Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

Abstract

Cancer remains the second leading cause of mortality worldwide. In the course of this multistage and multifactorial disease, a set of alterations takes place, with genetic and environmental factors modulating tumorigenesis and disease progression. Metabolic alterations of tumors are well-recognized and are considered as one of the hallmarks of cancer. Cancer cells adapt their metabolic competences in order to efficiently supply their novel demands of energy to sustain cell proliferation and metastasis. At present, there is a growing interest in understanding the metabolic switch that occurs during tumorigenesis. Together with the Warburg effect and the increased glutaminolysis, lipid metabolism has emerged as essential for tumor development and progression. Indeed, several investigations have demonstrated the consequences of lipid metabolism alterations in cell migration, invasion, and angiogenesis, three basic steps occurring during metastasis. In addition, obesity and associated metabolic alterations have been shown to augment the risk of cancer and to worsen its prognosis. Consequently, an extensive collection of tumorigenic steps has been shown to be modulated by lipid metabolism, not only affecting the growth of primary tumors, but also mediating progression and metastasis. Besides, key enzymes involved in lipid-metabolic pathways have been associated with cancer survival and have been proposed as prognosis biomarkers of cancer. In this review, we will analyze the impact of obesity and related tumor microenviroment alterations as modifiable risk factors in cancer, focusing on the lipid alterations co-occurring during tumorigenesis. The value of precision technologies and its application to target lipid metabolism in cancer will also be discussed. The degree to which lipid alterations, together with current therapies and intake of specific dietary components, affect risk of cancer is now under investigation, and innovative therapeutic or preventive applications must be explored.

Keywords: cancer prognosis; cancer risk; lipid metabolism; obesity; precision medicine; precision nutrition; tumor microenviroment (TME).

Figure 1

Relevance of lipid metabolism alterations in cancer. Illustrated is the crucial role of (i) oncogenic mutations supporting the lipid metabolism reprogramming in cancer, together with (ii) systemic lipid metabolic alterations associated with obesity—as an environmental modifiable risk factor. Precision interventions should include therapeutic clinical drugs targeting identified lipid metabolism molecular targets together with nutritional interventions—bioactive compounds, diet-derived ingredients—considering the nutritional and metabolic status of patients. T2DM, type 2 diabetes mellitus; IR, Insulin Resistance; TME, tumor microenviroment; CAAs, cancer-associated adipocytes; FAO, fatty acid oxidation; FA, fatty acid.

Figure 2

Main metabolic pathways related to lipid metabolism in cancer: Illustration of pathways and genes implicated in de novo lipogenesis—fatty acids and cholesterol biosynthesis. ABCA1, ATP-binding cassette subfamily A member 1; ABCG1, ATP-binding cassette subfamily G member 1; ABCG4, ATP-binding cassette subfamily G member 4; ABCG5, ATP-binding cassette subfamily G member 5; ABCG8, ATP-binding cassette subfamily G member 8; ACAT, acetyl-CoA acetyltransferase; ACC, acetyl- CoA carboxylase; ACLY, ATP citrate lyase; ACSL, acyl-CoA synthetase long chain; AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; CD36, CD36 molecule; CPT1, carnitine palmitoyltransferase; DGAT, diacylglycerol O-acyltransferase; FA, Fatty acids; FASN, fatty acid synthase; GPAT, glycerol-3-phosphate acyltransferase; HDL, high-density lipoprotein; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS, 3-hydroxy-3-methylglutaryl-CoA synthase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPIN, Lipin; NR1H2, nuclear receptor subfamily 1 group H member 2; NR1H3, nuclear receptor subfamily 1 group H member 3; PLIN, perilipin; PPARγ, peroxisome proliferator-activated receptor γ; PTGS, prostaglandin-endoperoxide synthase; SCD1, stearoyl-CoA desaturase; SREBP1, Sterol regulatory element binding transcription factor 1; SREBP2, sterol regulatory element binding transcription factor 2; TCA, tricarboxylic acid cycle.