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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 January 2025) | Viewed by 17765

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Special Issue Editors

Dr. Emil Malucelli

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Department of Pharmacy and Biotechnology, University of Bologna, 40127 Bologna, Italy
Interests: X-ray synchrotron-based techniques; biomineralization; osteoblastic differentiation; 3D cell culture; cellular imaging
Special Issues, Collections and Topics in MDPI journals

Dr. Concettina Cappadone

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Department of Pharmacy and Biotechnology, University of Bologna, 40127 Bologna, Italy
Interests: cancer; magnesium; MDR; cell cycle; bone; differentiation
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Dr. Alessandra Gianoncelli

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ELETTRA Sincrotrone Trieste S.C.p.A., 34149 Trieste, Italy
Interests: X-ray microscopy; X-ray fluorescence; ptychography and related applications in life sciences; environmental science and cultural heritage
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Special Issue Information

Dear Colleagues,

Metals are fundamental cellular elements for a number of biological processes, including the fundamental metabolic pathways such as energy transduction and cell proliferation. Several metals, such as Ca²⁺, K⁺, Na⁺, Mg²⁺, Zn²⁺, and Fe²⁺/Fe³⁺, are essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation, mitochondrial integrity, proliferative signal transduction, and apoptosis. As a consequence, alterations in metal levels and/or changes in the expression of proteins involved in metal metabolism have been documented in different pathologies and several types of cancers.

Moreover, considering the key role of metals for cell growth, the development of drugs capable of metal sequestration has become an attractive target for the development of novel anti-cancer agents.

Furthermore, a large body of preclinical and clinical studies on dietary deficiencies indicates that metal dis-regulation triggers neoplastic cell transformation and/or reduces the anti-tumor functions of immune cells by controlling a plethora of chemical and biological reactions.

This Special Issue aims to encourage innovation and research activities in this field.

We invite researchers to contribute original research and review articles regarding the involvement of metal level and metabolism in cancer occurrence, progression, and prognosis.

Dr. Emil Malucelli
Dr. Concettina Cappadone
Dr. Alessandra Gianoncelli
Guest Editors

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Keywords

cancer
metal
cell metabolism
mitochondria
cell proliferation

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Published Papers (7 papers)

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Research

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15 pages, 1681 KiB

Open AccessCommunication

Lead Decreases Bone Morphogenetic Protein-7 (BMP-7) Expression and Increases Renal Cell Carcinoma Growth in a Sex-Divergent Manner

by Elizabeth A. Grunz, Haley Anderson, Rebecka M. Ernst, Spencer Price, D’Artanyan Good, Victoria Vieira-Potter and Alan R. Parrish

Int. J. Mol. Sci. 2024, 25(11), 6139; https://doi.org/10.3390/ijms25116139 - 2 Jun 2024

Viewed by 1255

Abstract

Both tissue and blood lead levels are elevated in renal cell carcinoma (RCC) patients. These studies assessed the impact of the subchronic lead challenge on the progression of RCC in vitro and in vivo. Lead challenge of Renca cells with 0.5 μM lead acetate for 10 consecutive passages decreased E-cadherin expression and cell aggregation. Proliferation, colony formation, and wound healing were increased. When lead-challenged cells were injected into mice, tumor size at day 21 was increased; interestingly, this increase was seen in male but not female mice. When mice were challenged with 32 ppm lead in drinking water for 20 weeks prior to tumor cell injection, there was an increase in tumor size in male, but not female, mice at day 21. To investigate the mechanism underlying the sex differences, the expression of sex hormone receptors in Renca cells was examined. Control Renca cells expressed estrogen receptor (ER) alpha but not ER beta or androgen receptor (AR), as assessed by qPCR, and the expression of ERα was increased in tumors in both sexes. In tumor samples harvested from lead-challenged cells, both ERα and AR were detected by qPCR, yet there was a significant decrease in AR seen in lead-challenged tumor cells from male mice only. This was paralleled by a plate-based array demonstrating the same sex difference in BMP-7 gene expression, which was also significantly decreased in tumors harvested from male but not female mice; this finding was validated by immunohistochemistry. A similar expression pattern was seen in tumors harvested from the mice challenged with lead in the drinking water. These data suggest that lead promotes RCC progression in a sex-dependent via a mechanism that may involve sex-divergent changes in BMP-7 expression. Full article

(This article belongs to the Special Issue Metals and Cancer)

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16 pages, 3269 KiB

Open AccessArticle

Assessment of the Electrolyte Heterogeneity of Tissues in Mandibular Bone-Infiltrating Head and Neck Cancer Using Laser-Induced Breakdown Spectroscopy

by Philipp Winnand, Klaus Olaf Boernsen, Mark Ooms, Marius Heitzer, Nils Vohl, Matthias Lammert, Frank Hölzle and Ali Modabber

Int. J. Mol. Sci. 2024, 25(5), 2607; https://doi.org/10.3390/ijms25052607 - 23 Feb 2024

