Iron as a Central Player and Promising Target in Cancer Progression

In the paper

“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].”

What the sources say

• Not checked yetcites [66] Mertens, 2018, Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment, Oncoimmunology source

In the paper

“Furthermore, cancer-induced anemia as well as inflammation-associated anemia is characterized by reduced erythropoiesis [17].”

What the sources say

• Not checked yetcites [17] Nemeth, 2014, Anemia of inflammation, Hematol. Oncol. Clin. N. Am. source

In the paper

“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.”

What the sources say

• Not checked yetcites [32] Hentze, 2010, Two to tango: Regulation of Mammalian iron metabolism, Cell source
• Not checked yetcites [33] Muckenthaler, 2008, Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network, Annu. Rev. Nutr. source

In the paper

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

What the sources say

• Not checked yetcites [24] Theurl, 2016, On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver, Nat. Med. source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [26] Rossiello, 1984, Distribution of ferritin, transferrin and lactoferrin in breast carcinoma tissue, J. Clin. Pathol. source
• Not checked yetcites [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 yetcites [28] Wang, 2014, IRP2 regulates breast tumor growth, Cancer Res. source

In the paper

“DNA polymerases and helicases contain iron-sulfur groups that rely on iron as essential co-factors [7].”

What the sources say

• Not checked yetcites [7] Netz, 2011, Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes, Nat. Chem. Biol. source

In the paper

“Here, iron is crucial in remodeling the extracellular matrix and increasing the motility and invasion of cancer cells [13].”

What the sources say

• Not checked yetcites [13] Miklasova, 2015, Iron, inflammation and invasion of cancer cells, Clujul. Med.

In the paper

“Thus, when iron is high, mRNAs of TfR and DMT-1 are unstable and get degraded, which ultimately decreases iron uptake and transport.”

In the paper

“Interestingly, accumulation of iron-recycling macrophages was exclusively observed in the liver, thus identifying the liver as the main organ for RBC recycling.”

What the sources say

• Not checked yetcites [24] Theurl, 2016, On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver, Nat. Med. source

In the paper

“Thereby, excess iron that is not utilized, can be stored in the iron storage protein FT and can later be accessed by ferritinophagy [34].”

What the sources say

• Not checked yetcites [34] Donfrancesco, 1990, Effects of a single course of deferoxamine in neuroblastoma patients, Cancer Res.

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Inoue, 1987, Hydroxyl radical production and human DNA damage induced by ferric nitrilotriacetate and hydrogen peroxide, Cancer Res.
• Not checked yetcites [2] Tymoszuk, 2018, Iron in the Tumor Microenvironment-Connecting the Dots, Front. Oncol. source
• Not checked yetcites [3] Thanan, 2012, Inflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma, Free Radic. Biol. Med. source

In the paper

“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.”

In the paper

“In addition, cellular iron availability not only controls mitochondrial respiration, but also affects citric acid cycle enzymes [8,9].”

What the sources say

• Not checked yetcites [8] Oexle, 1999, Iron-dependent changes in cellular energy metabolism: Influence on citric acid cycle and oxidative phosphorylation, Biochim. Biophys. Acta source
• Not checked yetcites [9] Volani, 2017, Dietary iron loading negatively affects liver mitochondrial function, Metallomics source

In the paper

“Therefore, the Tf/TfR system not only enhances iron uptake, but also provokes tumor cell survival [31].”

What the sources say

• Not checked yetcites [31] Jian, 2011, Src regulates Tyr(20) phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival, J. Biol. Chem. source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [38] Mallon, 2000, The basic pathology of human breast cancer, J. Mammary Gland Biol. Neoplasia source
• Not checked yetcites [39] Mantovani, 2008, Cancer-related inflammation, Nature source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [42] Pinnix, 2010, Ferroportin and iron regulation in breast cancer progression and prognosis, Sci. Transl. Med. source

In the paper

“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.”

What the sources say

• Not checked yetcites [68] Gregory, 2004, The macrophage and the apoptotic cell: An innate immune interaction viewed simplistically?, Immunology source

In the paper

“Interestingly, large amounts of hepcidin are found both within the tumor microenvironment and systemically in cancer patients [73,74,75,76].”

What the sources say

• Not checked yetcites [73] Tesfay, 2015, Hepcidin regulation in prostate and its disruption in prostate cancer, Cancer Res. source
• Not checked yetcites [74] Miller, 2011, An iron regulatory gene signature predicts outcome in breast cancer, Cancer Res. source
• Not checked yetcites [75] Vela, 2018, Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications, Exp. Mol. Med. source
• Not checked yetcites [76] Zhang, 2014, Disordered hepcidin-ferroportin signaling promotes breast cancer growth, Cell Signal. source

In the paper

“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].”

