Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development

Abstract

An increased rate of lipid synthesis in cancerous tissues has long been recognised as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids to cellular transformation, tumour development and tumour progression, as well as their potential role in facilitating the spread of cancerous cells to secondary sites, are not yet fully understood. In this article, we review the recent findings that support the importance of lipid synthesis and metabolism in tumorigenesis. Specifically, we explore the role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis. These processes are crucial for the dissemination of tumour cells and formation of metastases, which constitute the main cause of cancer mortality.

Fig. 1.

Lipid biosynthesis. Schematic overview of the pathways involved in the synthesis of fatty acids (FAs), cholesterol, phosphoglycerides, eicosanoids and sphingolipids. The enzymes involved in catalysing steps in lipid biosynthetic pathways are indicated in red. (a) Glucose- or glutamine-derived citrate is first converted to acetyl-CoA by ACLY. (b) For FA biosynthesis, acetyl-CoA is converted into malonyl-CoA. The repeated condensation of acetyl-CoA and malonyl-CoA by the multifunctional enzyme FASN leads to the generation of palmitic acid, a fully saturated 16-carbon FA. The introduction of a double bond in the Δ9 position of the acyl chain by SCD generates mono-unsaturated FAs. (c) Subsequent elongation and further desaturation produces the repertoire of FAs with different saturation levels. (d) Essential FAs (ω3 and ω6 FAs) cannot be synthesised by human cells and need to be provided from dietary sources. (e,f) Saturated and unsaturated FAs are combined with glycerol-3-phosphate (glycerol-3-P) to generate (e) phosphoglycerides and (f) phosphoinositides. (g) Arachidonic acid, a long-chain polyunsaturated FA, is used for the synthesis of eicosanoids. (h) Sphingolipids contain acyl chains and polar head groups derived from serine, phosphocholine or phosphoethanolamine. (i) Cholesterol biosynthesis is initiated by the conversion of acetyl-CoA to acetoacetyl-CoA. Addition of another acyl group by HMGCS produces 3-methylglutaryl-3-hydroxy-CoA, which is converted to mevalonate by HMGCR. Subsequent reactions result in the production of farnesyl-pyrophosphate, an essential intermediate for protein prenylation. Cholesterol also forms the structural backbone for steroid hormone biosynthesis. Enzyme abbreviations: ACAT, acetyl-CoA acetyltransferase; ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; COX1/2, prostaglandin-endoperoxide synthase (PTGS); DGAT, diacylglycerol O-acyltransferase; ELOVL, fatty acid elongase; FADS, fatty acid desaturase; FASN, fatty acid synthase; GPAT, glycerol-3-phosphate acyltransferase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS, 3-hydroxy-3-methylglutaryl-CoA synthase; PPAP, phosphatidic acid phosphatase; SCD, stearoyl-CoA desaturase; SPHK, sphingosine-1-kinase. Metabolite abbreviations: α-KG, α-ketoglutarate; CDP-DAG, cytidine diphosphate-diacylglycerol; CER, ceramide; DAG, diacylglycerol; FA, fatty acid; LPA, lysophosphatidic acid; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGE₂, prostaglandin E₂; PGH₂, prostaglandin H₂; PI, phosphatidylinositol; PIPx, phosphatidylinositol phosphate; PS, phosphatidylserine; S1P, sphingosine-1-phosphate; SPH, sphingosine; TAG, triacylglyceride.

Fig. 2.

The roles of lipids in the tumour microenvironment. Lipids play important roles during tumour initiation and disease progression. Activation of HMGCR drives cell transformation (stage 1). Activation of SREBP and induction of enzymes of the mevalonate pathway are involved in the disruption of normal tissue architecture, and release of FAs by MAGL can promote cancer cell migration (stage 2). Lipids are also involved in the interaction of cancer cells with components of the tumour stroma. For example, cancer-associated fibroblasts (CAFs) show increased expression of FASN. Signalling lipids, including PGE₂, regulate the recruitment of cancer-promoting M2 macrophages, which can promote cancer cell migration and invasion (stage 3). LPA and S1P regulate the cytotoxic function of natural killer (NK) cells. PGE₂ can also act as a pro-angiogenic factor by promoting the outgrowth (sprouting) of vascular and lymphatic endothelial cells, and the dissemination of tumour cells into distant tissues during metastasis formation (stage 4). Adipocytes can induce the homing of metastatic cancer cells by releasing cytokines (stage 5). The metabolic coupling between adipocytes and cancer cells involves the release of FAs by adipocytes, which are then used for energy production by cancer cells (stage 6).