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 variety of cancer of the liver. The professional-inflammatory immune messenger interleukin 6 (IL-6) was found to be the driving force of carcinogenesis. Blocking of IL-6 reduced each the number and size of tumors in mice.

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 each types of cancer. This rare cHCC/CCA is taken into account very aggressive and responds extreme poorly to current treatments.

To discover potential targets for brand spanking new therapies, a team led by Mathias Heikenwälder of the German Cancer Research Center and Eithan Galun of the Hebrew University in Jerusalem looked for the cellular origin of those 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 almost definitely arises from damaged mature liver cells.

In cHCC/CCA cells, genes of the pro-inflammatory interleukin 6 (IL-6) signaling pathway are particularly energetic. The source of the IL-6 that prompts this signaling pathway are aging immune cells. The hallmark of cell aging, which scientists discuss with as “senescence”, is the discharge of a complete cocktail of pro-inflammatory signaling molecules, amongst which IL-6 plays the most important role.

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

Today, essentially the most effective therapy for cHCC/CCA is surgical removal of the tumors. It is barely successful if the cancer is detected at a really 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 such a cancer,” explains Mathias Heikenwälder, one among the corresponding authors of the present publication.

There may be now growing evidence that tumors actually diagnosed as hepatocellular carcinoma also partially contain cells of a cHCC/CCA. Because of this potential therapeutic approaches against cHCC/CCA could also profit some patients with hepatocellular cancer.”

Mathias Heikenwälder

Source:

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Journal reference:

Rosenberg, N., et al. (2022) Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends upon senescence and IL6 trans-signaling. Journal of Hepatology. doi.org/10.1016/j.jhep.2022.07.029.