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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 7521

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Dr. Yasumasa Okazaki

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Guest Editor

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai‐cho, Showa‐Ku, Nagoya, Aichi 466‐8550, 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

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Editorial

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Open AccessEditorial

Iron and Cancer: A Special Issue

Yasumasa Okazaki

and

Keisuke Hino

Cancers 2023, 15(7), 2097; https://doi.org/10.3390/cancers15072097 - 31 Mar 2023

Viewed by 498

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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Open AccessArticle

Role of Fe, Transferrin and Transferrin Receptor in Anti-Tumor Effect of Vitamin C

and

Cancers 2022, 14(18), 4507; https://doi.org/10.3390/cancers14184507 - 17 Sep 2022

Cited by 1 | Viewed by 919

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 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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Open AccessArticle

Importance of Locations of Iron Ions to Elicit Cytotoxicity Induced by a Fenton-Type Reaction

and

Cancers 2022, 14(15), 3642; https://doi.org/10.3390/cancers14153642 - 27 Jul 2022

Cited by 5 | Viewed by 1004

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), 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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Open AccessArticle

Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma

and

Cancers 2022, 14(9), 2066; https://doi.org/10.3390/cancers14092066 - 20 Apr 2022

Cited by 5 | Viewed by 1420

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) 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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Open AccessArticle

Exploratory Study of Superparamagnetic Iron Oxide Dose Optimization in Breast Cancer Sentinel Lymph Node Identification Using a Handheld Magnetic Probe and Iron Quantitation

and

Cancers 2022, 14(6), 1409; https://doi.org/10.3390/cancers14061409 - 10 Mar 2022

Cited by 3 | Viewed by 1008

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 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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The Role of Ferric Nitrilotriacetate in Renal Carcinogenesis and Cell Death: From Animal Models to Clinical Implications

Yasumasa Okazaki

Cancers 2022, 14(6), 1495; https://doi.org/10.3390/cancers14061495 - 15 Mar 2022

Cited by 5 | Viewed by 1936

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 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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