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Cited by 272Iron Metabolism and DisordersFerroptosis and cancer prognosisImmune cells in cancer

Iron as a central player and promising target in cancer progression

Open access
Jung, Michaela, Mertens, Christina, Tomat, Elisa, Brüne, Bernhard·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20020273PMC PMC6359419
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Abstract

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that iron metabolism is reprogrammed in cancer to support proliferation, survival, metastasis, and tumor microenvironment crosstalk, with tumor-associated macrophages acting as iron donors. It highlights therapeutic opportunities including hepcidin/FPN modulation, Tf/TfR targeting, iron chelators, and ferroptosis induction, while noting major clinical validation gaps.

Key findings

  • Iron is essential but redox-active; the Fenton reaction produces hydroxyl radicals, causing DNA strand breaks and protein/lipid modifications, while iron-dependent lipid peroxidation drives ferroptosis via glutathione depletion and GPX4 inactivation.
  • Cancer cells often increase iron uptake/storage and decrease export: high TfR1, FTL, and IRP-2 correlate with poor prognosis, higher tumor grade, and chemoresistance; low FPN correlates with worse survival, whereas higher FPN correlates with better outcome. Anemia is detected in approximately 40–70% of all cancer patients, linked to TNF-α/IL-6 and iron restriction.
  • Tumor-associated macrophages can adopt an iron-release/donor phenotype, including via Lcn-2 and independently of FPN, supporting tumor cell proliferation and growth; anti-inflammatory macrophages show CD163/CD91, HO-1, upregulated FPN, and reduced FT. Excess heme or iron may shift macrophages toward a pro-inflammatory, anti-tumoral phenotype.
  • Therapeutic strategies discussed include targeting hepcidin (antibodies/aptamers, BMP/SMAD, IL-6/STAT3), FPN stabilizers, anti-TfR antibodies and drug conjugates, ferritin nanocages, Lcn-2/siderophore pathways, iron chelators (DFO, DFX, Triapine, VLX600), and ferroptosis inducers; no iron chelator used clinically for iron overload has been approved for cancer.

Methods

  • Narrative review; no primary experimental data or systematic search is described. It synthesizes published literature on tumor cell iron metabolism, systemic iron homeostasis, TAM biology, and iron-targeting therapies.
  • Main analysis is thematic and descriptive, citing mechanistic studies, animal models, and clinical trials; it includes a summary table of pre-clinical studies and clinical trials (Table 1) and a scheme of tumor iron exploitation (Figure 1).

Limitations

  • Stated: prospective clinical data for targeting hepcidin are still missing; lack of long-term follow-up studies in cancer patients makes efficacy and safety difficult to predict; no clinically used iron chelator has obtained approval for the cancer setting; targeting iron in the tumor microenvironment remains largely unexplored.
  • Stated: mechanisms of Lcn-2 iron handling remain unclear, including how tumor cells selectively take up iron-loaded versus iron-free Lcn-2.
  • Evident: as a narrative review, it does not use a systematic search, risk-of-bias assessment, or quantitative synthesis, so conclusions depend on the selected cited literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms20020273

Cites

169 of 169 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 164 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Under these conditions, TAM expressed higher levels of the high-affinity iron-binding protein lipocalin-2 (Lcn-2).

    “Under these conditions, TAM expressed higher levels of the high-affinity iron-binding protein lipocalin-2 (Lcn-2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Mertens, 2018, Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment, Oncoimmunology source

      Not checked in the free run.

  • Findingcitation

    TAM adopt an iron-release phenotype due to their interaction with dying tumor cells, whereby iron availability was increased within the tumor microenvironment.

    “Recently, we provided evidence that TAM adopt an iron-release phenotype due to their interaction with dying tumor cells, whereby iron availability was increased within the tumor microenvironment [66].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Mertens, 2018, Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment, Oncoimmunology source

      Not checked in the free run.

  • Findingcitation

    Upon intracellular reduction, (TC3-S)2 is converted to the thiol chelator TC3-SH, which re-programmed macrophages from an iron release to an iron sequestration phenotype.

