Lipid metabolic reprogramming in cancer cells

Abstract

Many human diseases, including metabolic, immune and central nervous system disorders, as well as cancer, are the consequence of an alteration in lipid metabolic enzymes and their pathways. This illustrates the fundamental role played by lipids in maintaining membrane homeostasis and normal function in healthy cells. We reviewed the major lipid dysfunctions occurring during tumor development, as determined using systems biology approaches. In it, we provide detailed insight into the essential roles exerted by specific lipids in mediating intracellular oncogenic signaling, endoplasmic reticulum stress and bidirectional crosstalk between cells of the tumor microenvironment and cancer cells. Finally, we summarize the advances in ongoing research aimed at exploiting the dependency of cancer cells on lipids to abolish tumor progression.

Figure 1

A simplified map of the main altered lipid metabolic pathways in cancer cells. Lipid metabolic network (blue) includes import/export and catabolic pathways (FAO) as well as de novo synthesis pathways, such as lipogenesis (that is, synthesis of TGs and PLs) and cholesterol synthesis. Glucose- and/or glutamine-derived citrate, provided by the increased glycolysis and/or glutaminolysis (orange), are common precursors of lipogenesis and cholesterol synthesis. Cancer cells can also take up exogenous cholesterol, transported by LDL and very-low-density lipoproteins (VLDL), to meet their cholesterol requirement. When cholesterol, PLs and TGs are in excess in tumors, they are exported into circulation as high-density lipoproteins (HDLs) or locally stored into LDs. Exogenous FAs taken up by cancer cells are broken down to produce energy through mitochondrial FAO process. TCA cycle, tricarboxylic acid cycle αKG, α-Ketoglutarate.

Figure 2

Lipid rafts as platforms for cell signaling. (a) Lipid rafts are formed by a phospholipid bilayer enriched in cholesterol, sphingolipids and resident signaling proteins (AKT) and receptors (GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase including growth factor receptor (GFR); CXCR4, C-X chemokine receptor 4). Once activated by their respective ligands, the receptors recruit different signaling effectors that promote cell survival, cell migration and cell invasion, all of which contribute toward tumor growth. (b) Aggregation of death receptors (DR4/DR5, Fas) in lipid rafts forms CASMERs. Recruitment of CASMERs in a restricted space enhances fas-associated protein with death domain (FADD)/Caspase-8 death signaling pathway when compared with apoptotic signal induced by the activation of non-clustered death receptors.

Figure 3

Tumor–stroma bidirectional dialog. Schematic representation of lipid exchanges between cancer cells and the different cell types found in the TME. In adipocytes adjacent to cancer cells, the hydrolysis of TG, stored in LDs, releases free fatty acids (FFAs) which are taken up by cancer cells, transported through fatty acid binding protein 4 (FABP4) and degraded to provide ATP needed for their growth. Bioactive lipids secreted by cancer cells, PGE2 and S1P, exert their effects on stromal cells through paracrine mechanisms. The PGE2, transported or not by exosomes, promotes angiogenesis and also immunosuppression. The latter effect results from an activation of myeloid-derived suppressor cells and differentiation of monocytes into suppressor macrophages. Moreover, tumor-derived PGE2 induces kynurenine secretion by CAFs which in turn promote cancer cell invasiveness. S1P, by its binding on its specific receptor, promotes cancer cell proliferation and angiogenesis/lymphangiogenesis in an autocrine and paracrine manner, respectively. Taken together, FFA and free bioactive lipids contribute toward promoting tumor growth. Exosomes in TME contain high lipid levels within the membrane and lumen, and therefore constitute extracellular lipid sources which can be internalized by cancer cells and are responsible for the increased cell lipid concentration which triggers an ERS-induced cell death.