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Cancers
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Iron and Cancer
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Iron and Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 15411

Special Issue Editors

Dr. Yasumasa Okazaki

E-Mail Website
Guest Editor
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai‐cho, Showa‐Ku, Nagoya 466‐8550, Aichi, Japan
Interests: oxidative stress; iron metabolism; mesothelioma
Prof. Dr. Keisuke Hino

E-Mail Website
Guest Editor
Department of Hepatology and Pancreatology, Kawasaki Medical School, Okayama 701-0192, Japan
Interests: iron metabolism; mitochondria; ozidative stress

Special Issue Information

Dear Colleagues,

Iron is an essential element for all organisms. Iron-containing proteins play critical roles in cellular functions. The biological importance of iron is largely attributable to its chemical properties as a transitional metal. However, an excess of “free” reactive iron damages the macromolecular components of cells and cellular DNA through the production of harmful free radicals. These properties are closely associated with carcinogenesis. For instance, hepatocellular carcinoma, malignant mesothelioma, and ovarian clear cell carcinoma have been shown to develop in relation to excess iron and/or oxidative stress caused by free radicals. In the last decade, accumulating evidence regarding molecules regulating iron metabolism or iron-related cell death programmes such as ferroptosis has shed light on the relationship between excess iron and carcinogenesis. Furthermore, iron depletion by chelating is shown to be a promising therapeutic option in several cancers.

This Special Issue will highlight the current knowledge on iron- and metal-related biology for understanding pathogenesis-based therapy and prophylaxis.

Dr. Yasumasa Okazaki
Prof. Dr. Keisuke Hino
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (6 papers)

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Editorial

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3 pages, 199 KiB  
Editorial
Iron and Cancer: A Special Issue
by Yasumasa Okazaki and Keisuke Hino
Cancers 2023, 15(7), 2097; https://doi.org/10.3390/cancers15072097 - 31 Mar 2023
Cited by 1 | Viewed by 1468
Abstract
Iron is an essential element for all organisms, and iron-containing proteins play critical roles in cellular functions [...] Full article
(This article belongs to the Special Issue Iron and Cancer)

