Cited by 215Iron Metabolism and DisordersFerroptosis and cancer prognosisErythropoietin and Anemia Treatment

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The iron metabolism of neoplastic cells: alterations that facilitate proliferation?

Kwok, Juliana C, Richardson, Des R.·2002·Critical Reviews in Oncology/Hematology

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Abstract

For many years it has been known that neoplastic cells express high levels of the transferrin receptor 1 (TfR1) and internalize iron (Fe) from transferrin (Tf) at a tremendous rate. Considering the high requirement of neoplastic cells for Fe, understanding its metabolism is vital in terms of devising potential new therapies. Apart from TfR1, a number of molecules have been identified that may have roles in Fe metabolism and cellular proliferation. These molecules include transferrin (Tf), the oestrogen-inducible transferrin receptor-like protein, transferrin receptor 2 (TfR2), melanotransferrin (MTf), ceruloplasmin, and ferritin. In the present review these latter molecules are discussed in terms of their potential functions in tumour cell Fe metabolism and proliferation. Further studies are essential to determine the specific roles of these proteins in the pathogenesis of cancer.

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“It has been long been recognized that cancers exhibit an avidity for iron that seems to drive proliferation and metastasis [33,34].”
Background
Dihydroartemisinin induces apoptosis in human leukemia cells HL60 via downregulation of transferrin receptor expression
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Novel ruthenium(II) triazine complex [Ru(bdpta)(tpy)]2+ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells
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Anticancer activity of artemisinin-derived trioxanes
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“Iron plays an important role in cell growth as many key reactions in energy metabolism and DNA synthesis are catalysed by iron-containing enzymes [21].”
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Expression of iron regulatory genes in a rat model of hepatocellular carcinoma
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“Hepatocellular carcinomas (HCCs) demonstrate perturbations in their iron metabolism (1).”
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The Anticancer Agent, Di-2-Pyridylketone 4,4-Dimethyl-3-Thiosemicarbazone (Dp44mT), Up-Regulates the AMPK-Dependent Energy Homeostasis Pathway in Cancer Cells
Krishan, S., Richardson, D. R., & Sahni, S. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.09.011 · Cited by 45
Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status
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Loss of the von Hippel Lindau Tumor Suppressor Disrupts Iron Homeostasis in Renal Carcinoma Cells
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Dried leaf Artemisia annua efficacy against non-small cell lung cancer
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Cell Permeable Iron Chelators as Potential Cancer Chemotherapeutic Agents
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“It has been suggested that in some cases transferrin secreted from cancer cells has an autocrine function to enhance cell growth.[58] Many types of cancer cells express very high levels of TfR1, which often correlate with the pathological stage of the tumor.”
Background
Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer
Carneiro, M. L. B., Peixoto, R. C. A., Joanitti, G. A., Oliveira, R. G., Telles, L. A. M., Miranda‐Vilela, A. L., Bocca, A. L., Vianna, L. M., da Silva, I. C. R., de Souza, A. R., et al. (2013) · Journal of Nanobiotechnology · doi:10.1186/1477-3155-11-4 · Cited by 40
“efficacy of drug investigation [42].”
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“Consequently, carcinoma cells require larger amounts of micronutrients, particularly iron, which can be evidenced by the presence of more transferrin receptors in these [39].”
Background
Air pollutants disrupt iron homeostasis to impact oxidant generation, biological effects, and tissue injury
Ghio, A. J., Soukup, J. M., Dailey, L. A., & Madden, M. C. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.02.007 · Cited by 39
Innovative therapies for neuroblastoma: The surprisingly potent role of iron chelation in up-regulating metastasis and tumor suppressors and down-regulating the key oncogene, N-myc
Wijesinghe, T. P., Dharmasivam, M., Dai, C. C., & Richardson, D. R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105889 · Cited by 39
Artesunate exerts specific cytotoxicity in retinoblastoma cells via CD71
Zhao, F. L., WANG, H., KUNDA, P., Chen, X., LIU, Q.-L., & LIU, T. (2013) · Oncology Reports · doi:10.3892/or.2013.2574 · Cited by 38
Proteomic Analysis of Tumor Establishment and Growth in the B16-F10 Mouse Melanoma Model
Culp, W. D., Neal, R. E., Massey, R., Egevad, L., Pisa, P., & Garland, D. L. (2006) · Journal of Proteome Research · doi:10.1021/pr060059q · Cited by 38
Iron Oxide Nanoparticles: An Insight into their Biomedical Applications
Couto, D., Freitas, M., Carvalho, F. D., & Fernandes, E. G. R. (2015) · Current Medicinal Chemistry · doi:10.2174/0929867322666150311151403 · Cited by 37
“As a result, carcinoma cells necessitate larger amounts of micronutrients (namely iron), which can be evidenced by the increase of transferrin receptors in these cells [135, 136].”
Background
Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity
Moussa, R., Park, K. C., Kovačević, Ž., & Richardson, D. R. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.03.027 · Cited by 39
Iron and colorectal cancer: evidence from in vitro and animal studies
