Blocking an inflammatory signalling molecule causes liver tumours in mice
Liver cancer is one of the deadliest cancers worldwide; every year sees more than 400,000 new cases, and most of the victims die in less than one year. Despite extensive research, the underlying molecular mechanisms of the disease are poorly understood. A new study by researchers from the Mouse Biology Unit of the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, and the University of Cologne, Germany, now reveals that a cellular signalling pathway protects the liver from developing cancer. In the current issue of the journal Cancer Cell, the scientists report that blocking this pathway in mice causes chronic hepatitis and liver tumours.
A complex network of cellular signals protects liver cells from damage and death. One molecule that is critically involved in this process is the protein NF-κB. It acts as a survival signal and helps cells to escape programmed death. To investigate the role NF-κB plays in the liver, Manolis Pasparakis and his group at EMBL’s Mouse Biology Unit generated a mouse model that cannot activate the molecule in its liver cells.
“Using genetic methods we switched off a protein called NEMO, which is required to activate NF-κB,” says Pasparakis, who recently left EMBL to become a Professor at the University of Cologne. “The mice first developed a condition similar to fatty liver disease and hepatitis in humans and later on liver tumours. This suggests that NEMO and NF-κB have an important role in protecting the liver from cancer and could act as yet unknown tumour suppressors.”
Normally an intervention that shuts down a survival signal like NF-κB should lead to cell death, but instead Pasparakis and his colleagues observed enhanced proliferation resulting in tumours. “The cells lacking NEMO die as you would expect, which explains why these mice develop hepatitis,” says Tom Luedde from Pasparakis’ lab, “but their death also kicks off a compensatory response. The liver has unique ways to regenerate after injury; upon cell death it tells other cells to proliferate to make up for the loss. This situation is very stressful and energy consuming for the liver, so that errors and mutations are likely to happen which then lead to tumours.”
NF-κB is known as a messenger of inflammation and could act as a molecular link connecting inflammatory, survival and metabolic pathways in the liver. Drugs that interfere with NF-κB are considered a powerful approach to treat inflammatory and other disorders. The new insights gained into its role in the healthy and the cancerous liver raise questions about these therapies and possible side-effects.
“NF-κB signalling is incredibly complex, and a lot of research will be necessary to understand it to the point when we can safely manipulate it with drugs,” Pasparakis says. His mouse model will help to uncover some of the molecular mechanisms involved in the development of chronic hepatitis and liver cancer, and might lead to new therapeutic strategies for these conditions in the future.
T. Luedde, M. Pasparakis et al. Deletion of NEMO/IKKg in Liver Parenchymal Cells Causes Steatohepatitis and Hepatocellular Carcinoma, Cancer Cell, 12 February 2007
cancer, infectious disease, proteins, signalling, tumour
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