The cells of cHCC/CCA exhibit features of both forms of cancer. This rare type of cHCC/CCA is considered very aggressive and responds extremely poorly to current treatments.
To identify potential targets for new therapies, a team led by Mathias Heikenwalder of the German Center for Cancer Research and Eithan Galun of the Hebrew University of Jerusalem searched for the cellular origin of these tumors. . The researchers conducted their study in mice that had been genetically engineered to develop chronic hepatitis and hepatocellular carcinoma at an older age, and then also developed cHCC/ CCA. The molecular profile of the cHCC/CCA tumor cells in these animals largely matches that of the human cHCC/CCA cells.
New insights into liver cancer
The German-Israeli research team found that cHCC/CCA develops from precursors of degraded hepatocytes. In contrast, hepatocellular carcinoma most likely arises from damaged mature liver cells.
In cHCC/CCA cells, genes of the proinflammatory signaling pathway interleukin 6 (IL-6) are particularly active. The source of IL-6 that activates this signaling pathway is senescent immune cells. The hallmark of cellular aging, which scientists call “aging,” is the release of a whole mix of proinflammatory signaling molecules, of which IL-6 plays a key role.
Blocking IL-6 activity with specific antibodies reduced both the number and size of cHCC/CCA tumors in mice. An agent that promotes senescent cells to undergo apoptosis, thereby drying up the source of IL-6, also inhibits cHCC/CCA growth.
Today, the most effective therapy for cHCC/CCA is surgical removal of the tumors. It is only successful if the cancer is detected at a very early stage. Mathias Heikenwalder, one of the corresponding authors of the current publication, explains: “Blocking IL-6 or agents that kill senescent IL-6-producing cells could be further tested as promising treatments against this type of cancer,” explains Mathias Heikenwalder, one of the corresponding authors of the current publication. He adds: “There is increasing evidence that tumors that are actually diagnosed as hepatocellular carcinoma also contain a cellular fraction of cHCC/CCA. Potential therapy against cHCC/CCA may also be beneficial for some patients with hepatocellular carcinoma.”