Researchers Discover Rare form of Liver Cancer in Mice

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A White Mice

Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Hebrew University in Jerusalem have identified in mice the cell of origin of combined liver/biliary duct carcinomas, a rare type of cancer of the liver. The pro-inflammatory immune messenger, interleukin 6 (IL-6), was the driver of carcinogenesis. Blocking of IL-6 reduced both the number and size of tumours in mice.

Heidelberg, Germany (21th August 2022)

The term liver cancer includes liver cells carcinoma, intrahepatic carcinoma of the bile duct, and a mixed form, combined liver/biliary duct cacrinoma (cHCC/CCA). The cells of cHCC/CCA exhibit features of both forms of cancer. This rare cHCC/CCA is considered very aggressive and responds very poorly to current treatments.

To reach the potential targets for new therapies, a team led by Mathias Heikenwälder of the German Cancer Research Center and Eithan Galun of the Hebrew University in Jerusalem searched for the cellular origin of these tumours. The researchers conducted their studies in mice genetically modified to develop chronic liver inflammation and hepatocellular carcinoma at an older age and later developed cHCC/CCA. The molecular profile of the cHCC/CCA tumour cells in these animals primarily matched that of human cHCC/CCA cells.


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What did German-Israeli team found?

The German-Israeli team found that cHCC/CCA develops from degenerate liver cell precursors. In contrast, hepatocellular carcinoma in all probability arises from damaged liver cells.

In cHCC/CCA cells, genes of the pro-inflammatory interleukin 6 (IL-6) signaling pathway are exceptionally active. The source of the IL-6 that activates this signaling pathway are aging immune cells. The hallmark of cell aging, which scientists refer to as “senescence”, is the release of a whole cocktail of pro-inflammatory signaling molecules, among which IL-6 plays the main role.

Blocking of IL-6 action by specific antibodies reduced both the number and size of cHCC/CCA tumors in the mice. An agent that drives senescent cells into programmed cell death apoptosis, thereby drying up the source of IL-6, also inhibited the development of cHCC/CCA.

Today, the most effective therapy for cHCC/CCA is surgical removal of the tumors. It is only successful if the cancer is detected at a very early stage. “Blocking of IL-6 or agents that kill senescent IL-6-producing cells could now be further tested as promising treatment approaches against this type of cancer,” explains Mathias Heikenwälder, one of the corresponding authors of the current publication.

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