Research

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15 pages, 4648 KiB  
Article
Role of Fe, Transferrin and Transferrin Receptor in Anti-Tumor Effect of Vitamin C
by Jia Qiu, Renbo Wu, Yali Long, Lei Peng, Tianhong Yang, Bing Zhang, Xinchong Shi, Jianbo Liu and Xiangsong Zhang
Cancers 2022, 14(18), 4507; https://doi.org/10.3390/cancers14184507 - 17 Sep 2022
Cited by 7 | Viewed by 2309
Abstract
High-dose vitamin C (VC) exhibits anti-tumor effects, and the cytotoxicity of VC is correlated with oxidative stress. However, iron, as a redox metal, plays an important effect in redox cycling and free radical formation in cells. This study addresses the role of iron [...] Read more.
High-dose vitamin C (VC) exhibits anti-tumor effects, and the cytotoxicity of VC is correlated with oxidative stress. However, iron, as a redox metal, plays an important effect in redox cycling and free radical formation in cells. This study addresses the role of iron ion in the cytotoxicity of VC. We found that iron supplementation increases the anti-tumor effect of VC, which was influenced by the cellular iron uptake pathway–transferrin (TF)/transferrin receptor (TFR) system. The TFR expression of tumors can be assessed by 68Ga-citrate PET imaging, and it would be helpful to screen out the tumor type which is more sensitive to VC combined with an iron supplementation treatment. Full article
(This article belongs to the Special Issue Iron and Cancer)
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15 pages, 2088 KiB  
Article
Importance of Locations of Iron Ions to Elicit Cytotoxicity Induced by a Fenton-Type Reaction
by Kintaro Igarashi, Yoshimi Shoji, Emiko Sekine-Suzuki, Megumi Ueno, Ken-ichiro Matsumoto, Ikuo Nakanishi and Koji Fukui
Cancers 2022, 14(15), 3642; https://doi.org/10.3390/cancers14153642 - 27 Jul 2022
Cited by 8 | Viewed by 2182
Abstract
The impact of the site of the Fenton reaction, i.e., hydroxyl radical (•OH) generation, on cytotoxicity was investigated by estimating cell lethality in rat thymocytes. Cells were incubated with ferrous sulfate (FeSO4) and hydrogen peroxide (H2O2 [...] Read more.
The impact of the site of the Fenton reaction, i.e., hydroxyl radical (•OH) generation, on cytotoxicity was investigated by estimating cell lethality in rat thymocytes. Cells were incubated with ferrous sulfate (FeSO4) and hydrogen peroxide (H2O2), or pre-incubated with FeSO4 and then H2O2 was added after medium was replaced to remove iron ions or after the medium was not replaced. Cell lethality in rat thymocytes was estimated by measuring cell sizes using flow cytometry. High extracellular concentrations of FeSO4 exerted protective effects against H2O2-induced cell death instead of enhancing cell lethality. The pre-incubation of cells with FeSO4 enhanced cell lethality induced by H2O2, whereas a pre-incubation with a high concentration of FeSO4 exerted protective effects. FeSO4 distributed extracellularly or on the surface of cells neutralized H2O2 outside cells. Cytotoxicity was only enhanced when the Fenton reaction, i.e., the generation of •OH, occurred inside cells. An assessment of plasmid DNA breakage showed that •OH induced by the Fenton reaction system did not break DNA. Therefore, the main target of intracellularly generated •OH does not appear to be DNA. Full article
(This article belongs to the Special Issue Iron and Cancer)
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11 pages, 832 KiB  
Article
Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma
by Kota Hamaguchi, Koji Miyanishi, Takahiro Osuga, Shingo Tanaka, Ryo Ito, Hiroki Sakamoto, Tomohiro Kubo, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa and Junji Kato
Cancers 2022, 14(9), 2066; https://doi.org/10.3390/cancers14092066 - 20 Apr 2022
Cited by 10 | Viewed by 2556
Abstract
We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) [...] Read more.
We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the ‘high RER’ group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with “serum ferritin levels above the upper limits or iron staining-positive” and ‘8-oxo-dG high’ cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis. Full article
(This article belongs to the Special Issue Iron and Cancer)
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9 pages, 393 KiB  
Article
Exploratory Study of Superparamagnetic Iron Oxide Dose Optimization in Breast Cancer Sentinel Lymph Node Identification Using a Handheld Magnetic Probe and Iron Quantitation
by Kanae Taruno, Akihiko Kuwahata, Masaki Sekino, Takayuki Nakagawa, Tomoko Kurita, Katsutoshi Enokido, Seigo Nakamura, Hiroyuki Takei and Moriaki Kusakabe
Cancers 2022, 14(6), 1409; https://doi.org/10.3390/cancers14061409 - 10 Mar 2022
Cited by 5 | Viewed by 2084
Abstract
This exploratory study compared doses of ferucarbotran, a superparamagnetic iron oxide nanoparticle, in sentinel lymph nodes (SLNs) and quantified the SLN iron load by dose and localization. Eighteen females aged ≥20 years scheduled for an SLN biopsy with node-negative breast cancer were divided [...] Read more.
This exploratory study compared doses of ferucarbotran, a superparamagnetic iron oxide nanoparticle, in sentinel lymph nodes (SLNs) and quantified the SLN iron load by dose and localization. Eighteen females aged ≥20 years scheduled for an SLN biopsy with node-negative breast cancer were divided into two equal groups and administered either 1 mL or 0.5 mL ferucarbotran. Iron content was evaluated with a handheld magnetometer and quantification device. The average iron content was 42.8 µg (range, 1.3–95.0; 0.15% of the injected dose) and 21.9 µg (1.1–71.0; 0.16%) in the 1-mL and 0.5-mL groups, respectively (p = 0.131). The iron content of the closest SLN compared to the second SLN was 53.0 vs. 10.0 µg (19% of the injected dose) and 34.8 vs. 4.1 µg (11.1%) for the 1-mL and 0.5-mL groups, respectively (p = 0.001 for both). The magnetic field was high in both groups (average 7.30 µT and 6.00 µT in the 1-mL and 0.5-mL groups, respectively) but was not statistically significant (p = 0.918). The magnetic field and iron content were correlated (overall SLNs, p = 0.02; 1-mL, p = 0.014; 0.5-mL, p = 0.010). A 0.5-mL dose was sufficient for SLN identification. Primary and secondary SLNs could be differentiated based on iron content. Handheld magnetometers could be used to assess the SLN iron content. Full article
(This article belongs to the Special Issue Iron and Cancer)
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Review

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20 pages, 1818 KiB  
Review
The Role of Ferric Nitrilotriacetate in Renal Carcinogenesis and Cell Death: From Animal Models to Clinical Implications
by Yasumasa Okazaki
Cancers 2022, 14(6), 1495; https://doi.org/10.3390/cancers14061495 - 15 Mar 2022
Cited by 10 | Viewed by 3843
Abstract
Iron is essential for cellular growth, and various ferroproteins and heme-containing proteins are involved in a myriad of cellular functions, such as DNA synthesis, oxygen transport, and catalytic reactions. As a consequence, iron deficiency causes pleiotropic effects, such as hypochromic microcytic anemia and [...] Read more.
Iron is essential for cellular growth, and various ferroproteins and heme-containing proteins are involved in a myriad of cellular functions, such as DNA synthesis, oxygen transport, and catalytic reactions. As a consequence, iron deficiency causes pleiotropic effects, such as hypochromic microcytic anemia and growth disturbance, while iron overload is also deleterious by oxidative injury. To prevent the generation of iron-mediated reactive oxygen species (ROS), ferritin is synthesized to store excess iron in cells that are consistent with the clinical utility of the serum ferritin concentration to monitor the therapeutic effect of iron-chelation. Among the animal models exploring iron-induced oxidative stress, ferric nitrilotriacetate (Fe-NTA) was shown to initiate hepatic and renal lipid peroxidation and the development of renal cell carcinoma (RCC) after repeated intraperitoneal injections of Fe-NTA. Here, current understanding of Fe-NTA-induced oxidative stress mediated by glutathione-cycle-dependent iron reduction and the molecular mechanisms of renal carcinogenesis are summarized in combination with a summary of the relationship between the pathogenesis of human RCC and iron metabolism. In addition to iron-mediated carcinogenesis, the ferroptosis that is triggered by the iron-dependent accumulation of lipid peroxidation and is implicated in the carcinogenesis is discussed. Full article
(This article belongs to the Special Issue Iron and Cancer)
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