Do zombies turn liver disease into liver cancer?
Obesity is on the rise, and with it, so too is the number of patients developing metabolic syndrome(opens in new window). “While complications like heart disease, high blood pressure and diabetes have been studied in detail and can often be treated with medication, fatty liver disease and its possible consequences are less well understood and thus harder to treat,” explains Tom Luedde, a professor and chair of the Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf(opens in new window). One of those possible consequences is liver cancer. “While many people with fatty liver disease never experience serious problems, some go on to develop liver cancer, a life-threatening disease and one of the leading causes of cancer-related deaths worldwide,” adds Luedde. With the support of the EU-funded PhaseControl(opens in new window) project, Luedde set out to better understand the molecular mechanisms that cause liver cancer to develop from fatty liver disease.
Programmed cell death
According to Luedde, the human body has developed different programmes that allow cells to die in a controlled way. Often called ‘programmed cell death’, this process can help protect us by, for example, killing off cells that have been infected with viruses. “Our idea was that these cell death programmes might be activated in fatty liver disease, increasing inflammation in the liver and making the development of cancer more likely,” he says. To study how programmed cell death contributes to liver inflammation and cancer, the European Research Council(opens in new window) supported project used mouse models and cell culture systems, along with primary liver cells that were obtained during liver transplant procedures. Researchers also analysed anonymised patient data to see whether measuring the activation of these cell death programmes could help predict which patients are more at risk of developing liver cancer.
A zombie cell apocalypse
Based on this work, the project discovered a sublethal form of programmed necrosis known as necroptosis. During this process, necroptosis’ cell death pathway is activated, causing pores in the cell membrane to open. Although many substances that drive liver inflammation and promote cancer progression are released through these pores, instead of dying, these cells remain trapped in a sublethal state. In other words, they become ‘zombie cells’. Using a very advanced method called two-photon microscopy, researchers were able to make these zombie cells visible for the first time. “We believe that this process plays a critical role in the development of liver cancer in metabolic liver diseases,” remarks Luedde. The project also found that by activating programmed cell death, they could inhibit very early forms of pancreatic cancer from developing. “This discovery may open the door to a completely new way of treating early-stage pancreatic cancer,” adds Luedde.
New approaches to treating liver cancer
The data and ideas gathered during the PhaseControl project form the foundation for future research efforts – efforts that could eventually lead to new ways of treating, even preventing, liver cancer. “Our goal is to give back to EU citizens – who ultimately funded our research – by contributing to the development of new treatment approaches for a very widespread disease,” concludes Luedde.
