New research reported in the journal Cancer Cell, reported that scientists have discovered a protein mTOR that stimulates the production of lipids in liver tumours to satisfy the increased nutrient turnover and energy needs of cancer cells among other functions.
Lipid (fat) is an optimal energy source and an important cell component that is required for the rapid and uncontrolled growth of cancer cells. The researchers have gained new insights into liver tumour development and disease progression.
In mouse models and patient samples, the team has revealed 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 hepatocellular carcinoma.
Yakir Guri, first author of the study said liver 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 scientists initially investigated the progression of the disease in a mouse model. For this purpose, they constitutively activated mTOR specifically in liver cells. The researchers already knew that mTOR is involved in tumour development as it centrally controls cell growth.
However, in the case of HCC they did not know which downstream metabolic and signalling pathways are affected. 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.
In hepatocytes, mTORC2 stimulates, in particular, the production of two lipid species important for cell growth: sphingolipids and cardiolipins. The first is 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 tumour cells ensure their energy supply. "Cancer cells depend on the new synthesis of fatty acids and lipids; if you turn off the tap, you stop the development of tumours."
Analysis of tissue samples from patients with HCC confirmed the observations made in the mouse model. mTORC2 and its signalling pathways, which promote de novo synthesis of fatty acids and lipids, are also activated in tumour samples from patients.
The team said, thus, the protein complex plays a critical role in the progression of the benign fatty liver 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 tumour development.