Figure 1. Lipid metabolism reprogramming in cancer cells.

In addition to supporting tumor development, lipid metabolism reprogramming also alters the TME by affecting the recruitment, activation, and function of immune and stromal cells. On the one hand, tumor cells can actively modify the TME by secreting signaling molecules and metabolites, affecting the functions of cancer-associated fibroblasts (CAFs) and immune cells in the TME. On the other hand, lipid metabolic reprogramming, i.e., adaptive changes in cells within the TME manifested by increased lipid uptake and accumulation, or FAO, can drive the TME toward an immunosuppressive phenotype that supports tumor progression. For example, upregulated lipid uptake and FAO increase the lipid metabolism levels of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), promoting their immunosuppressive functions. In addition, the upregulation of CD36 in CD8 + T cells leads to excessive accumulation of lipids, which affects the secretion of anti-tumor factors such as IFN-γ, TNF-α, and ultimately inhibits their anti-tumor effects. Similarly, the upregulation of CD36 in natural killer cells (NK) can also weaken their tumor-killing activity through intracellular lipid accumulation. Studies have shown that blocking lipid uptake by inhibiting CD36 of cytotoxic CD8+ T cells or Tregs enhances anti-tumor immune responses.

Given the critical role of lipids in cancer progression, targeting lipid metabolism-related pathways provides new therapeutic opportunities for cancer. A large amount of evidence shows that inhibitors targeting tumor cell lipid uptake, adipogenesis, and FAO show significant therapeutic effects in various cancers. In addition, regulating lipid metabolism in stromal cells and immune cells also provides new options for anti-tumor treatment. In addition, it can be combined with chemotherapy and immunotherapy, providing a new comprehensive strategy for optimizing cancer treatment.

Current Status and Mechanisms of Lipid Metabolism Reprogramming in Cancer

Lipid Metabolism Reprogramming in Cancer

The majority of lipid molecules in the human diet are triacylglycerols (TAGs) and cholesterol. After TAGs are absorbed, they can be hydrolyzed into glycerol and fatty acids (FAs). Glycerol is then converted into glycerol-3-phosphate (G-3P), which enters the glycolysis process. FAs can either be stored as the main component of membrane synthesis or converted into acyl-CoA to provide energy for β-oxidation. In tumors, several steps of lipid metabolism are generally enhanced to sustain their biological progression. This includes increases in fat absorption, synthesis, storage and FAO.

Carcinogenic Factors Affecting Tumor Lipid Metabolism

Activation of oncogenes and loss of tumor suppressor gene function are the main causes of tumorigenesis. They also play an important role in the reprogramming of tumor metabolism by regulating the expression of lipid metabolism enzymes. Sterol regulatory element binding proteins (SREBPs) are key upstream regulators of lipid metabolism. SREBP is a transcription factor that promotes DNL by upregulating key enzymes such as ACLY, FASN, and SCD. These key enzymes are closely related to tumor proliferation, apoptosis, and invasion. Furthermore, SREBP maintains intracellular cholesterol levels by inducing LDL receptor-mediated cholesterol uptake and inhibiting abca1-mediated cholesterol export in an mTORC1-dependent manner. Mutations in SREBPs and oncogenes (such as PI3K and MYC) and tumor suppressor genes (such as p53 and PTEN) can induce downstream lipid reprogramming events.

Microenvironmental Factors Affecting Tumor Lipid Metabolism

Metabolic reprogramming of cancer cells is the result of a multifactorial process. The TME also plays a crucial role with the activation of oncogenic signals caused by mutations in tumor cells. The TME contains multiple factors, such as hypoxia, acidosis, and malnutrition, which promote tumor occurrence and progression by changing the lipid metabolism of tumor cells.

Current Status and Mechanisms of Lipid Metabolism Reprogramming in TME

As cancer progresses, the TME also undergoes reprogramming of lipid metabolism. It is worth noting that tumor cells play an important role in changing the TME (such as acidosis, lipid accumulation) by producing metabolites and lipid-related signaling molecules. This in turn affects the metabolic pattern and immune phenotype of TME cells, leading to remodeling of the immune microenvironment. For example, CAFs secrete lipids in the TME to directly provide an energy source for tumor cells, thus promoting tumor progression. In addition, the lipid metabolism reprogramming of CAFs also affects their own cytokine secretion function, thereby regulating immune responses and promoting the formation of an immunosuppressive microenvironment. In addition, changes in the lipid metabolism pattern of immune cells are also conducive to the construction of an immunosuppressive microenvironment and support tumor immune escape. Therefore, tumor progression is the result of a co-evolutionary process between the tumor and the TME.

The post Reprogramming of Lipid Metabolism in the Tumor Microenvironment first appeared on Creative Diagnostics.

It is well known that exposure to ROS levels above the steady-state threshold has been identified as the main cause of damage to cellular macromolecules. Among them, the most sensitive biological component to ROS damage is DNA, especially mitochondrial DNA. As we all know, mitochondria are the main source of oxidants in cells. The damage of oxidative stress to DNA molecules is particularly evident in the break of the double-stranded helix and the change of the nitrogen base. The most studied DNA damage is the formation of 8-OH-G. Generally, for proliferating young cells, damage can be repaired more effectively by using base or nucleotide excision repair pathways and homologous recombination. However, in cells derived from elderly individuals, these repair pathways are less efficient, which is the first step leading to an increased incidence of carcinogenesis and mutagenesis.

