Liver cancer occurs predominantly when the liver has been damaged as a result of chronic disease. Why this occurs was not previously understood. A new study by an international team of scientists from the German Cancer Research Center and the University of Zurich has shown that chronic cell death promotes the development of cancer. The more cells die, the more the remaining cells have to divide. In this process, they accumulate mutations: fertile ground for liver cancer to develop.
An international team of researchers led by Mathias Heikenwälder and his collaboration partner, Achim Weber from Zurich University, have discovered that caspase 8 plays an important dual role in this process. Caspase 8 is important for apoptosis. Cells that have undergone malignant transformation eliminate themselves by apoptosis in order to protect the organism. Therefore, it was believed that apoptosis protects from cancer. The current study shows that this only holds true for each individual cell and not for whole tissues.
If too many cells at a time undergo apoptosis, this promotes the development of cancer because the remaining hepatic cells have to divide at much higher rates in order to make up for lost tissue. "Hepatic cells are not used to high division rates, they cannot cope and make mistakes," explained Heikenwälder.
Patients with chronic inflammation of the liver accumulate high levels of DNA damage. The more mutations have accumulated in a cell's DNA, the more probable that the cell will break out from its normal life cycle and start proliferating and growing out of control.
However, caspase 8 has yet another, completely different function. The molecule is part of a newly identified larger complex that recognizes damage in DNA and triggers repair mechanisms. The functions in apoptosis and repair operate independently of each other. They can also be influenced separately from each other.
This is particularly important for the treatment of liver cancer and chronic liver disease. While complete elimination of caspase 8 would prevent programmed cell death and the development of cancer, it would also rob the cell of a DNA repair mechanism.
The scientists plan to investigate whether similar processes also proceed in other types of cancer next and to study the dynamics of this mechanism in more detail. "So far, we do not know when and why caspase 8 and the other molecules team up to search for DNA damage," Heikenwälder said.