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. 2021 Sep 15;12:730751. doi: 10.3389/fphar.2021.730751

FIGURE 1.

FIGURE 1

Lipid signals alteration in CSCs and TME. Intracellular lipid signals comprise of lipid uptake, lipolysis, fatty acid oxidation, lipid synthesis, lipid desaturation, and lipid peroxidation. In this figure, we have briefly exhibited the pathways of lipid uptake, lipolysis, fatty acid oxidation, lipid synthesis, and lipid desaturation. The metabolic products of other forms of metabolism, such as citrate produced in glucose metabolism, are transported out of mitochondria by citrate-pyruvate cycle. Then, citrate is converted to malonyl-CoA by the catalysis of ACLY and ACC. Malonyl-CoA is used by FASN to synthesize FAs. Redundant FAs result from de novo synthesis and uptake by CD36 are stored in LDs, and LDs provide FAs by lipolysis. Fatty acids can be converted into acyl-CoA, and the latter can be transported into mitochondria by CPT1 for fatty acid β-oxidation. Besides, SCD1 can catalyze FAs into MUFAs. In CSCs, these pathways are abnormally upregulated. The pathway of lipid synthesis is closely related with the stemness features, including cell growth and proliferation, invasion and metastasis, and resistance to therapy, in CSCs. The inhibition of lipid synthesis induces the death of CSCs. The upregulation of lipid desaturation supports the growth, proliferation, and resistance to therapy in CSCs. Inhibiting SCD1 improves the sensibility of CSCs to ferroptosis. The higher level of LDs promotes the growth and proliferation of CSCs. Blockage of lipolysis leads to the death of CSCs. The upregulation of lipid uptake supports the growth and proliferation of CSCs. The upregulation of FAO has a positive effect on the growth, proliferation, invasion, metastasis, and resistance to therapy in CSCs. Extracellular lipid signals in TME also support the stemness of CSCs. Mesenchymal stem cells induce the expression of AGAP2-AS1 and HCP5 to elevate FAO in CSCs to support the stemness of CSCs. Besides, CAAs improve the levels of LDs and the expression of CPT1 and CD36 by secreting cell factors or lipid transfer to support the stemness of CSCs. (ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; CAA, cancer-associated adipocytes; FA, fatty acid; FAO, fatty acid oxidation; FASN, fatty acid synthase; CD36, cluster of differentiation 36; LD, lipid droplet; CPT1, carnitine palmitoyltransferase-1; MUFA, monounsaturated fatty acid; MSC, mesenchymal stem cell; SCD1, stearoyl-CoA desaturase 1; TME, tumor microenvironment).