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.

Effects of the Combined Treatment with a G-Quadruplex-Stabilizing Ligand and Photon Beams on Glioblastoma Stem-like Cells: A Magnetic Resonance Study

“…Lipid metabolism has been regarded as one of the key factors for the correct function of pathways involved in GSC fate and characteristics, e.g., chemotherapy evasion [ 56 , 57 ]. Enhanced lipid metabolism is essential for the survival, growth, and oncogenicity of GSCs [ 58 , 59 ]. GSCs seem to have increased levels of lipids and fatty acid oxidation (FAO)-related genes and these can maintain GSC self-renewal by modulating lipid and membrane synthesis, quenching ROS through NADPH production, and promoting chemo-resistance [ 23 , 59 ].…”

“…Enhanced lipid metabolism is essential for the survival, growth, and oncogenicity of GSCs [ 58 , 59 ]. GSCs seem to have increased levels of lipids and fatty acid oxidation (FAO)-related genes and these can maintain GSC self-renewal by modulating lipid and membrane synthesis, quenching ROS through NADPH production, and promoting chemo-resistance [ 23 , 59 ].…”

Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches

“…In cancer cells, lipogenesis parallels elevated FAS expression, cell migration, evasion of apoptosis, and aggressiveness [33,34]. The accumulation of fatty acids by lipogenesis results in their storage in LDs, and cytoplasmic lipases catalyze their output.…”

Mechanism of cancer stemness maintenance in human liver cancer

“…Therefore, the reduction in unsaturated fatty acid synthesis by inhibiting SCD1 can inhibit the stemness of CSCs and improve the sensitivity of CSCs to other antitumor drugs in many tumors, such as LCSCs [ 45 ]. In addition, it is generally believed that there is a close relationship between unsaturated fatty acids in the cell membrane and ferroptosis [ 46 ], an iron-dependent, lipid-peroxide-driven form of programmed cell death that differs, from other forms of cell death. Of note, lethal lipid peroxide (LPO) is the main cause of ferroptosis; hence, eliminating LPO can protect cells from ferroptosis.…”

“…Of note, lethal lipid peroxide (LPO) is the main cause of ferroptosis; hence, eliminating LPO can protect cells from ferroptosis. The elimination of LPO depends on the NADPH/FSP1/coenzyme Q10 (CoQ10) and system X C − /GSH/GPX4 axes [ 46 ]. In fact, inhibiting the expression of some key regulators in the LPO process, such as system X C − , FSP1 and GPX4, has been proven to effectively inhibit the CSC stemness phenotype by inducing ferroptosis [ 47 ].…”