    “Upon intracellular reduction, (TC3-S)2 is converted to the thiol chelator TC3-SH, which re-programmed macrophages from an iron release to and iron sequestration phenotype [72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Mertens, C., Akam, E.A., Rehwald, C., Brune, B., Tomat, E., and Jung, M. (2016). Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression. PLoS ONE, 11. source

      Not checked in the free run.

  • Findingcitation

    Stromal Lcn-2 promoted metastasis by enhancing EMT and lymphangiogenesis.

    “While the majority of studies so far focused on mechanisms promoted by tumor cell-derived Lcn-2, recent data from our group suggest that stromal Lcn-2 promoted metastasis by enhancing EMT and lymphangiogenesis [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Jung, 2016, Lipocalin 2 from macrophages stimulated by tumor cell-derived sphingosine 1-phosphate promotes lymphangiogenesis and tumor metastasis, Sci. Signal. source

      Not checked in the free run.

  • Premisecitation

    Ferroptosis is a distinct type of cell death compared to apoptosis, necrosis, or autophagy.

    “This is a distinct type of cell death compared to apoptosis, necrosis, or autophagy [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Lu, 2017, The Role of Ferroptosis in Cancer Development and Treatment Response, Front. Pharmacol. source

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  • May combine two claims. 39
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingcitation

    Lcn-2 exports iron from TAM, while depletion of the established iron exporter FPN did not alter their iron release capacity.

    “Lcn-2 turned out to export iron from TAM, while depletion of the established iron exporter FPN did not alter their iron release capacity [66].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Mertens, 2018, Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment, Oncoimmunology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer-induced anemia and inflammation-associated anemia are characterized by reduced erythropoiesis.

    “Furthermore, cancer-induced anemia as well as inflammation-associated anemia is characterized by reduced erythropoiesis [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Nemeth, 2014, Anemia of inflammation, Hematol. Oncol. Clin. N. Am. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Binding of IRPs to IREs in the 5'-UTR attenuates translation, whereas binding to IREs in the 3'-UTR stabilizes respective mRNAs and fosters translation.

    “Binding of IRPs to IREs in the 5’-UTR attenuates translation, whereas binding to IREs in the 3’-UTR stabilizes respective mRNAs and fosters translation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Hentze, 2010, Two to tango: Regulation of Mammalian iron metabolism, Cell source

      Not checked in the free run.

    • cites [33] Muckenthaler, 2008, Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network, Annu. Rev. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent RBCs are taken up by monocytes in the bloodstream and transported to both liver and spleen.

    “Senescent RBCs are taken up by monocytes in the bloodstream and transported to both liver and spleen.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Theurl, 2016, On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression of iron-regulated genes such as TfR1, FTL, and IRP-2 in tumor cells correlated with a poor prognosis, a higher tumor grade, and increased chemoresistance.

    “Apparently, the expression of different iron-regulated genes such as the transferrin receptor (TfR1) [25], ferritin light chain (FTL) [26,27], and the iron regulatory protein (IRP)-2 [28] in tumor cells correlated with a poor prognosis, a higher tumor grade, and increased chemoresistance.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [25] Green, 2017, Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients, Oncotarget source

      Not checked in the free run.

    • cites [26] Rossiello, 1984, Distribution of ferritin, transferrin and lactoferrin in breast carcinoma tissue, J. Clin. Pathol. source

      Not checked in the free run.

    • cites [27] Jezequel, 2012, Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors: A multicentric 2004 national PHRC study, Int. J. Cancer source

      Not checked in the free run.

    • cites [28] Wang, 2014, IRP2 regulates breast tumor growth, Cancer Res. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DNA polymerases and helicases contain iron-sulfur groups that rely on iron as essential co-factors.

    “DNA polymerases and helicases contain iron-sulfur groups that rely on iron as essential co-factors [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Netz, 2011, Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron is crucial in remodeling the extracellular matrix and increasing motility and invasion of cancer cells.

    “Here, iron is crucial in remodeling the extracellular matrix and increasing the motility and invasion of cancer cells [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Miklasova, 2015, Iron, inflammation and invasion of cancer cells, Clujul. Med.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    When iron is high, mRNAs of TfR and DMT-1 are unstable and get degraded, decreasing iron uptake and transport.

