Unveiling Cancer’s Stealthy Strategy: How Molecules Alter the Liver’s Fate

Researchers from Weill Cornell Medicine have discovered that cancer releases molecules into the bloodstream, pathologically modifying the liver and causing inflammation, fat accumulation, and disruption of detoxification processes. This breakthrough reveals a hidden survival strategy of cancer and holds promise for novel diagnostics and therapeutics to identify and reverse this process.

How Molecules Alter the Liver's Fate

In the study, the researchers unveiled that a wide range of tumor types developing outside the liver secretes extracellular vesicles and particles (EVPs) containing fatty acids. Remarkably, these molecules can remotely reprogram the liver, leading to a condition similar to fatty liver disease. Both cancer patients and animal models exhibited signs of this mechanism, providing crucial insights.

Systemic complications caused by tumors, including liver disease, can potentially be addressed with future treatments, as stated by study co-senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics and of cell and developmental biology at Weill Cornell Medicine. Dr. Lyden, along with his research group, has dedicated two decades to studying the systemic effects of cancers and the strategies they employ to ensure their survival and progression.

Building upon their previous work, which demonstrated how pancreatic cancers prepare the liver to support metastatic tumors, the researchers explored a different set of liver changes induced by distant cancer cells. Animal models of bone, skin, and breast cancer, which metastasize to other organs but not the liver, exhibited fat molecule accumulation in liver cells, effectively reprogramming the liver to mimic fatty liver disease.

Reprogrammed livers displayed elevated inflammation levels, characterized by increased tumor necrosis factor-a (TNF-a), and decreased levels of drug-metabolizing enzymes called cytochrome P450. The reduction in cytochrome P450 levels may explain the decreased tolerance of cancer patients to chemotherapy and other drugs during disease progression.

The liver reprogramming was traced back to EVPs released by distant tumors, carrying fatty acids, particularly palmitic acid. These fatty acid cargoes, when taken up by liver-resident immune cells called Kupffer cells, triggered TNF-a production, ultimately leading to the formation of fatty liver.

While the study primarily employed animal models of cancer, similar liver changes were observed in newly diagnosed pancreatic cancer patients who later developed non-liver metastases. Co-first author Dr. Gang Wang, a postdoctoral associate in the Lyden laboratory, emphasized that the EVP-induced fatty liver condition did not co-occur with liver metastases, suggesting distinct strategies employed by cancers to manipulate liver function.

The researchers suspect that the fatty liver condition benefits cancer by converting the liver into a lipid-based energy source that fuels cancer growth. Dr. Robert Schwartz, co-senior author and associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, explained that not only do liver cells accumulate abnormal fat, but there is also a shift in lipid processing, favoring cancer growth.

Furthermore, this liver alteration may weaken anti-tumor immunity by affecting crucial molecules involved in immune cell function, according to co-senior author Dr. Haiying Zhang, assistant professor of cell and developmental biology in pediatrics at Weill Cornell Medicine.

To mitigate the systemic effects of tumors on the liver, the researchers implemented strategies such as blocking tumor-EVP release, inhibiting palmitic acid packaging, suppressing TNF-a activity, or eliminating Kupffer cells in experimental animal models. They are now further investigating the potential implementation of these strategies in human patients to counter the remote effects of tumors on the liver. Additionally, they are exploring the detection of palmitic acid in tumor EVPs circulating in

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