Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Hebrew University of Jerusalem have identified in mice the origin cell of mixed liver/biliary duct carcinomas, a rare form of liver cancer. It was discovered that the pro-inflammatory immunological messenger interleukin 6 (IL-6) drives carcinogenesis. The inhibition of IL-6 decreased the number and size of tumours in mice.
Cancer of the liver encompasses hepatocellular carcinoma, intrahepatic carcinoma of the bile duct, and a mixed type, combination liver/biliary duct cacrinoma (cHCC/CCA). The cells of cHCC/CCA display characteristics of both types of cancer. This unusual cHCC/CCA is regarded as extremely aggressive and responds poorly to available therapies.
A team lead by Mathias Heikenwalder of the German Cancer Research Center and Eithan Galun of the Hebrew University of Jerusalem sought for the biological origin of these cancers in order to uncover potential therapeutic targets. The investigations were conducted on mice that were genetically manipulated to develop chronic liver inflammation and hepatocellular carcinoma at a later age, as well as cHCC/CCA later on. The molecular profile of the cHCC/CCA tumour cells in these animals was very similar to that of human cHCC/CCA tumour cells.
The German-Israeli researchers discovered that cHCC/CCA develops from liver cell progenitors that have degenerated. Hepatocellular carcinoma, on the other hand, most likely starts from injured mature liver cells.
Genes of the pro-inflammatory interleukin 6 (IL-6) signalling pathway are highly activated in cHCC/CCA cells. Aging immune cells produce the IL-6 that triggers this signalling pathway. The characteristic of cell ageing, which scientists refer to as “senescence,” is the release of a complete cocktail of pro-inflammatory signalling chemicals, IL-6 being the most important.
Specific antibodies that inhibited the action of IL-6 lowered the number and size of cHCC/CCA tumours in mice. A substance that induces senescent cells to undergo programmed cell death apoptosis, hence eliminating the source of IL-6, reduced the formation of cHCC/CCA.
The most successful treatment for cHCC/CCA at now is surgical excision of the tumours. It is only effective if the cancer is diagnosed in its earliest stages. Mathias Heikenwalder, one of the publication’s corresponding authors, explains: “Blocking IL-6 or medicines that kill senescent IL-6-producing cells could now be evaluated as prospective treatment methods for this form of cancer.”
There is currently mounting evidence that some hepatocellular carcinoma tumours also contain cHCC/CCA cells. This indicates that certain people with hepatocellular cancer could possibly benefit from prospective therapies for cHCC/CCA.”
Rosenberg, N., et al. (2022) Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling. Journal of Hepatology. doi.org/10.1016/j.jhep.2022.07.029.