    “Thus, when iron is high, mRNAs of TfR and DMT-1 are unstable and get degraded, which ultimately decreases iron uptake and transport.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Accumulation of iron-recycling macrophages was exclusively observed in the liver, identifying the liver as the main organ for RBC recycling.

    “Interestingly, accumulation of iron-recycling macrophages was exclusively observed in the liver, thus identifying the liver as the main organ for RBC recycling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Theurl, 2016, On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excess iron that is not utilized can be stored in FT and later accessed by ferritinophagy.

    “Thereby, excess iron that is not utilized, can be stored in the iron storage protein FT and can later be accessed by ferritinophagy [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Donfrancesco, 1990, Effects of a single course of deferoxamine in neuroblastoma patients, Cancer Res.

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Iron is potentially mutagenic by causing DNA strand breaks, which provokes cellular transformations, or induces protein as well as lipid modifications within malignant cells.

    “As a result, iron is potentially mutagenic by causing DNA strand breaks, which provokes cellular transformations, or induces protein as well as lipid modifications within malignant cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Inoue, 1987, Hydroxyl radical production and human DNA damage induced by ferric nitrilotriacetate and hydrogen peroxide, Cancer Res.

      Not checked in the free run.

    • cites [2] Tymoszuk, 2018, Iron in the Tumor Microenvironment-Connecting the Dots, Front. Oncol. source

      Not checked in the free run.

    • cites [3] Thanan, 2012, Inflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma, Free Radic. Biol. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment.

    “Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cellular iron availability controls mitochondrial respiration and affects citric acid cycle enzymes.

    “In addition, cellular iron availability not only controls mitochondrial respiration, but also affects citric acid cycle enzymes [8,9].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Oexle, 1999, Iron-dependent changes in cellular energy metabolism: Influence on citric acid cycle and oxidative phosphorylation, Biochim. Biophys. Acta source

      Not checked in the free run.

    • cites [9] Volani, 2017, Dietary iron loading negatively affects liver mitochondrial function, Metallomics source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The Tf/TfR system enhances iron uptake and provokes tumor cell survival.

    “Therefore, the Tf/TfR system not only enhances iron uptake, but also provokes tumor cell survival [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Jian, 2011, Src regulates Tyr(20) phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    RBC recycling and iron storage in liver and spleen are compromised and erythropoiesis is significantly reduced, finally provoking anemia.

    “As a result, RBC recycling and iron storage in liver and spleen are compromised and erythropoiesis is significantly reduced, finally provoking anemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Marques et al. described an 'iron utilization' phenotype of tumor cells, whereas tumor-infiltrating macrophages and lymphocytes represented an 'iron donor' phenotype.

    “These observations were recently underlined by Marques et al., describing an “iron utilization” phenotype of tumor cells, whereas tumor-infiltrating macrophages and lymphocytes represented an “iron donor” phenotype [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Marques, O., Porto, G., Rema, A., Faria, F., Cruz Paula, A., Gomez-Lazaro, M., Silva, P., Martins da Silva, B., and Lopes, C. (2016). Local iron homeostasis in the breast ductal carcinoma microenvironment. BMC Cancer, 16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular FT stimulates proliferation of breast cancer cells independently of the iron content, acting as an inflammatory effector mechanism to directly support tumorigenesis.

    “Interestingly, extracellular FT stimulates proliferation of breast cancer cells independently of the iron content, acting as an inflammatory effector mechanism to directly support tumorigenesis [38,39,40].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Mallon, 2000, The basic pathology of human breast cancer, J. Mammary Gland Biol. Neoplasia source

      Not checked in the free run.

    • cites [39] Mantovani, 2008, Cancer-related inflammation, Nature source

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    • cites [40] Alkhateeb, 2013, Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages, Breast Cancer Res. Treat. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FPN expression in carcinomas inversely correlated with patient survival and disease outcome.

    “In invasive tumor areas, iron export via FPN is lower compared to normal tissue, with the notion that FPN expression in carcinomas inversely correlated with patient survival and disease outcome [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Pinnix, 2010, Ferroportin and iron regulation in breast cancer progression and prognosis, Sci. Transl. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alternatively activated macrophages scavenge senescent and/or apoptotic cells, playing an important role in tissue repair, regeneration, resolution of inflammation, and iron recycling.

