An Overview of Lipid Droplets in Cancer and Cancer Stem Cells

Abstract

For decades, lipid droplets have been considered as the main cellular organelles involved in the fat storage, because of their lipid composition. However, in recent years, some new and totally unexpected roles have been discovered for them: (i) they are active sites for synthesis and storage of inflammatory mediators, and (ii) they are key players in cancer cells and tissues, especially in cancer stem cells. In this review, we summarize the main concepts related to the lipid droplet structure and function and their involvement in inflammatory and cancer processes.

Figure 1

Growth of Web of Science-indexed publications, by year, using the key words “lipid droplets,” “lipid bodies,” “adiposomes,” or “oil bodies,” from 1950 to 2016.

Figure 2

Schematic overview of the metabolic pathways required for the de novo synthesis of triacylglycerols and their lipolysis. Simplified representations of de novo FA synthesis and LD biogenesis are also included. FA-coA and MUFA/PUFA-coA are in general referred to as FA-CoA. AMP: adenosine monophosphate; ATP: adenosine triphosphate; ACATs: acyl-coA:cholesterol acyltransferases; ACS: acyl-coA synthetase; AGPATs: 1-acyl-glycerol-3-phosphate acyltransferases; ATGL: adipose tissue triacylglycerol lipase; CEH: cholesteryl ester hydrolase; CEs: cholesteryl esters; CoA: coenzyme A; DAG: diacylglycerol; DGAT: diacylglycerol acyltransferase; DHAP: dihydroxyacetone phosphate; DHAP-OR: dihydroxyacetone phosphate oxidoreductase; DHAPAT: dihydroxyacetone phosphate acyltransferase; ER: endoplasmic reticulum; FA: fatty acid; FA-CoA: fatty acyl-coenzyme A; FFA: free fatty acid; sFA: saturated FA; FASN: fatty acid synthase; GLYK: glycerol kinase; GPATs: glycerol-3-phosphate acyltransferases; cGPDH: cytosolic glycerol-3-phosphate dehydrogenase; mGPDH: mitochondrial glycerol-3-phosphate dehydrogenase; HSL: hormone-sensitive lipase; LDAPs: lipid droplet-associated proteins; LP-CH: lipoprotein involved in transporting cholesterol; MAG: 1-acylglycerols; MGL: monoacylglycerol lipase; MUFA: monounsaturated FA; NAD: nicotinamide adenine dinucleotide; NADH: reduced nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; NADPH: reduced nicotinamide adenine dinucleotide phosphate; P: phosphate; PA-P: phosphatidic acid; PAP: phosphatidic acid phosphatase; PUFA: polyunsaturated FA; SCDs: stearoyl-CoA desaturases; TAG: triacylglycerol; TCA: tricarboxylic acid cycle.

Figure 3

Schematic model representing the mechanisms of PLIN1 and PLIN2 action and PLIN3, PLIN4, and PLIN5 localization. In basal conditions (left panel), PLIN1 forms a complex with CGI-58, while ATGL association with G0S2 impairs the enzyme activity. PLIN1 and PLIN 2 block the LD access to lipases, and only a low rate of lipolysis takes place. Under lipogenic stimuli or FA surplus (central panel), PLIN2, PLIN3, and PLIN4 localize on nascent LDs at ER. Lipolytic stimuli (right panel), such as β-adrenergic stimulation, activate PKA via increased levels of cAMP. PKA phosphorylates PLIN1 and HSL, inducing HSL translocation to LD surface and release of CGI-58. This latter can form a complex with ATGL, whose activity also requires the binding with GBF1 factor and with Arf/COPI complex resulting in activated lipolysis. GBF1: Golgi brefeldin A resistance guanine nucleotide exchange factor 1; G052: 33mer gliadin peptide; CGI-58: comparative gene identification-58; P1: perilipin 1; P2: perilipin 2; P3: perilipin 3; P4: perilipin 4; P5: perilipin 5; PKA: protein kinase A; Arf1/COPI: ADP ribosylation factor/coat protein complex.

Figure 4

The schematic model depicts the hypothetic CSC niche (on the left) in human tumors. The main elements are summarized: (i) the cellular components, such as CSCs, cancer cells, adipocytes, immune cells, and stroma cells [e.g., cancer-associated fibroblasts (CAFs) and mesenchymal stem cells (MSCs)]; (ii) ECM components: collagen, laminin, and so forth; and (iii) soluble factors (growth factors, proinflammatory cytokines, chemokines, exosomes, etc.) release from different cell types and nutrient supply from vasculature. A CSC (on the right) shows higher amount of LDs compared with other cells. Within tumor bulk, hypoxia develops due to limited vascularization. A continuous interplay among different factors inside the niche, including hypoxic/normoxic conditions, nutrient supply availability, the release of soluble factors, and cell‐cell interactions contributes to determine the CSC properties and influences their metabolic plasticity, as reviewed in [143, 163, 166, 174]. A single cancerous LD (bottom) is also schematically represented, based on [121, 178].

Figure 5

Hypothetical model of NF-kB/SCD1 pathway based on [177, 185]. Activated NF-kB pathway stimulates SCD1 upregulation, which could modulate several pathways (such as Wnt/β-catenin and YAP/TAZ signalings) resulting in CSC proliferation, cancer invasiveness, and tumorigenesis.