Cited by 2 | Viewed by 1757

Abstract

Laser-induced breakdown spectroscopy (LIBS) was recently introduced as a rapid bone analysis technique in bone-infiltrating head and neck cancers. Research efforts on laser surgery systems with controlled tissue feedback are currently limited to animal specimens and the use of nontumorous tissues. Accordingly, this study aimed to characterize the electrolyte composition of tissues in human mandibular bone-infiltrating head and neck cancer. Mandible cross-sections from 12 patients with bone-invasive head and neck cancers were natively investigated with LIBS. Representative LIBS spectra (n = 3049) of the inferior alveolar nerve, fibrosis, tumor stroma, and cell-rich tumor areas were acquired and histologically validated. Tissue-specific differences in the LIBS spectra were determined by receiver operating characteristics analysis and visualized by principal component analysis. The electrolyte emission values of calcium (Ca) and potassium (K) significantly (p < 0.0001) differed in fibrosis, nerve tissue, tumor stroma, and cell-rich tumor areas. Based on the intracellular detection of Ca and K, LIBS ensures the discrimination between the inferior alveolar nerve and cell-rich tumor tissue with a sensitivity of ≥95.2% and a specificity of ≥87.2%. The heterogeneity of electrolyte emission values within tumorous and nontumorous tissue areas enables LIBS-based tissue recognition in mandibular bone-infiltrating head and neck cancer. Full article

(This article belongs to the Special Issue Metals and Cancer)

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14 pages, 2031 KiB

Open AccessArticle

Quantitative MRI Evaluation of Ferritin Overexpression in Non-Small-Cell Lung Cancer

by Mekhla Singhania, Amira Zaher, Casey F. Pulliam, Khaliunaa Bayanbold, Charles C. Searby, Joshua D. Schoenfeld, Kranti A. Mapuskar, Melissa A. Fath, Bryan G. Allen, Douglas R. Spitz and Michael S. Petronek

Int. J. Mol. Sci. 2024, 25(4), 2398; https://doi.org/10.3390/ijms25042398 - 18 Feb 2024

Cited by 2 | Viewed by 2328

Abstract

Cancer cells frequently present elevated intracellular iron levels, which are thought to facilitate an enhanced proliferative capacity. Targeting iron metabolism within cancer cells presents an avenue to enhance therapeutic responses, necessitating the use of non-invasive models to modulate iron manipulation to predict responses. Moreover, the ubiquitous nature of iron necessitates the development of unique, non-invasive markers of metabolic disruptions to develop more personalized approaches and enhance the clinical utility of these approaches. Ferritin, an iron storage enzyme that is often upregulated as a response to iron accumulation, plays a central role in iron metabolism and has been frequently associated with unfavorable clinical outcomes in cancer. Herein, we demonstrate the successful utility, validation, and functionality of a doxycycline-inducible ferritin heavy chain (FtH) overexpression model in H1299T non-small-cell lung cancer (NSCLC) cells. Treatment with doxycycline increased the protein expression of FtH with a corresponding decrease in labile iron in vitro and in vivo, as determined by calcein-AM staining and EPR, respectively. Moreover, a subsequent increase in TfR expression was observed. Furthermore, T₂* MR mapping effectively detected FtH expression in our in vivo model. These results demonstrate that T₂* relaxation times can be used to monitor changes in FtH expression in tumors with bidirectional correlations depending on the model system. Overall, this study describes the development of an FtH overexpression NSCLC model and its correlation with T₂* mapping for potential use in patients to interrogate iron metabolic alterations and predict clinical outcomes. Full article

(This article belongs to the Special Issue Metals and Cancer)

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14 pages, 3493 KiB

Open AccessArticle

Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease

by Belén Callejón-Leblic, Saida Sánchez Espirilla, Carolina Gotera-Rivera, Rafael Santana, Isabel Díaz-Olivares, José M. Marín, Ciro Casanova Macario, Borja García Cosio, Antonia Fuster, Ingrid Solanes García, Juan P. de-Torres, Nuria Feu Collado, Carlos Cabrera Lopez, Carlos Amado Diago, Amparo Romero Plaza, Luis Alejandro Padrón Fraysse, Eduardo Márquez Martín, Margarita Marín Royo, Eva Balcells Vilarnau, Antonia Llunell Casanovas, Cristina Martínez González, Juan Bautista Galdíz Iturri, Celia Lacárcel Bautista, José Luis Gómez-Ariza, Antonio Pereira-Vega, Luis Seijo, José Luis López-Campos, Germán Peces-Barba and Tamara García-Barrera Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(18), 14250; https://doi.org/10.3390/ijms241814250 - 18 Sep 2023

Cited by 3 | Viewed by 1957

Abstract

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC. Full article

(This article belongs to the Special Issue Metals and Cancer)

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21 pages, 4173 KiB

Open AccessArticle

New Copper Complexes with Antibacterial and Cytotoxic Activity

by Adriana Corina Hangan, Roxana Liana Lucaciu, Alexandru Turza, Lucia Dican, Bogdan Sevastre, Emöke Páll, Luminița Simona Oprean and Gheorghe Borodi