    “As alternatively activated macrophages scavenge senescent and/or apoptotic cells [68], they play an important role in tissue repair, regeneration, resolution of inflammation, and iron recycling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Gregory, 2004, The macrophage and the apoptotic cell: An innate immune interaction viewed simplistically?, Immunology source

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  • May combine two claims.

    Premisecitation

    Large amounts of hepcidin are found both within the tumor microenvironment and systemically in cancer patients.

    “Interestingly, large amounts of hepcidin are found both within the tumor microenvironment and systemically in cancer patients [73,74,75,76].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [73] Tesfay, 2015, Hepcidin regulation in prostate and its disruption in prostate cancer, Cancer Res. source

      Not checked in the free run.

    • cites [74] Miller, 2011, An iron regulatory gene signature predicts outcome in breast cancer, Cancer Res. source

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    • cites [75] Vela, 2018, Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications, Exp. Mol. Med. source

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    • cites [76] Zhang, 2014, Disordered hepcidin-ferroportin signaling promotes breast cancer growth, Cell Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The FPN efflux system represents one of the key mechanisms to adjust the iron amount in the body and to affect the ratio of stored and released iron.

    “The FPN efflux system represents one of the key mechanisms to adjust the iron amount in the body and to affect the ratio of stored and released iron [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Donovan, 2005, The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-inflammatory macrophages are predisposed to iron export and the distribution of iron to the extracellular space, whereas iron storage is reduced.

    “In contrast, anti-inflammatory macrophages are predisposed to iron export and the distribution of iron to the extracellular space, whereas iron storage is reduced.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Recalcati, 2010, Differential regulation of iron homeostasis during human macrophage polarized activation, Eur. J. Immunol. source

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  • May combine two claims.

    Premisecitation

    Macrophages are capable of ferritin secretion, whereby tumor growth is promoted.

    “In addition, macrophages are capable of ferritin secretion, whereby tumor growth is promoted [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Alkhateeb, 2013, Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages, Breast Cancer Res. Treat. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The iron-release phenotype is associated with upregulation of the iron exporter FPN, while the iron storage protein FT is downregulated.

    “The iron-release phenotype is associated with upregulation of the iron exporter FPN, while the iron storage protein FT is downregulated [67].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Recalcati, 2010, Differential regulation of iron homeostasis during human macrophage polarized activation, Eur. J. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Levels of hepcidin are increased during inflammation and decreased by iron insufficiency and erythropoiesis.

    “Levels of hepcidin are increased during inflammation and decreased by iron insufficiency and erythropoiesis [45,46,47].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Ganz, 2003, Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation, Blood source

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    • cites [46] Nemeth, 2009, The role of hepcidin in iron metabolism, Acta Haematol. source

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    • cites [47] Darshan, 2009, Interacting signals in the control of hepcidin expression, Biometals source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Naturally occurring FT structures are advantageous over synthetic ones due to their low toxicity and negligible immune responses.

    “Such naturally occurring structures are advantageous over synthetically ones due to their low toxicity and negligible immune responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several studies in humans suggest Lcn-2 as a pro-tumorigenic factor in breast cancer, correlating with a decreased survival and reduced responsiveness to neoadjuvant chemotherapy.

    “Several studies in humans suggest Lcn-2 as a pro-tumorigenic factor in breast cancer, correlating with a decreased survival and reduced responsiveness to neoadjuvant chemotherapy [126,127].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [126] Wenners, A.S., Mehta, K., Loibl, S., Park, H., Mueller, B., Arnold, N., Hamann, S., Weimer, J., Ataseven, B., and Darb-Esfahani, S. (2012). Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer. PLoS ONE, 7. source

      Not checked in the free run.

    • cites [127] Yang, 2013, Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer, FASEB J. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    No direct correlation of synergistically blocking the IL-6 and IL-8 receptors and hepcidin expression or the effect on cancer-related anemia was reported in this study.

    “However, no direct correlation of synergistically blocking the IL-6 and IL-8 receptors and hepcidin expression or the effect on cancer-related anemia was reported in this study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Jayatilaka, 2017, Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration, Nat. Commun. source

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  • May combine two claims.

