Cholangiocarcinoma may not be a household word unless, of course, you happen to be a pathologist studying hepatic cancers. Still, it does affect a fair number of individuals, typically over the age of 50. Cholangiocarcinoma is a group of cancers that begin in the bile ducts, which carry digestive fluid to the small intestine. Cholangiocarcinomas are classified by their location in relation to the liver and typically grouped in with other types of liver cancer. Now, a team of investigators at the Spanish National Cardiovascular Research Centre (CNIC) believe they have uncovered a mechanism that controls the development of intrahepatic cholangiocarcinoma.

Findings from the new study—published recently in PNAS through an article entitled “JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma”—identified a protein that, when blocked, dramatically reduces the impact and progression of the cancer.

Liver cancer is the fifth most frequent cancer and the second main cause of cancer-related deaths worldwide. Cholangiocarcinoma, the second most common liver cancer, starts in the bile ducts and has a clinically symptomless progression. Because there are no early markers, most patients are diagnosed at an advanced stage and die due to the spread of cancer or metastasis.

“Obesity is associated with hepatic steatosis and activation of the cJun NH2-terminal kinase (JNK) stress-signaling pathway,” the authors wrote. “Studies in mice demonstrate that JNK deficiency in the liver prevents the development of hepatic steatosis. This observation suggests that inhibition of JNK signaling may represent a possible treatment for hepatic steatosis. However, the long-term consequences of JNK inhibition are poorly understood.”

In the current study, the researchers bred mice that do not express JNK1 and JNK2 proteins in their livers. “These proteins are activated when we overeat and are partly responsible for excess fat being stored in the liver (i.e., fatty liver or steatosis), and for the development of insulin resistance,” explained senior study author Guadalupe Sabio, DVM, PhD, a principal investigator at CNIC. The proteins are, therefore, “very significant for obesity and diabetes studies,” she added.

Additionally, the CNIC researchers found that these two proteins control the production of bile acids in the liver, which is essential for proper fat digestion and the absorption of fat-soluble vitamins (A, D, E, and K). “A lack of JNK1 and JNK2 in the liver leads to changes in the enzymes responsible for metabolizing cholesterol and bile acids,” noted co-senior study author Alfonso Mora, DVM, PhD, a research investigator at CNIC. In the analyzed mice, “we have observed excess blood levels of bile acids.”

The authors went on to explain that, over time, this accumulation of bile acids has a “toxic effect” on the liver. Bile ducts begin to proliferate excessively, triggering the formation of multiple cholangiocarcinomas with clinical markers, which are remarkably similar to those of patients with this type of cancer. In fact, “it is the first time that we have found the increase of a cholangiocarcinoma patient marker in mice models.” This indicates that these mice could offer new clues to assess novel cholangiocarcinoma therapies.

This model has allowed CNIC researchers, in collaboration with the laboratory of Roger Davis, PhD, at the University of Massachusetts School of Medicine, to find a protein playing a key role in this tumor process, PPARα. The protein regulates the metabolism of bile acids and liver lipids. According to Mora, the mice lacking PPARα “have significantly fewer tumors or none at all.”

Although it is still not known if these data can be extrapolated to human patients, the fact that this first animal model exists will allow the study of a type of tumor that can still only be diagnosed in its very late stages, when metastases have already happened.

Earlier studies had shown that JNK blockading prevented the development of steatosis in the liver. This is why a variety of clinical trials with inhibitors of these proteins have been launched. The researchers believe that the new findings are a “wake-up call” for these drugs. However, Sabio said we need to be cautious since “a continuous inhibition of JNK can lead to undesirable side effects.”

“This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome,” the authors concluded.

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