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| Monterotondo/Cologne, 12 February 2007 |
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| A signal that protects the liver from hepatitis and
cancer
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Blocking an inflammatory signalling molecule causes liver tumours in mice
Press
Release 12 February 2007 [PDF]
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.
Source Article
T. Luedde, M. Pasparakis et al. Deletion of NEMO/IKKg in Liver Parenchymal Cells Causes Steatohepatitis and Hepatocellular
Carcinoma, Cancer Cell, 12 February 2007
Press Contact
Anna-Lynn Wegener
Press Officer
EMBL Heidelberg
Tel: +49 6221 387-8452
Email: wegener@embl.de |
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