    Premisecitation

    FT assembles into spherical cage-like structures and has the potential to reversibly disassemble within cells, representing an attractive target for nanostructure research in the cancer context.

    “Since FT assembles into spherical cage-like structures and has the potential to reversibly disassemble within cells, it represents an attractive target for nanostructure research in the cancer context [114].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Truffi, 2016, Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer, Pharmacol. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase I trials of anti-TfR monoclonal antibodies provided promising results, without any indication of major side effects in patients.

    “Phase I trials provided promising results, without any indication of major side effects in patients [97,98].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] Brooks, 1995, Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6, Clin. Cancer Res.

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    • cites [98] Taetle, 1986, Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies, Cancer Res.

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Siderophores are small, low-molecular-mass iron-binding ligands known from iron acquisition mechanisms used by bacteria.

    “Siderophores are small, low-molecular-mass iron-binding ligands known from iron acquisition mechanisms used by bacteria [119].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Saha, 2016, Microbial siderophores and their potential applications: A review, Environ. Sci. Pollut. Res. Int. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Secreted FT is taken up by the TfR.

    “Another consideration is the uptake of secreted FT by the TfR [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Li, 2010, Binding and uptake of H-ferritin are mediated by human transferrin receptor-1, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils from Lcn-2-/- animals do not migrate to sites of infection and do not respond to chemotactic stimuli.

    “Neutrophils from Lcn-2–/– animals do not migrate to sites of infection and do no longer respond to chemotactic stimuli [124], which however can be reverted by the addition of recombinant Lcn-2 [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Liu, 2013, Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections, J. Immunol. source

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  • May combine two claims.

    Premisecitation

    Macrophages exposed to hemolytic RBCs during sickle cell anemia acquire a more pro-inflammatory phenotype and exacerbate tissue damage.

    “These observations are somehow mirrored when macrophages are exposed to hemolytic RBCs during e.g., sickle cell anemia [78]. Based on the heme-induced polarization shift, macrophages acquire a more pro-inflammatory phenotype and exacerbate tissue damage [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Vinchi, 2016, Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease, Blood source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Cancer cells might have evolved alternative strategies to take up iron through hitherto-unappreciated transport proteins.

    “It needs also consideration that cancer cells might have evolved alternative strategies to take up iron trough hitherto-unappreciated transport proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lcn-2 controls neutrophil function.

    “Another aspect of Lcn-2 during infectious diseases is its ability to control neutrophil function [124,125].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [124] Liu, 2013, Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections, J. Immunol. source

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    • cites [125] Schroll, 2012, Lipocalin-2 ameliorates granulocyte functionality, Eur. J. Immunol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A recent study proposes that bacterial siderophores do not only serve as iron scavengers to limit bacterial growth, but are also able to support the host's iron homeostasis.

    “A recent study proposes that bacterial siderophores do not only serve as iron scavengers to limit bacterial growth, but are also able to support the host’s iron homeostasis [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Qi, 2018, Microbial Siderophore Enterobactin Promotes Mitochondrial Iron Uptake and Development of the Host via Interaction with ATP Synthase, Cell source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Lcn-2 might accomplish such a role due to its ability to scavenge iron-loaded siderophores.

    “Lcn-2 might accomplish such a role due to its ability to scavenge iron-loaded siderophores [117,118].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Behnsen, J., and Raffatellu, M. (2016). Siderophores: More than Stealing Iron. MBio, 7. source

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    • cites [118] Smith, 2007, Iron metabolism at the host pathogen interface: Lipocalin 2 and the pathogen-associated iroA gene cluster, Int. J. Biochem. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Maturing erythroid cells would severely be affected by anti-TfR antibodies, which may disturb erythropoiesis and cause anemia.

    “The problem may arise that maturing erythroid cells would severely be affected by anti-TfR antibodies, which, in turn, may disturb erythropoiesis and cause anemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    A higher reducing environment in cancer cells compared to the surrounding tissue makes reductive activation an attractive strategy to enhance cancer cell specificity, owing to higher amounts of reduced glutathione compared to healthy, neighboring cells.

