Their discovery sheds light on one of cancer’s more stealthy survival mechanisms and suggests potential approaches for detecting and reversing this process.
In a study published in the journal Nature, WCM researchers found that a wide variety of tumor types growing outside the liver remotely reprogram this vital organ and gland to a state resembling fatty liver disease via secretion of extracellular vesicles and particles (EVPs) containing fatty acids.
The scientists found evidence of this process in animal models of cancer and in the livers of human cancer patients.
"Our findings show that tumors can lead to significant systemic complications, including liver disease, but also suggest that these complications can be addressed with future treatments," said study co-senior author Dr. David Lyden, a pediatric hematologist-oncologist at WCM.
For the past two decades, Lyden and his research group have been studying the systemic effects of cancers, including how cancers secure their survival and speed their progression.
In their work published in the journal Nature Cell Biology, 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 outgrowth of new, metastatic tumors.
During metastasis, cancer cells break away from the original (primary) tumor, travel through the blood or lymph system, and form a new tumor in other organs or tissues of the body. The new, metastatic tumor is the same type of cancer as the primary tumor.
In the new study, the researchers uncovered a different set of liver changes caused by distant cancer cells they observed in animal models of bone, skin and breast cancer that metastasize to other organs – but not to the liver.
The study’s key finding is that these tumors induce the accumulation of fat molecules in liver cells, consequently reprogramming the liver in a way that resembles the obesity- and alcohol-related condition known as fatty liver disease.
The team also observed that reprogrammed livers have high levels of inflammation, marked by elevated levels of tumor necrosis factor-alpha (TNF-a) – an inflammatory cytokine produced by macrophages/monocytes during acute inflammation – 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 illness progresses.
The researchers traced this liver reprogramming to extracellular vesicles and particles (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 cargo triggers the production of TNF-a, which consequently drives fatty liver formation.
Although the researchers principally used animal models of cancers in the study, they observed similar changes in the livers of newly diagnosed pancreatic cancer patients who later developed non-liver metastases.
"One of our more striking observations was that this EVP-induced fatty liver condition did not co-occur with liver metastases. This suggests that causing fatty liver and preparing the liver for metastasis are distinct strategies that cancers use to manipulate liver function,” said co-first authors Dr. Gang Wang and Dr. Jianlong Li in the Lyden laboratory.
The scientists suspect that the fatty liver condition benefits cancers, in part by turning the liver into a lipid-based source of energy to fuel cancer growth.
"We see in liver cells not only an abnormal accumulation of fat, but also a shift away from the normal processing of lipids or fatty compounds so that the lipids that are being produced are more advantageous to cancer,” said co-senior author Dr. Robert Schwartz, a hepatologist at New York-Presbyterian/Weill Cornell Medical Center and associate professor of medicine in the Division of Gastroenterology and Hepatology at WCM.
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 altered in these fatty livers, hinting that this condition may also weaken anti-tumor immunity," said co-senior author Dr. Haiying Zhang, assistant professor of cell and developmental biology in pediatrics at WCM.
To mitigate these systemic effects of tumors on the liver, the researchers implemented strategies, such as
The researchers are further investigating the potential of implementing these strategies in human patients to block these remote effects of tumors on the liver. (Related: Top 4 ways to improve liver function.)
They are also now exploring the possibility of using the detection of palmitic acid in tumor EVPs circulating in the blood as a potential warning sign of advanced cancer.
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