Int. J. Mol. Sci. 2023, 24(18), 13819; https://doi.org/10.3390/ijms241813819 - 7 Sep 2023

Cited by 15 | Viewed by 2685

Abstract

The discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu⁺² complexes, [Cu₄(L1)₄(OH)₄(DMF)₂(H₂O)] (C1) (HL1 = N-(5-ethyl-[1,3,4]–thiadiazole–2-yl)-benzenesulfonamide) and [Cu(L2)₂(phen)(H₂O)] (C2) (HL2 = N-(5-(4-methylphenyl)-[1,3,4]–thiadiazole–2-yl)-naphtalenesulfonamide), with two new ligands were synthesized. The X-ray crystal structures of the complexes were determined. In both complexes, Cu⁺² is five-coordinated, forming a CuN₂O₃ and CuN₄O chromophore, respectively. The ligands act as monodentate, coordinating the metal ion through a single N_thiadiazole atom; for the two complexes, the molecules from the reaction medium (phenantroline, dimethylformamide and water) are also involved in the coordination of Cu⁺². The complexes have a distorted square pyramidal square-planar geometry. The compounds were characterized by FT-IR and UV-Vis spectroscopy. Using the microdilution method, the antibacterial activity of the complexes was determined against four Gram-positive and two Gram-negative bacteria, with Gentamicin as the positive control. Cytotoxicity studies were carried out on two tumor cell lines (HeLa, DLD-1) and on a normal cell line (HFL1) using the MTT method and Cisplatin as a positive control. Flow cytometric assessment of apoptosis induced by the complexes on the three cell lines was also performed. Both complexes present in vitro biological activities but complex C2 is more active. Full article

(This article belongs to the Special Issue Metals and Cancer)

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Review

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19 pages, 1327 KiB

Open AccessReview

Toxicological Aspects Associated with Consumption from Electronic Nicotine Delivery System (ENDS): Focus on Heavy Metals Exposure and Cancer Risk

by Silvia Granata, Fabio Vivarelli, Camilla Morosini, Donatella Canistro, Moreno Paolini and Lucy C. Fairclough

Int. J. Mol. Sci. 2024, 25(5), 2737; https://doi.org/10.3390/ijms25052737 - 27 Feb 2024

Cited by 9 | Viewed by 3792

Abstract

Tobacco smoking remains one of the leading causes of premature death worldwide. Electronic Nicotine Delivery Systems (ENDSs) are proposed as a tool for smoking cessation. In the last few years, a growing number of different types of ENDSs were launched onto the market. Despite the manufacturing differences, ENDSs can be classified as “liquid e-cigarettes” (e-cigs) equipped with an atomizer that vaporizes a liquid composed of vegetable glycerin (VG), polypropylene glycol (PG), and nicotine, with the possible addition of flavorings; otherwise, the “heated tobacco products” (HTPs) heat tobacco sticks through contact with an electronic heating metal element. The presence of some metals in the heating systems, as well as in solder joints, involves the possibility that heavy metal ions can move from these components to the liquid, or they can be adsorbed into the tobacco stick from the heating blade in the case of HTPs. Recent evidence has indicated the presence of heavy metals in the refill liquids and in the mainstream such as arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), copper (Cu), and lead (Pb). The present review discusses the toxicological aspects associated with the exposition of heavy metals by consumption from ENDSs, focusing on metal carcinogenesis risk. Full article

(This article belongs to the Special Issue Metals and Cancer)

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26 pages, 2924 KiB

Open AccessReview

Cancer 3D Models for Metallodrug Preclinical Testing

by Diogo M. Engrácia, Catarina I. G. Pinto and Filipa Mendes

Int. J. Mol. Sci. 2023, 24(15), 11915; https://doi.org/10.3390/ijms241511915 - 25 Jul 2023

Cited by 4 | Viewed by 2629

Abstract

Despite being standard tools in research, the application of cellular and animal models in drug development is hindered by several limitations, such as limited translational significance, animal ethics, and inter-species physiological differences. In this regard, 3D cellular models can be presented as a step forward in biomedical research, allowing for mimicking tissue complexity more accurately than traditional 2D models, while also contributing to reducing the use of animal models. In cancer research, 3D models have the potential to replicate the tumor microenvironment, which is a key modulator of cancer cell behavior and drug response. These features make cancer 3D models prime tools for the preclinical study of anti-tumoral drugs, especially considering that there is still a need to develop effective anti-cancer drugs with high selectivity, minimal toxicity, and reduced side effects. Metallodrugs, especially transition-metal-based complexes, have been extensively studied for their therapeutic potential in cancer therapy due to their distinctive properties; however, despite the benefits of 3D models, their application in metallodrug testing is currently limited. Thus, this article reviews some of the most common types of 3D models in cancer research, as well as the application of 3D models in metallodrug preclinical studies. Full article

(This article belongs to the Special Issue Metals and Cancer)

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