Lipid synthesis promotes tumor formation in liver

Lipids comprise an optimal energy source and an important cell component. Researchers from the have 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 mouse models and patient samples, researchers 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 hepatocellular carcinoma.

Liver stores and recycles nutrients, produces hormone precursors and detoxifies the body by eliminating harmful substances, such as drugs and alcohol. 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 liver cells. mTOR is involved in tumor development as it centrally controls cell growth. 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. Human body contains more lipid species than genes. It is assumed that there are thousands of different types.

In hepatocytes, mTORC2 stimulates in particular the production of two lipid 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 cells depend on the new synthesis of fatty acids and lipids. 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 fatty acids and lipids, are also activated in tumor samples from patients. Thus, the protein complex plays a critical role in the progression of 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 tumor development.
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