Cancers in distant organs impair liver function

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In the study, published May 24 in Nature, the researchers found that a wide variety of tumor types growing outside the liver remotely reprogram the liver to a fatty liver disease-like state through the secretion of vesicles and extracellular particles (EVPs) containing fatty acids. The scientists found evidence of this process in animal models of cancer and in the liver of human cancer patients.

“Our findings show that tumors can lead to significant systemic complications, including liver disease, but also suggest that these complications may be addressed with future treatments,” said study co-senior author David Lyden, MD, the Stavros S. Niarchos in Pediatric Cardiology. and professor of pediatrics and of cell and developmental biology at Weill Cornell Medicine.

For the past two decades, Dr. Lyden, who is also a member of the Gale and Ira Drukier Institute for Children’s Health and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and his research group have been studying the systemic effects of cancers . These effects reflect specific strategies that cancers use to ensure their survival and accelerate their progression. In their work published in 2015, for example, the team discovered that pancreatic cancers secrete molecules encapsulated in extracellular vesicles, which travel through the bloodstream, are taken up by the liver, and prepare the organ to support the growth of new metastatic tumors. .

In the new study, the researchers discovered a different set of liver changes caused by distant cancer cells than they saw in animal models of bone, skin and breast cancer that metastasize to other organs but not the liver. The key finding of the study is that these tumors induce the accumulation of fat molecules in liver cells, thereby reprogramming the liver in a way that resembles the obesity and alcohol-related condition known as fatty liver disease. .

The team also observed that the reprogrammed livers have high levels of inflammation, marked by an elevated level of tumor necrosis factor-α (TNF-α) and low levels of drug-metabolizing enzymes called cytochrome P450, which break down potentially toxic molecules, including many drug molecules. The observed reduction in cytochrome P450 levels could explain why cancer patients often become less tolerant of chemotherapy and other drugs as their disease progresses.

The researchers traced this reprogramming of the liver to EVPs that are released by distant tumors and carry fatty acids, especially palmitic acid. When taken up by liver-resident immune cells called Kupffer cells, the fatty acid load triggers the production of TNF-α, which consequently drives the formation of fatty liver.

Although the researchers primarily used animal models of cancer in the study, they observed similar changes in the livers of patients with newly diagnosed pancreatic cancer who later developed non-hepatic metastases.

“One of our most surprising observations was that this EVP-induced fatty liver condition did not coincide with liver metastases, suggesting that causing fatty liver and preparing the liver for metastasis are distinct strategies that cancers use to manipulate liver function. said co-first author Dr. Gang Wang, a postdoctoral associate in Lyden’s lab. Dr. Jianlong Li, a scientific collaborator in Lyden’s lab, is also a co-author on the study.

Scientists suspect that the fatty liver condition partly benefits cancers by turning the liver into a lipid-based powerhouse to fuel cancer growth.

“We see in liver cells not only abnormal accumulation of fat, but also a departure from normal lipid processing, so that the lipids that are produced are more advantageous for cancer,” said co-senior author Dr. Robert Schwartz. , associate professor of medicine in the Division of Gastroenterology and Hepatology and a member of the Meyer Cancer Center at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center.

That may not be the only benefit that cancers derive from this liver alteration. “There are also crucial molecules involved in immune cell function, but their production is impaired in these fatty livers, suggesting that this condition may also weaken antitumor immunity,” said co-senior author Dr. Haiying Zhang, professor pediatric cell and developmental biology assistant at Weill Cornell Medicine.

Investigators were able to mitigate these systemic effects of liver tumors by implementing strategies such as blocking tumor EVP release, inhibiting palmitic acid packaging in tumor EVPs, suppressing TNF-α activity, or the elimination of Kupffer cells in experimental animal models. . The investigators are further investigating the potential of implementing these strategies in human patients to block these remote effects of tumors on the liver, and exploring the possibility of using palmitic acid detection of tumor EVPs circulating in the blood as a possible warning sign of advanced disease. cancer.