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Tumor Microenvironment and Its Actors: Are Ion Channels Relevant?

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 9928

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Special Issue Editors

Dr. Maria Beatrice Morelli

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Guest Editor

School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: glioblastoma; TRP channel; mucolipins; autophagy; overall survival; transient receptor potential channels; tumor progression; chemotherapy resistance;cancer biology; cancer stem cell; circulating tumor cell; liquid biopsy; biomarkers; ion channel; natural compound; cannabinoids
Special Issues, Collections and Topics in MDPI journals

Dr. Amantini Consuelo

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Guest Editor

School of Bioscience and Biotechnology, University of Camerino, 62032 Camerino, Italy
Interests: TRP; cancer biology; apoptosis; autophagy; senescence; circulating stem cell; chemoresistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer research is opening new perspectives in the field of patient management, focusing mainly on factors that promote tumor progression. The environment surrounding the tumor mass, consisting of resident cells and extracellular matrix, plays an important role in maintaining a condition conducive to the growth and progression of the disease. This also results in the establishment of resistance to the main therapeutic standards, such as chemotherapy and radiotherapy. Oncology research is making great strides, bringing to light new prognostic and therapeutic biomarkers. Among all, it has been demonstrated that the ion channel family is involved in several type of cancers. For this reason, the goal of this Special Issue is to bring together experts and scientists who work on ion channels to collect information and data regarding their involvement not only in tumor but also in its microenvironment.

The ultimate purpose is to identify, at the molecular level, the contribution of ion channels to the various cancerous processes, ranging from signaling pathways involved in tumor growth, invasion, angiogenesis, drug resistance, metastasis formation, up to immune escape.

Dr. Maria Beatrice Morelli
Dr. Amantini Consuelo
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 short 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Keywords

ion channels
tumor microenvironment
niche
calcium signaling
mechanism
leukocyte
fibroblast
endothelial cell
metastasis
angiogenesis

Published Papers (4 papers)

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Research

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19 pages, 9676 KiB

Open AccessArticle

The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left–Right Functional Differences

by Sofía Masuelli, Sebastián Real, Patrick McMillen, Madeleine Oudin, Michael Levin and María Roqué

Int. J. Mol. Sci. 2023, 24(13), 11121; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241311121 - 05 Jul 2023

Viewed by 2348

Abstract

Breast cancer is a complex and heterogeneous disease that displays diverse molecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect their biological behavior, the underlying mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential between left (L)- and right (R)-sided breast tumors. In this current study, we aimed to identify the ion channels responsible for this phenomenon and determine any associated phenotypic features. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. The results revealed that L-sided tumors have a more depolarized state than R-sided. We identified a 6-ion channel-gene signature (CACNA1C, CACNA2D2, CACNB2, KCNJ11, SCN3A, and SCN3B) associated with the side: L-tumors exhibit lower expression levels than R-tumors. Additionally, in silico analyses show that the signature correlates inversely with DNA methylation writers and with key biological processes involved in cancer progression, such as proliferation and stemness. The signature also correlates inversely with patient survival rates. In an in vivo mouse model, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and a similar tendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into the potential impact of anatomical location on breast cancer biology and highlights the need for further investigation into possible differential treatment options. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Its Actors: Are Ion Channels Relevant?)

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30 pages, 9406 KiB

Open AccessArticle

Achievement of the Selectivity of Cytotoxic Agents against Cancer Cells by Creation of Combined Formulation with Terpenoid Adjuvants as Prospects to Overcome Multidrug Resistance

by Igor D. Zlotnikov, Natalia V. Dobryakova, Alexander A. Ezhov and Elena V. Kudryashova

Int. J. Mol. Sci. 2023, 24(9), 8023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098023 - 28 Apr 2023

