Study points to new ways to prevent liver cancer

Almost all liver cancers develop after decades of chronic liver disease, but a new discovery by Columbia researchers could lead to treatments that could break the link.

The new research shows that during chronic liver disease, a change in the balance of quiescent and activated liver stellate cells not only promotes fibrosis, but also sets the stage for the most common type of primary liver cancer. , called hepatocellular carcinoma.

The results, published online in Naturesuggest that it may be possible to prevent the development of liver cancer, the fourth leading cause of cancer death worldwide, by interfering with stellate cell activation.

Hepatic stellate cells have two identities: protective and tumor promoting. During chronic liver disease, a dynamic shift in cell balance towards tumor-promoting cells sets the stage for liver cancer. Image of stellate cells from the laboratory of Robert Schwabe.

Hepatocellular carcinoma develops almost exclusively in patients with chronic liver disease, including cirrhosis, hepatitis, or non-alcoholic fatty liver disease. These diseases often cause extensive and progressive scar tissue (aka fibrosis) in the liver.

“Although fibrosis almost always precedes cancer, little is known about the causal relationships between the two and how we might interrupt this process,” says the study leader. Robert F. Schwabe, MDprofessor of medicine and director of the Digestive and Liver Disease Research Center at Columbia University Vagelos College of Physicians and Surgeons.

Schwabe and his team focused on liver stellate cells, so named for the multiple protrusions that give them a star shape, as they are strongly implicated in liver fibrosis.

After developing new genetic tools that allowed researchers to manipulate and analyze stellate cells in mice, Schwabe discovered that the population of these cells changes as cancer grows.

“In a healthy liver, stellate cells are quiescent and express factors, including hepatocyte growth factor, that protect the organ,” he says. “In the presence of chronic liver disease, however, the number of quiescent protective stellate cells decreases while more stellate cells activate.”

Activated cells express tumor-promoting factors, particularly collagen, the building block of scar tissue. This dynamic shift from protective cells to tumor promoting cells paves the way for liver cancer.

The same imbalance in stellate cells and its association with an increased risk of cancer development has been observed in patients with liver cancer, suggesting that the same process occurs in humans.

Hepatocellular carcinomas are usually detected too late to be cured, and most patients die within two years of diagnosis despite newer, more effective medical therapies such as the combination of atezolizumab and bevacizumab. The incidence of hepatocellular carcinoma has tripled over the past 30 years and is expected to increase further due to rising rates of non-alcoholic fatty liver disease due to increasing obesity.

This discovery opens up the prospect of preventing liver cancer by restoring the normal balance of stellate cells.

“I don’t think we’ll be able to treat cancer by restoring balance to stellar cells,” says Schwabe. “Activated stellate cells create a favorable environment for cancer development, but they do not appear to play a role in cancer progression once the tumor has developed.

“But restoring the balance of cells or associated mediators in people with chronic liver disease can reduce the risk of developing tumors in the first place. That would be a huge benefit for the millions of people with chronic liver disease. chronic liver disease, who are very likely to develop liver cancer.

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