveal a strong connection between MASH-induced DNA damage and an elevated risk of liver cancer.
These findings suggest that developing therapies aimed at either preventing or repairing DNA damage could be a promising approach to treating liver cancer, especially for patients suffering from MASH.
Karin also pointed out several hypotheses for future treatment avenues.
For instance, diets rich in fats might interfere with the essential building blocks required for DNA synthesis and repair, hinting that medications or nutritional supplements could address these deficiencies.
Furthermore, the development of targeted antioxidants could offer a way to alleviate or reverse the cellular stress leading to DNA damage.
This research enhances our understanding of the relationship between aging and cancer as well.
Karin noted that aging often correlates with an increased risk of nearly all cancer types and is associated with cellular senescence.
This presents an interesting paradox, as senescence is designed to protect against cancer but may, in some cases, permit cells to resume proliferation after this protective phase.
Their findings may have implications for various forms of cancer.
Moreover, the results shed new light on the detrimental effects of unhealthy dietary habits on cellular metabolism.
Karin warned that poor nutrition could disrupt cellular functions at the DNA level, comparable to the long-term dangers associated with smoking.
This underscores the importance of effective public health campaigns aimed at raising awareness about fatty liver disease and the critical role of dietary choices in health.
Source: Science daily