Scientists from the German Cancer Research Center (Deutsche, DKFZ) and the Hebrew University in Jerusalem have identified in mice the cell of origin of combined liver/biliary duct carcinomas, a rare type of cancer of the liver. The pro-inflammatory immune messenger interleukin 6 (IL-6) was found to be the driver of carcinogens. Blocking of IL-6 reduced both the number and size of tumors in mice.
Liver cancer includes hepatocellular carcinoma, intrahepatic carcinoma of the bile duct, and a mixed form, combined liver/biliary duct carcinoma (CCA). The cells of CCA exhibit features of both forms of cancer. This rare CCA is considered very aggressive and responds extremely poorly to current treatments.
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To identify potential targets for new therapies, a team led by Mathias of the German Cancer Research Center and Ethan Galen 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 CCA. The molecular profile of the CCA tumor cells in these animals primarily matched that of human CCA cells.
In contrast, hepatocellular carcinoma most likely arises from damaged mature liver cells. In CCA cells, genes of the pro-inflammatory interleukin 6 (IL-6) signaling pathway are particularly active. The source of the IL-6 that activates this signaling pathway is 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 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 CCA.
Today, the most effective therapy for CCA is the surgical removal of the tumors. It is only successful if the cancer is detected 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, explains Mathias, one of the corresponding authors of the current publication.
"There is now growing evidence that tumors diagnosed as hepatocellular carcinoma also partially contain cells of a CCA. This means that potential therapeutic approaches against CCA could also benefit some patients with hepatocellular cancer." Mathias
Additionally, researchers found that patients who were receiving anti-cancer therapy at the time they were vaccinated for COVID-19 were 2.7 times as likely to have breakthrough infections resulting in COVID-19, regardless of what type of cancer they were fighting. Anti-cancer therapies include chemotherapy, immunotherapy and radiation.
Why blood cancers?
Figuring out why blood-related cancers have a higher rate of COVID breakthrough infection than other cancers was not the focus of the study either, but Rooney said he can hypothesize. Blood-related cancers hit the immune system harder than other types of cancers because "they are often cancers of the immune cells themselves," he said.
"As such, patients with blood-related cancers are often not able to mount as robust of a response to vaccination and may not have the same degree of protection after receiving vaccines," Rooney said.
Another reason might be the type of treatments used in these types of cancers, which can suppress the immune system even more than other cancers' methods of treatment, he added.
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