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New driver for a rare form of liver cancer discovered

No. 45c | 19/08/2022 | by Koh

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 found to be the driver of carcinogenesis. Blocking of IL-6 reduced both the number and size of tumors in mice.

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The term liver cancer includes hepatocellular 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 extreme poorly to current treatments.

To identify 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 tumors. The researchers conducted their studies in mice that were genetically modified to develop chronic liver inflammation and hepatocellular carcinoma at an older age, and later also developed cHCC/CCA. The molecular profile of the cHCC/CCA tumor cells in these animals largely matched that of human cHCC/CCA cells.

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

In cHCC/CCA cells, genes of the pro-inflammatory interleukin 6 (IL-6) signaling pathway are particularly 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. He adds: "There is now growing evidence that tumors actually diagnosed as hepatocellular carcinoma also partially contain cells of a cHCC/CCA. This means that potential therapeutic approaches against cHCC/CCA could also benefit some patients with hepatocellular cancer."

Nofar Rosenberg, Matthias Van Haele, Tali Lanton, Neta Brashi, Zohar Bromberg, Hanan Adler, Hilla Giladi, Amnon Peled, Daniel S. Goldenberg, Jonathan H. Axelrod, Alina Simerzin, Chofit Chai, Mor Paldor, Auerlia Markezana, Dayana Yaish, Zohar Shemuliam, Dvora Gross, Shanny Barnoy, Maytal Gefen, Osher Amran, Sofie Claerhout, Mirian Fernández-Vaquero, María García-Beccaria, Danijela Heide, Michal Shoshkes-Carmel, Dirk Schmidt Arras, Sharona Elgavish, Yuval Nevo, Hadar Benyamini, Janina E.E. Tirnitz-Parker, Aranzazu Sanchez, Blanca Herrera, Rifaat Safadi, Klaus H. Kaestner, Stefan Rose-John, Tania Roskams, Mathias Heikenwälder*, Eithan Galun*: Combined hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling
Journal of Hepatology 2022, DOI: https://doi.org/10.1016/j.jhep.2022.07.029 

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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