How fatty liver promotes colorectal cancer spread

Investigators found that fatty liver, a condition closely associated with obesity, promotes the spread of colorectal cancer to the liver. Their study, published in the peer-reviewed journal Cell Metabolism, details the process at the cellular level and could change the way doctors manage the disease in some patients.

“Currently 25% to 30% of U.S. adults are obese, making it likely that they also have fatty liver,” said the senior author of the study. “Our study found that fatty liver cells secrete sacs of proteins and genetic material that promote the spread of colorectal cancer to the liver, suggesting doctors should manage colorectal cancer patients with fatty liver differently.”

The senior author noted that the study examined a mild form of fatty liver—one that clinicians might not be aware of or on the lookout for. The further emphasized that this condition is likely underdiagnosed.

“Our study showed that even mild fatty liver increased the risk of cancer spread,” the author said. “Thus, we are urging doctors to really pay attention to colorectal cancer patients who might have fatty liver. Among our patient samples, we noted that more than 40% of patients had fatty liver, but doctors often do not order the specialized MRI required to detect it, meaning many cases are missed.”

Ultimately, 70% of patients with colorectal cancer will develop liver metastasis, which is the major cause of death for these patients, according to the author. The investigators sought to discover why some patients develop aggressive metastasis while others do not, and to determine why only some patients respond well to therapy.

“Our hypothesis was that fatty liver does something to cause these differences,” the senior author said.

The team examined laboratory mice with colorectal cancer liver metastasis, some of which had been fed a high-fat diet that caused them to develop fatty liver. They noted that liver cells in the mice with fatty liver produced greater amounts of extracellular vesicles—particles that are released from cells and carry proteins and genetic material from the parent cell.

“The extracellular vesicles produced by fatty liver cells contain three types of microRNA that stimulate cancer proliferation, migration and invasion,” the author said. “The cancer cells take in these extracellular vesicles and these microRNA react with another protein called yes-associated protein to promote tumor growth. So the primary cancer in fatty liver mice becomes more aggressive and more metastatic.”

These yes-associated proteins also suppress the immune system in the environment immediately surrounding tumors, which the author theorized could make them resistant to immunotherapy, a common cancer-fighting treatment.

The investigators found the same types of conditions when they compared tissue samples from human patients with and without fatty liver who also had colorectal cancer liver metastasis.

The author said further studies are needed to examine whether fatty liver in lean patients, which is common in Asian populations, has the same effect on cancer spread. Additional research could also help determine whether metastatic colorectal cancer is resistant to immunotherapy in patients with fatty liver, and how that resistance might be reversed.