Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Hebrew University of Jerusalem have discovered the cell of origin of mixed liver/biliary carcinoma, a rare type of liver cancer, in mice. Interleukin 6 is a pro-inflammatory immunological messenger that is associated with the development of cancer (IL-6). The number and size of tumors were reduced in mice after IL-6 was blocked. Hepatocellular carcinoma, intrahepatic bile duct carcinoma, and a hybrid form known as combined liver/biliary carcinoma (cHCC/CCA) are all included under the term “liver cancer.” cHCC/CCA cells show characteristics of both types of cancer. This unusual cHCC/CCA is considered extremely aggressive and responds horribly to current therapies.
A group led by Mathias Heikenwalder of the German Cancer Research Center and Eitan Galun of the Hebrew University of Jerusalem investigated the cellular basis of these tumors to find potential targets for new therapies. The study subjects were genetically engineered mice that had hepatocellular carcinoma and chronic inflammation of the liver at an earlier age, as well as later development of cHCC/CCA. The cHCC/CCA tumor cells in these animals largely shared the same molecular profile as human cHCC/CCA cells.
The German-Israeli team found that the precursors of degenerated liver cells are where cHCC/CCA develops. On the other hand, hepatocellular carcinoma is likely the result of damaged mature liver cells. Genes involved in the pro-inflammatory interleukin 6 (IL-6) signaling pathway are highly active in cHCC/CCA cells. Senescent immune cells are the source of IL-6, which activates this signaling pathway. Senescence, as scientists refer to the process of cell aging, is characterized by the release of a wide range of pro-inflammatory signaling molecules, the main one being IL-6.
Specific antibodies that block the action of IL-6 reduced the number and size of cHCC/CCA tumors in mice. cHCC/CCA growth was also inhibited by a substance that induces senescent cells to undergo programmed cell death, or apoptosis, which eliminates the source of IL-6. Today, surgical removal of tumors is the most effective treatment for cHCC/CCA. It is only effective if the cancer is detected very early. According to Mathias Heikenwalder, one of the corresponding authors of the current study, “Blocking IL-6 or agents that kill IL-6-producing senescent cells could now be further tested as promising treatment approaches against this type of cancer.”
He adds: “Growing evidence suggests that tumors that have been identified as hepatocellular carcinoma may also partially contain cHCC/CCA cells. This means that some patients with hepatocellular carcinoma may benefit from potential therapeutic strategies against cHCC/CCA.” At the DKFZ, more than 1,300 researchers study how cancer develops, determine cancer risk factors and find new ways to prevent cancer. New techniques are being developed to more accurately identify tumors and successfully treat cancer patients. The DKFZ Cancer Information Service (KID) offers individual answers to all cancer-related questions for patients, interested citizens and professionals.