Liver cancer: Lipid synthesis promotes tumor formation

December 11, 2017, University of Basel
Lipid accumulation (red) in liver tissue promotes development of hepatocellular carcinoma. Credit: Biozentrum, University of Basel

Lipids comprise an optimal energy source and an important cell component. Researchers from the Biozentrum of the University of Basel and from the University of Geneva have now discovered that the protein mTOR stimulates the production of lipids in liver tumors to satisfy the increased nutrient turnover and energy needs of cancer cells, among other functions. This process has also been observed in patients with liver cancer as the scientists report in Cancer Cell.

In Switzerland, about 650 new cases of are diagnosed every year. The incidence of the malignant and aggressive liver cell carcinoma has doubled in the last 20 years, especially in developed countries. One possible reason is the increase in obesity and diabetes. The scientists, led by Prof. Michael N. Hall at the Biozentrum, University of Basel, and Prof. Howard Riezman, University of Geneva, have gained new insights into and disease progression. In mouse models and patient samples, they have demonstrated that the growth regulator mTOR—mammalian target of rapamycin—promotes de novo lipid synthesis and thus tumorigenesis. The accumulation of fatty acids and lipids in the liver is one of the major causes of .

"The liver is, in a way, our body's kitchen," explains Yakir Guri, medical doctor and first author of the study. "It stores and recycles nutrients, produces hormone precursors and detoxifies the body by eliminating harmful substances, such as drugs and alcohol." Not only excessive alcohol consumption, but also obesity and diabetes combined with lack of exercise can damage the liver. A first asymptomatic syndrome is so-called "fatty liver," which may cause inflammation that can progress to hepatocellular carcinoma (HCC). The aggressive and rapidly proliferating HCC cells ultimately destroy the surrounding healthy liver tissue, leading to liver failure.

The researchers initially investigated the progression of the disease in a mouse model. For this purpose, they constitutively activated mTOR specifically in . "We already knew that mTOR is involved in development as it centrally controls cell growth. However, in the case of HCC we did not know which downstream metabolic and signaling pathways are affected," says Guri. The researchers have now discovered that mTORC2—mTOR forms two protein complexes termed mTORC1 and mTORC2—promotes the new synthesis of fatty acids and certain lipids. Most people do not realize that our body contains more lipid species than genes. It is assumed that there are thousands of different types," says Guri. "Together with Howard Riezman's team, we have been able to analyze a broad spectrum of such lipids."

In hepatocytes, mTORC2 stimulates in particular the production of two species important for cell growth: sphingolipids and cardiolipins. The first are structural components of cell membranes, which have to be continuously supplied in rapidly proliferating cells. Cardiolipins are located in the cellular powerhouse, the mitochondria, and are involved in energy production. By enhancing cardiolipin synthesis, the energy-hungry tumor cells ensure their energy supply. "Cancer depend on the new synthesis of fatty acids and lipids; if you turn off the tap, you stop the development of tumors."

Analysis of tissue samples from patients with HCC confirmed the observations made in the mouse model. mTORC2 and its signaling pathways, which promote de novo synthesis of and lipids, are also activated in tumor samples from patients. Thus, the protein complex plays a critical role in the progression of benign "fatty " to aggressive HCC. The study provides important insights for the development of potential therapeutic interventions, as it shows that targeted lipogenesis inhibitors may have the potential to prevent tumor development.

Explore further: Trigger for fatty liver in obesity found

More information: Cancer Cell (2017). DOI: 10.1016/j.ccell.2017.11.011

Related Stories

Trigger for fatty liver in obesity found

September 7, 2017
Morbid obesity affects the liver: Almost one-third of all adults suffer from chronic fatty liver disease, which can lead to infections and even trigger cancer. Researchers at the University Children's Hospital Zurich and ...

Insulin signaling molecule in liver controls levels of triglyceride in blood

October 19, 2017
A new animal study shows how insulin controls the movement and storage of fat molecules in the liver and how a breakdown in this system could lead to non-alcoholic fatty liver disease and changes in circulating lipid levels ...

Aberrant mTOR signaling impairs whole body physiology

August 11, 2014
The protein mTOR is a central controller of growth and metabolism. Deregulation of mTOR signaling increases the risk of developing metabolic diseases such as diabetes, obesity and cancer. In the current issue of the journal ...

Fat hormone linked to progression of fatty liver disease may hold key to new treatments

November 6, 2017
The rising obesity epidemic has brought with it an army of maladies. One, in particular, is threatening to outpace many of the disorders that accompany obesity, in terms of occurrence and severity: nonalcoholic fatty liver ...

Study identifies miR122 target sites in liver cancer and links a gene to patient survival

August 22, 2017
A new study of a molecule that regulates liver-cell metabolism and suppresses liver-cancer development shows that the molecule interacts with thousands of genes in liver cells, and that when levels of the molecule go down, ...

Recommended for you

Standard chemotherapy treatment for HPV-positive throat cancer remains the most effective, study finds

November 15, 2018
A new study funded by Cancer Research UK and led by the University of Birmingham has found that the standard chemotherapy used to treat a specific type of throat cancer remains the most effective.

New 'SLICE' tool can massively expand immune system's cancer-fighting repertoire

November 15, 2018
Immunotherapy can cure some cancers that until fairly recently were considered fatal. In addition to developing drugs that boost the immune system's cancer-fighting abilities, scientists are becoming expert at manipulating ...

Anti-malaria drugs have shown promise in treating cancer, and now researchers know why

November 15, 2018
Anti-malaria drugs known as chloroquines have been repurposed to treat cancer for decades, but until now no one knew exactly what the chloroquines were targeting when they attack a tumor. Now, researchers from the Abramson ...

Researchers identify a mechanism that fuels cancer cells' growth

November 14, 2018
Scientists at the UCLA Jonsson Comprehensive Cancer Center have identified sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can utilize to obtain glucose, which is key to their survival and promotes ...

A new approach to detecting cancer earlier from blood tests: study

November 14, 2018
Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined "liquid biopsy", epigenetic alterations and machine learning to develop a blood test to detect and classify ...

New antibody breakthrough to lead the fight against cancer

November 14, 2018
Scientists at the University of Southampton have developed a new antibody that could hold the key to unlocking cancer's defence against the body's immune system.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.