Padmanabhan, H., Brookes, M., & Iqbal, T. H. (2015) · Nutrition Reviews · doi:10.1093/nutrit/nuu015 · Cited by 35
miR signatures and the role of miRs in acute myeloid leukaemia
Seca, H., Almeida, G. M., Guimarães, J. E., & Vasconcelos, M. H. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.03.031 · Cited by 35
Designing Tailored Thiosemicarbazones with Bespoke Properties: The Styrene Moiety Imparts Potent Activity, Inhibits Heme Center Oxidation, and Results in a Novel “Stealth Zinc(II) Complex”
Dharmasivam, M., Kaya, B., Wijesinghe, T. P., Azad, M. G., Gonzálvez, M. A., Hussaini, M., Chekmarev, J., Bernhardt, P. V., & Richardson, D. R. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01600 · Cited by 34
Alterations in expression profile of iron-related genes in colorectal cancer
Hamara, K., Bielecka-Kowalska, A., Przybyłowska-Sygut, K., Sygut, A., Dziki, A. J., & Szemraj, J. (2013) · Molecular Biology Reports · doi:10.1007/s11033-013-2659-3 · Cited by 35
“cell surface and Fn are the most well known modifications [26].”
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Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis
Gannon, P. O., Medelci, S., Page, C. L., Beaulieu, M., Provencher, D. M., Mes‐Masson, A., & Santos, M. M. (2010) · International Journal of Cancer · doi:10.1002/ijc.25577 · Cited by 33
“Tumor cells express high levels of TfR and internalize iron from transferrin at a tremendous rate.(1) In vitro, overexpression of HFE in cancer cell lines leads to a decrease in transferrin-mediated iron uptake and the consequent Key words: ovarian cancer, HFE mutations, hemochromatosis, iron,”
Background
The role of the NDRG1 in the pathogenesis and treatment of breast cancer
Zhao, X., & Richardson, D. R. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188871 · Cited by 34
The Myc Family and the Metastasis Suppressor NDRG1: Targeting Key Molecular Interactions with Innovative Therapeutics
Deng, Z., & Richardson, D. R. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000795 · Cited by 32
“…is important for cellular growth and proliferation (Richardson and Ponka, 1997; Targeting Interactions of Myc and NDRG1 with Therapeutics 1009 a t A SP ET J ou r n a l s on O c t ob e r 30 , 2023 ph a r m r e v . a s p e tj ou r n a l s . o r g D o w n l o a d e d fr o m Kwok and Richardson, 2002).”
Background
Lipocalin-2: A Nurturer of Tumor Progression and a Novel Candidate for Targeted Cancer Therapy
Živalj, M., Ginderachter, J. A. V., & Stijlemans, B. (2023) · Cancers · doi:10.3390/cancers15215159 · Cited by 35
“Dysregulated iron homeostasis is associated with the malignant cancer phenotype, whereby the change in the expression of iron-regulating genes promotes higher metabolic needs of cancer cells [41].”
Background
Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer.
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Proteomic Analysis of HCV Cirrhosis and HCV-Induced HCC: Identifying Biomarkers for Monitoring HCV-Cirrhotic Patients Awaiting Liver Transplantation
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“Perturbations in iron metabolism have been described in HCC (40, 41).”
Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors
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“Iron is an essential trace element for both physiological cellular functions and neoplastic cell growth [1].”
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Pathophysiological aspects of transferrin-A potential nano-based drug delivery signaling molecule in therapeutic target for varied diseases
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“Tf, Transferrin; TfR1, Transferrin receptor 1; DMT1, divalent metal transporter. uptake; instead, it might promote accelerated proliferation of tumor cells by acting as an iron scavenger on the cell surface to hinder lipid peroxidation (Kwok and Richardson, 2002).”
Background
Antitumor effect of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles on mice bearing breast cancer: a systemic toxicity assay
Peixoto, R. C. A., Miranda‐Vilela, A. L., Filho, J. D. S., Carneiro, M. L. B., Oliveira, R. G. S., da Silva, M. O., de Souza, A. R., & Báo, S. N. (2014) · Tumor Biology · doi:10.1007/s13277-014-2966-x · Cited by 31
Increased expression of Ki-67 in mantle cell lymphoma is associated with de-regulation of several cell cycle regulatory components, as identified by global gene expression analysis.
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“In general, neoplastic cell metabolism is faster than that of normal cells, demanding larger amounts of nutrients, such as iron, which can be evidenced by the presence of more transferrin receptors.(34) This may explain the evidence obtained from the morphological analysis (Perls’ staining) which indicates that MSE-NC…”
Background
Artesunate mitigates proliferation of tumor cells by alkylating heme-harboring nitric oxide synthase
Zeng, Q.-P., & Zhang, P.-Z. (2010) · Nitric Oxide · doi:10.1016/j.niox.2010.12.005 · Cited by 30
“Although the major target of artemisinin towards tumor cells are still under debate [5], an iron-dependent mechanism of artemisinin in anticarcinogenesis has been proposed [6].”
Background
Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells
Reynolds, L., Mulik, R. S., Treuren, T. V., Kim, S. Y., & Corbin, I. R. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.07.004 · Cited by 30
“Thus, within the confines of lysosomes from cancer cells DHA will be exposed to increasing concentrations of ROS and labile iron [51].”
Background
EPR Study of Iron Ion Complexes in Human Blood
Krzyminiewski, R., Kruczyński, Z., Dobosz, B., Zając, A., Mackiewicz, A. A., Leporowska, E., & Folwaczna, S. (2011) · Applied Magnetic Resonance · doi:10.1007/s00723-011-0219-3 · Cited by 29

