Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment – PMC

γ, lipopolysaccharide, or GM-CSF]nHighlight:M2 macrophages (anti-inflammatory phenotype, driven by IL-4, IL-13, or CSF-1), which is determined by the surrounding microenvironmentnHighlight:Early in tumor development, M1-polarized macrophages are potent effector cells that are able to elicit tumor cell disruption.nHighlight:as tumorigenesis progresses, the TME favors the transition of infiltrated macrophages to the M2 phenotype with protumorigenic activitiesnHighlight:TAMs are widely considered to be M2 macrophages, in that they promote tumor angiogenesis, cancer progression, and immunosuppressionnHighlight:M2-like TAMs inhibit cytotoxic CD8+ T cell antitumor activity and DC maturation by the secretion of transforming growth factor-β (TGF-β) and IL-10nHighlight:programmed cell death-ligand 1 (PD-L1) is upregulated, not only in malignant cells but also in TAMs in response to IFN-γ from effector cellsnHighlight:interaction of PD-L1 with programmed cell death protein 1 (PD-1) expressed on activated T cells facilitates immune escapenHighlight:M2-like TAMs deplete amino acids and secrete lactate among the TME, resulting in functional impairment of effector NK and T cellsnHighlight:iron is a necessary, but potentially toxicnHighlight:uptake, storage, and utilizationnHighlight:iron exportation is mediated by ferroportin (FPN)nHighlight:divalent metal transporter 1 (DMT1) expressed on duodenum enterocytesnHighlight:Circulating iron predominantly binds to transferrin (TF), forming a complex named TF-bound iron (TBI), which recognizes transferrin receptor 1 (TFR1)nHighlight:iron is reduced by six-transmembrane epithelial antigen of the prostate 3 (STEAP3) within the endosome and is subsequently released into the cytosol through DMT1nHighlight:cytoplasmic labile iron pool (LIP)nHighlight:stored in the form of ferritin (FT), utilized for various metabolic needs, or exported out of cells by FPNnHighlight:At the systemic level, iron homeostasis is primarily maintained by hepcidin, an important iron regulatory hormonenHighlight:Under high-iron conditions, hepcidin is released by the liver and induces FPN degradation, preventing iron export from duodenum enterocytes, hepatocytes, and macrophages into the blood streamnHighlight:Dysregulated iron homeostasis is considered one of the metabolic hallmarks of malignant cancer cellnHighlight:alterations of iron import-export, storage, and regulation have been identifiednHighlight:TFR1 is overexpressed in several cancers,nHighlight:Increases in TFR1 are also directly driven by the proto-oncogene, c-MycnHighlight:TFR1 expression determines the sensitivity of tumor cells to oxidative stressnHighlight:overexpressed DMT1, which is responsible for ferrous iron entry.nHighlight:ferrireductases, particularly members of the STEAP family, are involved in iron reduction for cellular uptakenHighlight:Ferritin, composing ferritin heavy chains (FTH) and ferritin light chains (FTL), plays a central role in iron storage.nHighlight:Among cancer patients, high concentrations of plasma FT correlate with a higher tumor stage and poor clinical outcome, suggesting that FT can serve as a prognostic factor in some types of cancernHighlight:downregulation of FT accounts for increased chemosensitivity [, ], as well as inhibition of tumor growth and developmentnHighlight:The iron export system is controlled by the only known iron exporter, FPN, and its modulator, hepcidinnHighlight:expression levels of FPN are substantially reduced in prostate and breast cancer compared to those in normal tissues, and they correlate with the degree of tumor aggressivenessnHighlight:suppressing FPN expression in triple negative breast cancer cells results in epithelial-mesenchymal transition, cell proliferation, and migrationnHighlight:reduced FPN levels are independently associated with a significant decrease in patient progression-free survivalnHighlight:Hepcidin can be synthesized in cancer cells, functioning as an autocrine hormone to degrade membrane FPN, increase intracellular concentration, and promote tumor survival, a process jointly controlled by bone morphogenetic protein and IL-6 nHighlight:immune cells compete with tumor cells for iron uptake in the TME.nHighlight:immune cells modify the polarization state to modulate iron metabolism at both local tumor and systemic levelsnHighlight:TAMs supply iron to accelerate tumor growth through three major pathways: (a) iron is exported via FPN and gets oxidized by CP and is then bound to TF to be taken up by tumor cells via TFR. (b) TAMs secrete LCN2, and then LCN2-bound iron is taken up by LCN2R on tumor cell surface. (c) TAM-released FT might be taken up by Scara5 (ferritin light chain binding protein). nHighlight:upregulated TFR and DMT1, overexpressed FT, and dysregulated hepcidin-FPN axisnHighlight:iron is involved in T cell activation, Th1/Th2 polarization, and the downregulated surface expression of CD2/CD4.nHighlight:T cells secrete TNF-α and IFN-γ, which reduce FPN levels, but increase DMT1 levels, thus promoting iron-sequestering M1 macrophage polarization.nHighlight:heme is released and catabolized by heme oxygenase (mainly HO-1) to produce iron.nHighlight:early stages of tumorigenesis, proinflammatory cytokines promote M1-like macrophages (with low levels of FPN and high levels of FT) to display an iron sequestering phenotype as an antitumor responsenHighlight:M2-like macrophages exhibit an iron-release phenotype with higher expression of the iron exporter, FPN, and lower expression of the storage protein, FT, thus increasing iron recycling and export into the extracellular space.nHighlight:macrophages are able to secrete FT into the microenvironment to stimulate tumorigenesis, though this proliferative effect is possibly iron-independent nHighlight:the Food and Drug Administration- (FDA-) approved iron chelators, deferoxamine and deferasirox, are proven to be effective in preclinical studies of leukemia [, ], neuroblastomas [], and colorectal [], pancreatic [], and breast [] cancers.n]]>

Picture of About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.


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