Primary liver cancer is a life-threatening illness and one of the fastest-growing cancer types in the United States. Most primary liver cancer is cancer in your liver and cancer in the bile ducts in your liver. Sometimes the cause of liver cancer is known, and there are certain risk factors that may play a role in the disease. However, sometimes liver cancer happens in people with no underlying diseases and it’s not clear what causes it. Now, a recent mouse study uncovers a new driver of liver cancer and a potential strategy to reduce tumors.

Scientists from the German Cancer Research Center and Hebrew University in Jerusalem have identified in mice that the pro-inflammatory immune messenger interleukin 6 (IL-6), was found to be the driver of carcinogenesis. Their findings are published in the Journal of Hepatology in a paper titled, “Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling.”

“Primary liver cancers include: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and combined HCC-CCA tumors (cHCC-CCA),” wrote the researchers. “It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA, or both types of tumors.”

The team of 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 researchers observed that cHCC-CCA develops from degenerate liver cell precursors.

In cHCC-CCA cells, genes of the pro-inflammatory 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.

Today, the most effective therapy for cHCC-CCA is surgical removal of the tumors, however, 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,” explained Mathias Heikenwälder, PhD, group leader and professor, German Cancer Research Center, and one of the corresponding authors of the current publication. He added: “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.”

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