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Lipids, including sterols, isoprenoids, acylglycerols and phospholipids, are hydrophobic biomolecules. They are components of biological membranes, are used in energy metabolism and storage, and have important roles as signalling molecules. Many lipids are synthesized from fatty acids (FAs), a diverse class of molecules consisting of hydrocarbon chains of different lengths and degrees of desaturation. FAs form the hydrophobic tails of phospholipids and glycolipids, which, together with cholesterol, represent major components of biological membranes. Membrane lipids also give rise to second messengers, such as diacylglycerol (DAG) and phosphatidyl inositol-3,4,5-trisphosphate (PIP3; also known as PtdIns(3,4,5)P3), which are formed in response to extracellular stimuli. FAs can also be assembled into triacylglycerides (TAGs), nonpolar lipids that are synthesized and stored during high nutrient availability and that release ample energy when brokendown.
Warburg etal.1 discovered in the 1920s that tumours have a high rate of glucose uptake and perform glucose fermentation independently of oxygen availability. Later, Medes etal.2 established that tumours convert glucose or acetate into lipids at a rate similar to that observed in liver2. Although this study concluded that this process is probably too slow to supply the lipid needs of a rapidly growing tumour, and the tumour must therefore obtain its lipids preformed by the host, another study found that tumour cells generate almost all their cellular FAs through denovo synthesis3. Several decades later, fatty acid synthase (FASN) was identified as the tumour antigen OA-519 in aggressive breast cancer4. Numerous studies have since confirmed the importance of FA biosynthesis for cancer cell growth and survival5,6 (FIG.1).
The modular nature of lipids, particularly those containing several FAs, determines the enormous structural complexity in this class of molecules7. Moreover, lipids
are energy-rich compounds that can be degraded to provide ATP and contribute to cellular bioenergetics. The regulation of lipid synthesis, modification, uptake and degradation is therefore essential for the maintenance of cellular physiology, and perturbation of the processes controlling lipid provision can inhibit cell survival. It is therefore no surprise that lipid metabolism, in particular FA biosynthesis, is increasingly recognized as a potential therapeutic target incancer.
This Review summarizes the evidence for alterations in FA metabolism in cancer. We discuss the regulation of lipid metabolism and the contribution of the tumour microenvironment to lipid provision. We also explore roles...