Medicine in focusCholesterol metabolism: At the cross road between cancer cells and immune environment
Section snippets
Cholesterol metabolism in cancer
Cholesterol is synthesized from acetyl Coenzyme A (AcCoA) in the so called “mevalonate (MVA) pathway”. Most of the enzymes of the MVA pathway are upregulated in tumors (Yang et al., 2020). This finding explains why tumor tissues have higher levels of cholesterol than non-transformed tissues. The pacemaker enzyme 3-β-3-hydroxymethylglutaryl Coenzyme A reductase (HMGCR) is a sterol sensitive enzyme and is transcriptionally induced by the sterol regulatory element binding proteins (SREBPs) (Lee et
Cholesterol metabolism regulates the tumor-immune system interaction
If cancer cells have usually a high MVA pathway activity, immune cells display a variable situation, depending on their state. Upon activation, the canonical anti-tumor populations – cytotoxic CD8+T lymphocytes, M1 polarized tumor associated macrophages (TAMs) and mature dendritic cells (DCs) – upregulate the Ras/PI3K/mTOR axis that increases SREBP transcriptional activity and MVA pathway. By contrast, quiescent or tumor tolerant immune cells – such as memory T lymphocytes, M2 polarized TAMs,
Therapeutic implications of targeting cholesterol metabolism and future perspectives
Despite the high MVA pathway activity in cancer cells, all the regulatory mechanisms are still preserved and sensitive to pharmacological inhibitors. Modulating cholesterol metabolism may have a deep impact on the immune recognition of cancer cells. Statins and aminobisphosphonates, inhibitors of HMGCR and FPP synthase, respectively, have been already used in various cancer types. The HMG synthase inhibitor dipyridamole, the squalene epoxidase inhibitor terfinabine, as well as inhibitors of
Funding
This work was supported by the Italian Association of Cancer Research (AIRC; IG21408 to CR). The funding agency has no role in preparing the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest.
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2021, Drug Resistance UpdatesCitation Excerpt :Lactate, produced either by tumor cells or immune-infiltrating cells, also impairs the maturation of dendritic cells (DCs) (Sangsuwan et al., 2020) that support CD8+ T-lymphocytes exapnsion. Sometimes, vicious regulatory loops occur; for instance, M1-polarized TAMs and DCs (Kopecka et al., 2020a, b, c) are high producers of lactate in hypoxic tumor areas. Contrarily to the expectations, blocking the lactate exporter monocarboxylate transporter 4 (MCT4) in these cells increases the M2/M1 ratio and reduces the ability of DCs to recruit anti-tumor cytotoxic CD8+ T-lymphocytes (Sangsuwan et al., 2020).