Authors: Kwok, J. C., & Richardson, D. R.
Affiliations: The Heart Research Institute (AU)
Corresponding author: Richardson, Des R.
ORCID: Richardson, Des R.
Venue: Critical Reviews in Oncology/Hematology
Publisher: Elsevier BV
Published: 2002-04
Volume: 42
Issue: 1
Pages: 65-78
ISSN: 1040-8428 (ISSN-L)
DOI: 10.1016/s1040-8428(01)00213-x
OpenAlex: W2049332203
Cited by: 215
References: 162
Citations by year: 2026: 2 · 2025: 1 · 2024: 14 · 2023: 15 · 2022: 5 · 2021: 11 · 2020: 10 · 2019: 8 · 2018: 6 · 2017: 13 · 2016: 9 · 2015: 13 · 2014: 10 · 2013: 18 · 2012: 9
FWCI: 1.04
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Critical Reviews in Oncology/Hematology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords: iron metabolism, neoplastic cells, transferrin receptor 1, transferrin receptor 2, transferrin, melanotransferrin, ceruloplasmin, ferritin, tumor cell proliferation, carcinogenesis, iron transport
MeSH terms: Animals, Antigens, Neoplasm, Biological Transport, Cell Division, Ceruloplasmin, Endocytosis, Estrogens, Ferritins, Humans, Iron, Neoplasm Proteins, Neoplasms, Receptors, Transferrin, Transferrin, Nonheme Iron Proteins, Melanoma-Specific Antigens

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The iron metabolism of neoplastic cells: alterations that facilitate proliferation?

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