Chronic cell death promotes liver cancer

September 11, 2017, German Cancer Research Center

Liver cancer occurs predominantly in patients whose liver has been damaged as a result of chronic disease. Until now, it was not known how these events are linked at the molecular level. An international team of scientists from the German Cancer Research Center and the University of Zurich has now 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.

Liver (hepatocellular carcinoma) used to be among the less common cancer types in Germany. In recent decades, however, the numbers of people diagnosed with this disease have been rising. People who suffer from , hepatitis B or C, obesity, or type 2 diabetes mellitus are particularly at risk of developing . Liver cancer most frequently develops as a consequence of , which is increasingly common in Germany.

An international team of researchers led by Mathias Heikenwälder and his collaboration partner, Achim Weber from Zurich University, have now discovered that an enzyme called caspase 8 plays an important dual role in this process. The studies were performed in mice as a first step. Patient data show that the results can be transferred to humans.

On the one hand, caspase 8 is important for the process of , or apoptosis. Cells that have undergone malignant transformation eliminate themselves by apoptosis in order to protect the organism. Therefore, researchers long 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 simultaneously undergo apoptosis, the development of cancer is more likely. The reason is that the remaining hepatic cells have to divide at much higher rates in order to make up for lost tissue. "Hepatic are not used to high division rates, they cannot cope and therefore make mistakes," explained Mathias Heikenwälder from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

Patients with chronic inflammation of the accumulate high levels of DNA damage, which is fertile ground for cancer. 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 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 the caspase 8 enzyme would prevent programmed and the development of cancer, it would also rob the cell of a DNA repair mechanism. This effect must be avoided.

In a next step, the scientists plan to investigate whether similar processes also proceed in other types of cancer 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. "Many questions are still unanswered."

Explore further: Trigger for fatty liver in obesity found

More information: A dual role of caspase 8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell 2017, DOI: 10.1016/j.ccell.2017.08.010

Related Stories

Trigger for fatty liver in obesity found

September 7, 2017
Morbid obesity affects the liver: Almost one-third of all adults suffer from chronic fatty liver disease, which can lead to infections and even trigger cancer. Researchers at the University Children's Hospital Zurich and ...

Scientists discover potential new improved way to kill cancer cells

August 29, 2017
Scientists at the University of Glasgow have discovered a process to trigger the death of cancer cells that could be more effective than current methods.

Liver cancer due to chronic inflammation: Tumour growth follows programmed cell death (apoptosis)

August 30, 2013
The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver. This insight significantly contributes to ...

Researchers find link between common enzyme and cancer prevention

January 24, 2017
A common enzyme found in mammals that kills damaged cells before they become cancerous is being hailed as an important breakthrough in understanding the treatment of the disease.

How bile duct cancer develops and how it can be prevented

June 12, 2017
Two different types of cancer can develop in the liver. The more common malignant tumors are hepatocellular carcinomas, which arise from liver cells. Less common in the liver is bile duct cancer (cholangiocarcinoma), which ...

New study questions the safety of caspase inhibitors for the treatment of liver disease

September 9, 2016
Many acute and chronic liver diseases, including alcoholic hepatitis, result from apoptotic (programmed) cell death mediated by the enzyme caspase. Caspase inhibitors have therapeutic potential to treat and prevent apoptosis-mediated ...

Recommended for you

Researchers create a drug to extend the lives of men with prostate cancer

March 16, 2018
Fifteen years ago, Michael Jung was already an eminent scientist when his wife asked him a question that would change his career, and extend the lives of many men with a particularly lethal form of prostate cancer.

Machine-learning algorithm used to identify specific types of brain tumors

March 15, 2018
An international team of researchers has used methylation fingerprinting data as input to a machine-learning algorithm to identify different types of brain tumors. In their paper published in the journal Nature, the team ...

Higher doses of radiation don't improve survival in prostate cancer

March 15, 2018
A new study shows that higher doses of radiation do not improve survival for many patients with prostate cancer, compared with the standard radiation treatment. The analysis, which included 104 radiation therapy oncology ...

Joint supplement speeds melanoma cell growth

March 15, 2018
Chondroitin sulfate, a dietary supplement taken to strengthen joints, can speed the growth of a type of melanoma, according to experiments conducted in cell culture and mouse models.

Improved capture of cancer cells in blood could help track disease

March 15, 2018
Tumor cells circulating throughout the body in blood vessels have long been feared as harbingers of metastasizing cancer - even though most free-floating cancer cells will not go on to establish a new tumor.

Area surrounding a tumor impacts how breast cancer cells grow

March 14, 2018
Cancer is typically thought of as a tumor that needs to be removed or an area that needs to be treated with radiation or chemotherapy. As a physicist and cancer researcher, Joe Gray, Ph.D., thinks differently.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Sep 11, 2017
Could this indicate a potential problem with enhancing longevity with senolytic drugs

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.