Iron imbalance in cancer: Intersection of deficiency and overload – PMC

+3) and soluble ferrous (Fe⁺²nHighlight:potential toxicity towards cells under imbalanced conditions, despite being a key factor in normal anatomical functioning.nHighlight:iron deficiency and overload may be detrimental to optimal body functioning, consequentially catalysing cancer incidence, recurrence and chronic infectionsnHighlight:irrational iron administration or chronic red blood cell (RBC) transfusion therapies clinically prescribed for treatment of iron deficient or chemotherapy‐induced anaemia (CIA), may lead to unwanted risks of iron overload, further aggravating the diseasenHighlight:cancer‐driven chronic anaemia clinically indicated by deficient available or functional iron that might render iron administration counterproductive, thus intensifying risks of malignancynHighlight:healthy human body contains approximately 3–4 grams of iron, majorly intracellularlynHighlight:64% circulating as haemoglobin (Hb) in erythrocytes, or as stored as ferritin reserves in hepatocytes, along with about 21% contained in macrophages, and 14% in myoglobinnHighlight:transferrin (Tf), with its iron‐binding sites approximately 20%–40% saturated with ferric (Fe⁺³) atomsnHighlight:Under optimal health conditions, dietary or cellular iron in Fe⁺³ form complexed with Tf binds to the cell surface transferrin receptor (TfR)nHighlight:Fe⁺² is released into circulation via ferroportin (FPN)nHighlight:Excessive iron is stored as ferritin reserves in macrophages, until required for erythropoiesisnHighlight:FPN regulation is partially driven by hepcidin, a hepatic peptide identified as the systemic iron regulatornHighlight:Hepcidin‐FPN interplay in liaison with, hephaestin, therefore, controls intestinal iron absorption, plasma iron concentration and its circulatory release throughout the bodynHighlight:The iron‐regulatory mechanism is however disrupted in cancer and cancer‐associated chronic inflammationnHighlight:Tumour microenvironment is actively regulated and modulated by inflammatory cells through a single or a concerted effect of several cytokines including interleukins, oncostatin and leptinsnHighlight:induces hepcidin release, thus disrupting the FPN/hepcidin channel, and inhibiting macrophageal iron export, leading to an ‘iron‐blockage’nHighlight:Resulting reduced serum iron and increased ferritin stores lead to a state of ‘functional iron deficiency’ (FID) in cancer patientsnHighlight:cancer patients possess adequate or increased iron stores with elevated hepcidin, this iron is inaccessible for erythropoiesisnHighlight:FID prevalence increases with cancer stages and is correlated to treatment‐associated underperformance in cancer patients.nHighlight:AID, marked by a complete depletion of iron reserves and iron unavailability for RBC synthesisnHighlight:Mutations in iron‐regulatory genes, including HFE result in functional hepcidin deficiency and duodenal FPN overexpression, thus causing iron over‐absorption in the gastrointestinal tract, one of the suspected contributors in malignancy, particularly hepatic and colorectal cancersnHighlight:Resulting increased intestinal iron transfer to plasma saturates Tf, releasing free iron known as ‘non‐transferrin bound iron’ (NTBI).ⁿ²⁰ⁿ NTBI is potent reactive oxygen species (ROS) generator resulting in tissue injury and lipid peroxidation, eventually inducing DNA damage and therefore, are drivers for cancer progressionnHighlight:One of the predominant mechanisms governing iron’s association with cancer initiates as a protective mechanism of the cell’s intrinsic property to eliminate superoxides (O2^•‐)nHighlight:proactive metabolic state of tumour cells, overly accumulated ROS along with overall enhanced oxidative stress promote accumulation of endogenous free radical, hydrogen peroxide (H₂O₂), a step catalysed by an antioxidant, superoxide dismutase which in presence of excess Fe⁺² generates a hydroxyl radical (OH⁻) flux through a process called Fenton reactionnHighlight:ferroptosisnHighlight:ferroptosis in cancer cells have been reported to induce prostaglandin E2 release thus affecting its role in immunosuppression, in turn driving chemotherapy resistance and tumour cell proliferationnHighlight:Diet‐induced iron overload risks have also been confirmed through epidemiological and meta‐analytical evidence reporting positive correlation between excess red and processed meat ingestion and increased risks of gastric, colorectal, prostate, lung, breast cancers and renal cell carcinoma, including other chronic disorders like coronary heart failure in patients with type II diabetesnHighlight:Higher red meat intake in premenopausal women has also been observed to increase progesterone and oestrogen receptor positive breast cancer risksnHighlight:excessive red meat consumption (seven times per week) in subjects with elevated Tf levels has been associated with higher mortalitynHighlight:Red meat carcinogenicity has been attributed to its heme iron content, which due to its structural composition, allows iron to escape absorption inhibition, thus leading it to contribute to >10% of the absorbed ironnHighlight:iron overload has been reported to increase ROS levelsn]]>