Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy

Abstract

Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.

Keywords: cancer stem cell; ferroptosis; lipid metabolism; therapeutic target; tumor environment.

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).

FIGURE 2

The pathways of lipid peroxidation and ferroptosis. The production of LPO mainly results from auto-oxidation of lipids and enzymatic lipid peroxidation. Auto-oxidation of lipid is a radical reaction, which means the upstream reaction can induce the downstream reaction. PL is converted to PL• by ROS, which is the production of Fe²⁺ and H₂O₂. PL• reacts with O₂ to form PL-OO•, which further reacts with a new PL to form PL-OOH and a new PL•, proceeding downstream radical reaction. Enzymatic lipid peroxidation mainly takes place in AA or AdA. AA and AdA can be converted into PE-AA-OOH and PE-AdA-OOH by the catalysis of ACSL4, LPCAT3, and 15-LOX. The elimination of LPO mainly relies on GPX4 and FSP1. Cystine is transported into cells via system x_c ⁻, which is the raw material for the production of GSH. GPX4 converts GSH to GSSH and reduces LPO in the meantime. Besides, FPS1 converts CoQ₁₀ to ubiquinol, which reduces LPO. The accumulation of LPO, caused by excessive production or blockage of elimination of LPO, leads to ferroptosis. (15-LOX, 15-lipoxygenases; AA, arachidonoyl; ACSL4, acyl-CoA synthetase long-chain family member 4; AdA, adrenoyl; CoQ₁₀, coenzyme Q₁₀; FSP1, ferroptosis suppressor protein 1; LPO, lethal lipid peroxides; LPCAT3, lysophosphatidylcholine acyltransferase 3; PL, phospholipids; PL•, phospholipid radical; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; ROS, reactive oxygen species).

FIGURE 3

Drugs targeting lipid metabolism. In this figure, we presented related drugs, which were listed in Table 1, in the boxes and linked them to the targets of lipid metabolism including lipid uptake, lipolysis, fatty acid oxidation, lipid synthesis, lipid desaturation, the mevalonate pathway and lipid peroxidation. (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; LPO, lethal lipid peroxides).