In addition to DNA, proteins in the body are also affected by elevated ROS levels in terms of structure and function. Among them, the most easily oxidized components are the cysteine and methionine residues of the protein side chain. This is due to the formation of reducing disulfide bonds between the thiol groups of the protein. Normally, the proteasome in the body is responsible for breaking down oxidized proteins. However, as cells begin to age, the level of proteasome activity will be greatly reduced, leading to the accumulation of these oxidized proteins in the cell, which in turn leads to the activation of cell death pathways.

The last biological component to which cells are particularly sensitive to oxidants are lipids, especially the fatty acid residues of phospholipids in cells. The lipid peroxidation process involves various carbon-carbon bonds of free radical substances and produces products similar to hydroperoxides, which have been identified as potential indicators of oxidative stress in various tissues. Free radicals have the ability to damage cell membranes and cell integrity. From a macro point of view, the oxidation of lipids will change fluidity and cause severe physiological and membrane damage, which is also obvious in certain diseases. At the cellular level, ROS and OS induce a variety of related cell fates, such as apoptosis, necrosis, autophagy, and senescence, which may adversely affect tissue structure and function.

Since oxidative stress markers are necessary for accurate evaluation to study various pathological conditions and evaluate the effectiveness of drugs, biomarkers that can be used to evaluate oxidative stress have attracted much attention. From a clinical point of view, the use of biomarkers to assess the degree of oxidative stress is very valuable. The markers found in blood, urine and other biological fluids may provide information of diagnostic value, but it would be ideal if the organs and tissues suffering from oxidative stress can be directly observed in a way similar to scanning imaging. In recent years, attempts have been made to realize this idea using electron spin resonance technology, but it will take time to apply this method to humans. Since oxidative damage is bound to exist in the human body, some of its components may be damaged by free radicals, so oxidation products are usually used as markers. Many markers have been proposed, including lipid peroxides, malondialdehyde and 4-hydroxynonenal as markers of lipid oxidative damage. Isoprostaglandins are the products of arachidonic acid free radical oxidation; 8-oxoguanine (8-hydroxyguanine) and thymine diol can indicate DNA oxidative damage; and various oxidation products of protein and amino acid oxidation, Including carbonyl protein, hydroxybutyrin, hydrovaline and nitrotyrosine. Even in relatively early studies, lipid peroxides have been evaluated in clinical samples, and the analysis and detection methods for this substance have been improved. Among them, substances used to measure the reaction with thiobarbituric acid have been widely used in clinical and experimental research. Such substances have become the most commonly used indicators of oxidative stress, partly because lipid peroxidation is an important mechanism for cell membrane destruction. Lipid peroxidation is a chain reaction through which unsaturated fatty acids in cell membranes are oxidized. When hydrogen atoms are removed from fatty acid molecules for some reason, free radical chain reactions will proceed. Therefore, free radicals that can participate in the extraction of hydrogen atoms from lipids include hydroxyl (HO), hydroperoxide radicals (HOO), lipid peroxy radicals (LOO) and alkoxy radicals (LO). Metal-oxygen complexes, especially iron-oxygen complexes, are also important in the body. Once started, the peroxide chain reaction will propagate itself. The process of generating lipid radicals (L) from lipids (LH) is called chain initiation reaction. The lipid radicals (L) thus produced immediately react with oxygen to form LOO, which attacks another lipid and removes hydrogen atoms from it, resulting in the formation of lipid hydroperoxide (lipid peroxide; LOOH) and another An L. L also reacts with oxygen and forms LOO. LOO attacks another lipid to generate lipid peroxide, so as the chain reaction progresses, lipid peroxide will accumulate.

Among substances that protect human lipids from peroxidation, vitamin E is considered the most important. This vitamin has attracted widespread attention as an antioxidant because it can scavenge lipid peroxidation free radicals, thereby preventing the propagation of free radical chain reactions. The lipid peroxy radical removes a hydrogen atom from the phenyl group of vitamin E and has stabilized the hydrogen atom. In turn, vitamin E is converted into free radicals, which are stable and less reactive. Therefore, such free radicals derived from vitamins are unlikely to attack lipids and perpetuate the chain reaction. Instead, it can react with another peroxy radical and become stable as a result. This antioxidant reaction protects biological membranes from free radicals and lipid peroxides. However, despite the presence of a sufficient concentration of vitamin E, lipid peroxides are still produced in the plasma.
Therefore, plasma vitamin E level seems unlikely to be a useful biomarker of oxidative stress. In addition, vitamin E is fat-soluble, so its blood level varies according to the lipid content. Studies have found that when encountering oxidative stress, vitamin C decreases first, followed by coenzyme Q-10 (Panthenol 10). This indicates that vitamin C and panthenol 10 are the most sensitive antioxidants to oxidative stress. Vitamin E is an important antioxidant, so it can be protected by vitamin C and panthenol 10.

The post Oxidative Stress Markers first appeared on Creative Diagnostics.