It has been known for a while that chronic infection with the hepatitis B virus can lead to liver cancer. But how exactly that happens is largely unclear. It’s a subject that is difficult to investigate. The virus only infects human cells, so a good animal model was lacking. Research with cell lines is the alternative, but these results are hard to translate to the situation in a patient’s body.
The emergence of liver organoids – first developed in the lab of Hans Clevers lab at the Hubrecht Institute in Utrecht – has changed that. Liver organoids are a kind of mini-livers, grown in the laboratory from human liver tissue. ‘This gives us the unique opportunity to look patient-specifically at how hepatitis B virus infection progresses and how it can lead to liver cancer,’ explains research leader Dr Tokameh Mahmoudi of Erasmus MC.
In the scientific journal eLife, Mahmoudi and colleagues from the Hubrecht Organoid Technology (HUB), the Erasmus MC department of transplantation and surgery, and Alexander Fleming Biomedical Sciences Research Center in Greece now present the first results of their research. In addition to infecting healthy human liver organoids with hepatitis B virus in vitro and studying various aspects of the infection, they made liver organoids from tissue of hepatitis B patients who had to undergo a liver transplant.
The tissue contained scars, so-called cirrhosis, but no signs of liver cancer were visible to the naked eye. ‘We were therefore surprised to find the first signs of liver cancer at the molecular level’, says Mahmoudi. In more detail: the genes expressed in the hepatitis B infected patient-derived liver organoids of cirrhotic liver tissue were more similar to liver cancer tissue than to healthy liver tissue. The researchers found signs of the same early molecular signature of liver cancer even in liver organoids made from liver donors who had recovered from hepatitis B.
Global health problem
Their findings are important in the surveillance of patients with chronic hepatitis B, Mahmoudi states. ‘Hepatitis B and subsequent liver cancer are a major global health problem. An estimated one-third of the world’s population becomes infected with the virus. In only a small proportion does the infection become chronic, but the diagnosis of liver cancer is often made late. The early signature could potentially serve as a biomarker to detect liver cancer earlier.’
Liver organoids can also help hepatitis B research in other ways, Mahmoudi thinks. ‘The great advantage of organoids is that it is patient-specific living tissue. We can store it in biobanks, grow it, test new drugs on it, and study in detail how infection with hepatitis B virus proceeds.’