    “It can be envisioned that a higher reducing environment in cancer cells, compared to the surrounding tissue, makes reductive activation an attractive strategy to enhance cancer cell specificity [153,154], owing to higher amounts of reduced glutathione compared to healthy, neighboring cells [69].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [153] Akam, 2014, Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators, Metallomics source

      Not checked in the free run.

    • cites [154] Chang, 2013, Disulfide/thiol switches in thiosemicarbazone ligands for redox-directed iron chelation, Dalton Trans. source

      Not checked in the free run.

    • cites [69] Apte, 2010, Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling, Exp. Hematol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because of the stability of disulfide linkages in blood plasma, an advantage of the prochelator strategy is their potential supplementation at high doses, which may foster their uptake by tumor cells, while avoiding unwanted side effects in plasma.

    “Because of the stability of disulfide linkages in blood plasma, an advantage of the prochelator strategy is their potential supplementation at high doses, which may foster their uptake by tumor cells, while avoiding unwanted side effects in plasma.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These strategies may also be exerted to achieve selectivity in targeting the iron pool of tumor cells.

    “These strategies may also be exerted to achieve selectivity in targeting the iron pool of tumor cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ferroptosis was recently shown to be executed via the tumor suppressor p53, suggesting a natural anti-tumor role of ferroptosis.

    “This type of cell death was recently shown to be executed via the tumor suppressor p53 [162,163], suggesting a natural anti-tumor role of ferroptosis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] Gnanapradeepan, 2018, The p53 Tumor Suppressor in the Control of Metabolism and Ferroptosis, Front. Endocrinol. source

      Not checked in the free run.

    • cites [163] Jiang, 2015, Ferroptosis as a p53-mediated activity during tumour suppression, Nature source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Macrophages constitute a major infiltrate in solid tumors and take a pivotal role in iron metabolism, these immune cells are likely a worthwhile target in anti-cancer strategies.

    “Considering that macrophages constitute a major infiltrate in solid tumors and taking their pivotal role in iron metabolism into account, these immune cells are likely a worthwhile target in anti-cancer strategies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Expression of Lcn-2R is indicative for a poor prognosis, and a reduced survival rate but increased invasion in several cancer entities.

    “Corroborating the role of Lcn-2, expression of Lcn-2R is also indicative for a poor prognosis, and a reduced survival rate but increased invasion in several cancer entities [131,132].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [131] Autelitano, F., Loyaux, D., Roudieres, S., Deon, C., Guette, F., Fabre, P., Ping, Q., Wang, S., Auvergne, R., and Badarinarayana, V. (2014). Identification of novel tumor-associated cell surface sialoglycoproteins in human glioblastoma tumors using quantitative proteomics. PLoS ONE, 9. source

      Not checked in the free run.

    • cites [132] Miyamoto, 2011, Immunohistochemical detection of a specific receptor for lipocalin2 (solute carrier family 22 member 17, SLC22A17) and its prognostic significance in endometrial carcinoma, Exp. Mol. Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Akam et al. explored glucose-conjugated thiosemicarbazone prochelators in colon carcinoma, proving enhanced prochelator accumulation in malignant cells.

    “Akam et al. explored glucose-conjugated thiosemicarbazone prochelators in colon carcinoma [157], proving enhanced prochelator accumulation in malignant cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Akam, 2016, Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators, Bioconjug. Chem. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Fundamental to successfully approach chelation therapy in cancer will be the capacity to target iron selectively in malignant cells without affecting normal tissue or the extracellular space.

    “Fundamental to successfully approach chelation therapy in cancer will be the capacity to target iron selectively in malignant cells without affecting normal tissue or the extracellular space.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Chelators derived from bacterial siderophores or other high-affinity scaffolds lack the required selectivity and thus are not designed to target specifically the higher iron demand of malignant cancer cells, which generally show normal or low systemic iron levels.

    “Chelators derived from bacterial siderophores (e.g., DFO) or other high-affinity scaffolds (e.g., Triapine) lack the required selectivity and thus are not designed to target specifically the higher iron demand of malignant cancer cells, which generally show normal or low systemic iron levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High-throughput screening identified an iron chelating agent as a promising drug candidate for colon cancer (VLX600), which entered a Phase I clinical trial for refractory advanced solid tumors.

