Cancer Discovery: How the Liver Defends Itself

Cedars-Sinai investigators have discovered how the liver defends itself against cancer. Their study, published in the peer-reviewed Journal of Hepatology, suggests targets for therapies to protect the liver both from cancers that originate there and cancers that spread to the liver from other parts of the body.

“Ours is the first study to show that the liver has protective mechanisms for defending itself against cancer,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and senior author of the study. “We discovered that two proteins in healthy liver cells, working together, curb the action of a third protein that makes the liver a fertile place for cancer to grow.”

Cancer that originates in the liver is one of the leading causes of cancer death. The liver is also a common site for cancer to spread to—most often from colorectal cancer.

“Harnessing the power of the body’s own defense mechanisms represents a promising way forward in the battle against some deadly cancers,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “This study builds on years of work and is an important step in that direction.”

Two proteins long studied by Lu—prohibitin 1 and methionine adenosyltransferase 1A—are found in healthy liver cells. Previous research by Lu and her team has shown that when either of these proteins is missing in laboratory mice, the mice develop liver cancer, but investigators didn’t yet understand fully why this happens.

“We have been studying these two proteins for several decades,” Lu said. “In this new study, we found that they work together to suppress a particular protein called matrix metalloproteinase-7, which is well known among cancer researchers as one that breaks down the matrix that holds cells together and allows invasion of cancer cells to occur.”

In their latest study, investigators found that prohibitin 1 and methionine adenosyltransferase 1A partner together to shut down expression of cancer-promoting matrix metalloproteinase-7.

“This prevents cancer from taking hold,” Lu said.

Investigators edited the DNA of laboratory mice to knock out expression of the partnering proteins. In some of those mice, investigators also knocked out expression of the cancer-promoting protein. They then studied what happened in a mouse model of colon cancer liver metastasis.

“We found that with either of the partnering protective proteins eliminated, the mice were wildly sensitive to cancer metastasis,” Lu said. “It grows like wildfire. But if you also silence the cancer-promoting protein, that sensitization is gone and the cancer does not grow. This provides strong evidence that it is the cancer-promoting protein that is sensitizing the liver to cancer metastasis, and the combination of the two partnering proteins is keeping its expression down. This is the defense mechanism that no one had yet discovered.”

Investigators will next examine strategies to prevent the partnering protective proteins from being downregulated, so that they suppress the cancer-promoting protein and prevent metastases to the liver, Lu said.

Funding: This study was supported by National Institutes of Health grants P01CA233452 and R01DK123763, Cedars-Sinai Cancer Developmental Funds, Plan Nacional of I+D grant SAF2017-88041-R, and American Heart Association grant 23CDA1052548.

Read more on the Cedars-Sinai Blog: The Liver/Cancer Connection