Research Suggests Liver Cells are More Susceptible to Cancer

Researchers at the Abramson Cancer Center of the University of Pennsylvania have found that hepatocytes, the chief functional cells of the liver, are at the center of a chain reaction that makes them, and consequently the liver, particularly susceptible to cancer cells.

The researchers found that a previously developed “soil-and-seed hypothesis” largely involve hepatocytes cells. The hepatocytes respond to inflammation by activating a protein called STAT3, which in turn increases their production of other proteins called SAA. These proteins remodel the liver and create the “soil” needed to cancer cells to “seed.” The researchers found that stopping this process by using antibodies that block IL 6—the inflammatory signal that drives this chain reaction—can limit the potential of cancer to spread to the liver.

"The seed-and-soil hypothesis is well-recognized, but our research now shows that hepatocytes are the major orchestrators of this process," said senior author Gregory L. Beatty, MD, PhD.

According to the press release, the investigators used mouse models of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer and currently the third leading cause of cancer death in the United States. They found that nearly all hepatocytes showed STAT3 activation in mice with cancer, compared with less than 2% of hepatocytes in mice without tumors. The study authors then partnered with investigators at the Mayo Clinic in Arizona and other Penn colleagues to show that this same biology could be seen in patients with pancreatic cancer as well colon and lung cancers.

The investigators found that genetically deleting STAT3 in hepatocytes effectively decreased the liver’s susceptibility to cancer seeding in mice. The team then collaborated with the University of Kentucky to demonstrate that Il-6 controls STAT3 signaling in these cells and instructs hepatocytes to make SAA, which acts as an alarm to attract inflammatory cells and initiate a fibrotic reaction that together establish the “soil.”

According to the study, IL-6 drives changes in the liver whether there's a tumor present or not, implying that any condition associated with increased IL-6 levels—such as obesity or cardiovascular disease—could affect the liver's receptiveness to cancer. The researchers said this provides evidence that therapies targeting hepatocytes may be able to prevent cancer from spreading to the liver, a major cause of cancer mortality.