Cited by 4 | Viewed by 1510

Abstract

Oncological diseases are difficult to treat even with strong drugs due to development the multidrug resistance (MDR) of cancer cells. A strategy is proposed to increase the efficiency and selectivity of cytotoxic agents against cancer cells to engage the differences in the morphology and microenvironment of tumor and healthy cells, including the pH, membrane permeability, and ion channels. Using this approach, we managed to develop enhanced formulations of cytotoxic agents with adjuvants (which are known as efflux inhibitors and as ion channel inhibitors in tumors)—with increased permeability in A549 and a protective effect on healthy HEK293T cells. The composition of the formulation is as follows: cytotoxic agents (doxorubicin (Dox), paclitaxel (Pac), cisplatin) + adjuvants (allylbenzenes and terpenoids) in the form of inclusion complexes with β–cyclodextrin. Modified cyclodextrins make it possible to obtain soluble forms of pure substances of the allylbenzene and terpenoid series and increase the solubility of cytotoxic agents. A comprehensive approach based on three methods for studying the interaction of drugs with cells is proposed: MTT test—quantitative identification of surviving cells; FTIR spectroscopy—providing information on the molecular mechanisms inaccessible to study by any other methods (including binding to DNA, surface proteins, or lipid membrane); confocal microscopy for the visualization of observed effects of Dox accumulation in cancer or healthy cells depending on the drug formulation as a direct control of the correctness of interpretation of the results obtained by the two other methods. We found that eugenol (EG) and apiol increase the intracellular concentration of cytostatic in A549 cells by 2–4 times and maintain it for a long time. However, an important aspect is the selectivity of the enhancing effect of adjuvants on tumor cells in relation to healthy ones. Therefore, the authors focused on adjuvant’s effect on the control healthy cells (HEK293T): EG and apiol demonstrate “protective” properties from cytostatic penetration by reducing intracellular concentrations by about 2–3 times. Thus, a combined formulation of cytostatic drugs has been found, showing promise in the aspects of improving the efficiency and selectivity of antitumor drugs; thereby, one of the perspective directions for overcoming MDR is suggested. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Its Actors: Are Ion Channels Relevant?)

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17 pages, 19676 KiB

Open AccessArticle

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism

by Jing Fan, Ruofei Tian, Xiangmin Yang, Hao Wang, Ying Shi, Xinyu Fan, Jiajia Zhang, Yatong Chen, Kun Zhang, Zhinan Chen and Ling Li

Int. J. Mol. Sci. 2022, 23(13), 6958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136958 - 23 Jun 2022

Cited by 12 | Viewed by 2008

Abstract

The presence of liver cancer stem cells (LCSCs) is one of the reasons for the treatment failure of hepatocellular carcinoma (HCC). For LCSCs, one of their prominent features is metabolism plasticity, which depends on transporters and ion channels to exchange metabolites and ions. The K⁺ channel protein KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) has been reported to promote cell metabolism and malignant progression of HCCs, but its influence on LCSC stemness has remained unclear. Here, we demonstrated that KCNN4 was highly expressed in L-CSCs by RT-PCR and Western blot. Then, we illustrated that KCNN4 promoted the stemness of HC-C cells by CD133⁺CD44⁺ LCSC subpopulation ratio analysis, in vitro stemness transcription factor detection, and sphere formation assay, as well as in vivo orthotopic liver tumor formation and limiting dilution tumorigenesis assays. We also showed that KCNN4 enhanced the glucose metabolism in LCSCs by metabolic enzyme detections and seahorse analysis, and the KCNN4-promoted increase in LCSC ratios was abolished by glycolysis inhibitor 2-DG or OXPHOS inhibitor oligomycin. Collectively, our results suggested that KCNN4 promoted LCSC stemness via enhancing glucose metabolism, and that KCNN4 would be a potential molecular target for eliminating LCSCs in HCC. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Its Actors: Are Ion Channels Relevant?)

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Review

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38 pages, 3007 KiB

Open AccessReview

Ca²⁺ Signalling and Hypoxia/Acidic Tumour Microenvironment Interplay in Tumour Progression

by Madelaine Magalì Audero, Natalia Prevarskaya and Alessandra Fiorio Pla

Int. J. Mol. Sci. 2022, 23(13), 7377; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137377 - 02 Jul 2022

Cited by 8 | Viewed by 2604

Abstract

Solid tumours are characterised by an altered microenvironment (TME) from the physicochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hypoxia results from uncontrolled proliferation, aberrant vascularization and altered cancer cell metabolism. Tumour cellular apparatus adapts to hypoxia by altering its metabolism and behaviour, increasing its migratory and metastatic abilities by the acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance via the selection of more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca²⁺ channels represent good target candidates due to their ability to integrate signals from the TME. Ca²⁺ channels are pH and hypoxia sensors and alterations in Ca²⁺ homeostasis in cancer progression and vascularization have been extensively reported. In the present review, we present an up-to-date and critical view on Ca²⁺ permeable ion channels, with a major focus on TRPs, SOCs and PIEZO channels, which are modulated by tumour hypoxia and acidosis, as well as the consequent role of the altered Ca²⁺ signals on cancer progression hallmarks. We believe that a deeper comprehension of the Ca²⁺ signalling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutic targets. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Its Actors: Are Ion Channels Relevant?)

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