    “More recently, high-throughput screening identified an iron chelating agent as a promising drug candidate for colon cancer (VLX600) [140], which entered a Phase I clinical trial (identifier: NCT02222363) for refractory advanced solid tumors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Zhang, 2014, Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments, Nat. Commun. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    While most studies aim at targeting iron in tumor cells, approaches to addressing iron chelation in cells of the tumor microenvironment is still lacking.

    “While most studies aim at targeting iron in tumor cells, approaches to addressing iron chelation in cells of the tumor microenvironment is still lacking.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    While most of the current chelator-based intervention strategies focus on tumor cells, targeting iron in the tumor microenvironment has not been explored significantly.

    “While most of the current chelator-based intervention strategies focus on tumor cells, targeting iron in the tumor microenvironment has not been explored significantly.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The use of disulfide bonds as the activation switch of iron prochelators showed encouraging results in vitro, as iron coordination only occurs following intracellular disulfide reduction, leading to the formation of high-affinity tridentate thiolate chelators.

    “The use of disulfide bonds as the activation switch of iron prochelators showed encouraging results in vitro, as iron coordination only occurs following intracellular disulfide reduction, leading to the formation of high-affinity tridentate thiolate chelators [153].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Akam, 2014, Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators, Metallomics source

      Not checked in the free run.

52 of 52

  • The paper relies on this without support.

    Iron is essential for virtually all organisms.

    “Iron is an essential element for virtually all organisms.”

  • The paper relies on this without support.

    Iron is a growth-limiting factor for virtually all organisms.

    “Iron is the most abundant element by mass on the Earth and is a growth-limiting factor for virtually all organisms.”

  • The paper relies on this without support.

    There is no excretory route for excess iron.

    “Considering the poor bioavailability of iron, the interplay of different proteins involved in iron import, storage, and export has to be tightly regulated, as there is no excretory route for excess iron.”

  • The paper relies on this without support.

    Findings from mouse models of cancer translate to human cancer.

    “Mice fed a low-iron diet prior to implanting tumor cells showed significantly delayed tumor growth [22].”

  • The paper relies on this without support.

    In vitro findings about iron handling translate to in vivo tumor behavior.

    “This iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo [64,66,67,70,71,72].”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the tumor microenvironment, M2 TAMs which are iron-releasing support tumor growth while M1 iron-retaining limit tumor progression.

    “However, in the context of the tumor microenvironment (TME), the situation is quite complicated as M2 TAMs (tumor-infiltrating macrophages) which are “iron-releasing” will support tumor growth while M1 “iron-retaining” limit tumor progression (Jung et al., 2019).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Jung et al., 2019

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposite associations reported for ferroportin and patient outcome

    Minor

    The paper first says ferroportin expression is inversely correlated with survival and disease outcome, but then says increased ferroportin expression correlates with better patient outcome.

1 of 1

Cites

Flagged first, then by citations

11 of the 180 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Jung, M., Mertens, C., Tomat, E., & Brüne, B.
Affiliations
  • Goethe University Frankfurt (DE)
  • University of Arizona (US)
Corresponding author
Brüne, Bernhard
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-01-11
Volume
20
Issue
2
Pages
273
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms20020273
PMC
PMC6359419
OpenAlex
W2910083100
Semantic Scholar
714cc6f101914382c4609796c780897112029c2e
Cited by
268
References
180
Citations by year
2026: 12 · 2025: 32 · 2024: 32 · 2023: 39 · 2022: 58 · 2021: 50 · 2020: 33 · 2019: 12
FWCI
6.08
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion, other-oa)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (SFB815)
  • Wilhelm Sander-Stiftung (2017.130.1)
  • National Institutes of Health (GM127646)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
iron metabolism, tumor progression, tumor microenvironment, tumor-associated macrophages, iron homeostasis, oxidative stress, metastasis, iron acquisition, iron export, iron storage, cancer therapy, redox biology
MeSH terms
Antineoplastic Agents, DNA Damage, Humans, Iron, Neoplasms, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Oxidative Stress, Disease Progression, Metabolic Networks and Pathways, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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