Study Identifies Origin of Aggressive Liver Cancer

A collaboration between researchers in Germany and Israel has identified the origin cell for combined liver/biliary duct carcinoma (cHCC/CCA), a rare and deadly type of liver cancer. The pro-inflammatory immune messenger interleukin 6 (IL-6) was found in mice to be the driver of carcinogenesis, and subsequent work blocking IL-6 reduced both the number and size of tumors in mice.

Liver cancer includes hepatocellular carcinoma, intrahepatic carcinoma of the bile duct, and the mixed form, cHCC/CCA. A rare cancer that is very aggressive and responds poorly to current treatments, cHCC/CCA exhibits features of both forms of cancer. Today, the most effective therapy for cHCC/CCA is surgical removal of the tumors, but it is only successful if the cancer is detected at a very early stage.

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 team found that cHCC/CCA develops from degenerate liver cell precursors—in contrast to hepatocellular carcinoma, which most likely arises from damaged mature liver cells.  In cHCC/CCA cells, genes of the pro-inflammatory IL-6 signaling pathway are particularly active, and 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.

"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," says Heikenwälder. "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."

The findings were published in the Journal of Hepatology.