What the sources say

• Not checked yetcites [41] Donovan, 2005, The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis, Cell Metab. source

In the paper

“In contrast, anti-inflammatory macrophages are predisposed to iron export and the distribution of iron to the extracellular space, whereas iron storage is reduced.”

What the sources say

• Not checked yetcites [67] Recalcati, 2010, Differential regulation of iron homeostasis during human macrophage polarized activation, Eur. J. Immunol. source

In the paper

“In addition, macrophages are capable of ferritin secretion, whereby tumor growth is promoted [40].”

What the sources say

• Not checked yetcites [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

In the paper

“The iron-release phenotype is associated with upregulation of the iron exporter FPN, while the iron storage protein FT is downregulated [67].”

What the sources say

• Not checked yetcites [67] Recalcati, 2010, Differential regulation of iron homeostasis during human macrophage polarized activation, Eur. J. Immunol. source

In the paper

“Levels of hepcidin are increased during inflammation and decreased by iron insufficiency and erythropoiesis [45,46,47].”

What the sources say

• Not checked yetcites [45] Ganz, 2003, Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation, Blood source
• Not checked yetcites [46] Nemeth, 2009, The role of hepcidin in iron metabolism, Acta Haematol. source
• Not checked yetcites [47] Darshan, 2009, Interacting signals in the control of hepcidin expression, Biometals source

In the paper

“Such naturally occurring structures are advantageous over synthetically ones due to their low toxicity and negligible immune responses.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [127] Yang, 2013, Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer, FASEB J. source

In the paper

“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.”

What the sources say

• Not checked yetcites [85] Jayatilaka, 2017, Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration, Nat. Commun. source

In the paper

“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].”

What the sources say

• Not checked yetcites [114] Truffi, 2016, Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer, Pharmacol. Res. source

In the paper

“Phase I trials provided promising results, without any indication of major side effects in patients [97,98].”

What the sources say

• Not checked yetcites [97] Brooks, 1995, Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6, Clin. Cancer Res.
• Not checked yetcites [98] Taetle, 1986, Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies, Cancer Res.

In the paper

“Siderophores are small, low-molecular-mass iron-binding ligands known from iron acquisition mechanisms used by bacteria [119].”

What the sources say

• Not checked yetcites [119] Saha, 2016, Microbial siderophores and their potential applications: A review, Environ. Sci. Pollut. Res. Int. source

In the paper

“Another consideration is the uptake of secreted FT by the TfR [113].”

What the sources say

• Not checked yetcites [113] Li, 2010, Binding and uptake of H-ferritin are mediated by human transferrin receptor-1, Proc. Natl. Acad. Sci. USA source

In the paper

“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].”

What the sources say

• Not checked yetcites [124] Liu, 2013, Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections, J. Immunol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [78] Vinchi, 2016, Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease, Blood source

In the paper

“It needs also consideration that cancer cells might have evolved alternative strategies to take up iron trough hitherto-unappreciated transport proteins.”

In the paper

“Another aspect of Lcn-2 during infectious diseases is its ability to control neutrophil function [124,125].”

What the sources say

• Not checked yetcites [124] Liu, 2013, Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections, J. Immunol. source
• Not checked yetcites [125] Schroll, 2012, Lipocalin-2 ameliorates granulocyte functionality, Eur. J. Immunol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [123] Qi, 2018, Microbial Siderophore Enterobactin Promotes Mitochondrial Iron Uptake and Development of the Host via Interaction with ATP Synthase, Cell source

In the paper

“Lcn-2 might accomplish such a role due to its ability to scavenge iron-loaded siderophores [117,118].”

What the sources say

• Not checked yetcites [117] Behnsen, J., and Raffatellu, M. (2016). Siderophores: More than Stealing Iron. MBio, 7. source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [153] Akam, 2014, Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators, Metallomics source
• Not checked yetcites [154] Chang, 2013, Disulfide/thiol switches in thiosemicarbazone ligands for redox-directed iron chelation, Dalton Trans. source
• Not checked yetcites [69] Apte, 2010, Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling, Exp. Hematol. source

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [162] Gnanapradeepan, 2018, The p53 Tumor Suppressor in the Control of Metabolism and Ferroptosis, Front. Endocrinol. source
• Not checked yetcites [163] Jiang, 2015, Ferroptosis as a p53-mediated activity during tumour suppression, Nature source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Akam et al. explored glucose-conjugated thiosemicarbazone prochelators in colon carcinoma [157], proving enhanced prochelator accumulation in malignant cells.”

What the sources say

• Not checked yetcites [157] Akam, 2016, Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators, Bioconjug. Chem. source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [140] Zhang, 2014, Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments, Nat. Commun. source

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [153] Akam, 2014, Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators, Metallomics source