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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 (31 July 2025) | Viewed by 6230

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Special Issue Editor

Dr. Christos Mikropoulos

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Guest Editor

St Luke’s Cancer Centre, Royal Surrey Hospital, Guildford GU1 1EB, UK
Interests: cancer genetics; biomarkers; SABR; brachytherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Following the discovery of the first tumor biomarker by Henry Bence-Jones in 1847, the study of new cancer biomarkers has accelerated, propelled onwards by advancements in molecular technology. The identification of novel cancer biomarkers now utilizes modified immunoassay, molecular hybridization, next-generation nucleic acid sequencing, gene amplification, gene editing and liquid biopsy technology.

Within the current era of innovation and development, recent publications have explored the use of circulating tumor DNA (ctDNA) and circulating micro-RNA (c-miRNA) for the diagnosis and prognosis of colorectal cancer, esophageal cancer and non-small cell lung cancer. The unique methylation profile of cancer cells identified from gene methylation can differentiate between several gastrointestinal cancers, which can be used to predict the origin of tumors in metastatic disease. Tumor-infiltrating lymphocytes (TILs) have prognostic potential in triple-negative breast cancer and are predictors of patients’ response in melanoma. TILs have even been studied for their therapeutic potential, leading to the FDA approval of Lifileucel for advanced melanoma, demonstrating the importance of molecular studies in transforming our understanding at the cellular level and driving precision medicine. Proteomics and metabolomics further represent emerging research, with attempts to identify cancer-specific biomarkers and predict drug sensitivity in ovarian and breast cancer through mass spectrometry.

Within the cornucopia of available literature on cancer biomarkers, the International Journal of Molecular Sciences (IJMS) has published over 500 articles on cancer biomarkers in the last two years alone and continues to pioneer experimental and theoretical progress. This Special Issue focuses on advancements in cancer biomarkers to update and orientate the scientific community on the continual expansive field of molecular oncology. We hope to unite specialists from various disciplines, including molecular biology, biochemistry, biophysics, biogenetics, computational biology and biotechnology, including artificial intelligence.

This Special Issue is led by Dr. Christos Mikropoulos and assisted by our GE's Assistant Editor, Dr. Michael Hannides (<michael.hannides@nhs.net>, Clinical Oncology, Royal Surrey NHS Foundation Trust, Egerton Road, Surrey, Guildford GU2 7XX, UK). Please note that this Special Issue is focused on molecular research, so pure clinical research will not be accepted, but we welcome clinical submissions with biomolecular experiments.

Dr. Christos Mikropoulos
Guest Editor

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.

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Keywords

biomarkers
ctDNA
mircroRNA
proteomics
gene methylation
TIL
transcriptomics
micro RNA
tumor microenvironment
gene methylation
proteomics

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Published Papers (8 papers)

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Research

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25 pages, 3899 KB

Open AccessArticle

Exploring the Heterogeneity of Cancer-Associated Fibroblasts via Development of Patient-Derived Cell Culture of Breast Cancer

by Anna Ilyina, Anastasia Leonteva, Ekaterina Berezutskaya, Maria Abdurakhmanova, Mikhail Ermakov, Sergey Mishinov, Elena Kuligina, Sergey Vladimirov, Maria Bogachek, Vladimir Richter and Anna Nushtaeva

Int. J. Mol. Sci. 2025, 26(16), 7789; https://doi.org/10.3390/ijms26167789 - 12 Aug 2025

Viewed by 407

Abstract

Cancer-associated fibroblasts (CAFs) constitute a heterogeneous population of cells within the tumor microenvironment and are associated with cancer development and drug resistance. The absence of a universal classification for CAFs hinders their research and therapeutic targeting. To define CAF phenotypes, we developed patient-derived cell cultures of breast cancer (BC) and validated and characterized four distinct CAF subtypes (S1–S4) by Costa’s classification. Three out of five primary cell cultures of BC demonstrated different functional features rather than fixed cellular states due to the plasticity of the CAF phenotype. CAF crosstalk with cancer cells supported their survival in the presence of anticancer drugs. Based on the analysis of the cytotoxic effect of doxorubicin, cisplatin and tamoxifen, it was demonstrated that CAF-S4 and CAF-S1 cells were sensitive to the action of all drugs investigated, despite the fact that they possessed different mechanisms of action. CAF-S2 cells exhibited the highest level of resistance to the antitumour agents. Homotypic and heterotypic spheroids with CAFs could be used to model the fibrotic area of BC in vitro. The patient-derived cell cultures of CAFs formed spheroids. Hypoxia-activated CAF-S4 have been shown to stimulate the metastatic potential of triple-negative BC cells in a heterotypic spheroid model. Consequently, this study could be a starting point for the development of novel therapeutic strategies that target CAFs and their interactions with cancer cells. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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13 pages, 1291 KB

Open AccessArticle

Preoperative Expression Profiles of miR-146a and miR-221 as Potential Biomarkers for Differentiating Benign from Malignant Thyroid Nodules

by Mervat Matei, Sergiu-Ciprian Matei, Cristina Stefania Dumitru, Roxana Popescu, Ligia Petrica, Ioana Golu, Marioara Cornianu, Isabella Ionela Stoian and Mihaela Maria Vlad

Int. J. Mol. Sci. 2025, 26(15), 7564; https://doi.org/10.3390/ijms26157564 - 5 Aug 2025

Viewed by 206

Abstract

Thyroid cancer is the most common endocrine malignancy, and preoperative distinction between benign and malignant nodules remains challenging, especially in cytologically indeterminate cases. Circulating microRNAs (miRNAs) have gained interest as non-invasive biomarkers due to their stability and involvement in tumorigenesis. This study aimed to assess the preoperative diagnostic value of circulating miR-146a and miR-221 in patients undergoing thyroidectomy. A total of 56 patients were included, of whom 24 had malignant and 32 had benign thyroid lesions confirmed by histopathology. Preoperative plasma levels of miR-146a and miR-221 were quantified using qRT-PCR, and relative expression was calculated with the 2^−ΔΔCt method. miR-221 expression was significantly higher in malignant cases, with an area under the ROC curve of 1.00, achieving 100% sensitivity and specificity at the optimal threshold. miR-146a showed no significant discriminatory ability. Weak correlations were observed between miRNA expression and clinical parameters such as age, TIRADS score, or thyroid volume. Logistic regression including miR-221 led to perfect separation, indicating strong predictive capacity but precluding multivariate modeling. These findings suggest that circulating miR-221 may serve as a highly accurate biomarker for thyroid malignancy and warrant further validation in larger, prospective cohorts. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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14 pages, 8052 KB

Open AccessArticle

Unraveling TNXB Epigenetic Alterations Through Genome-Wide DNA Methylation Analysis and Their Implications for Colorectal Cancer

by Jesús Pilo, Alejandro Rego-Calvo, Libia-Alejandra García-Flores, Isabel Arranz-Salas, Ana Isabel Alvarez-Mancha, Andrea G. Izquierdo, Ana B. Crujeiras, Julia Alcaide, Maria Ortega-Castan, Hatim Boughanem and Manuel Macías-González

Int. J. Mol. Sci. 2025, 26(15), 7197; https://doi.org/10.3390/ijms26157197 - 25 Jul 2025

Viewed by 265

Abstract

Aberrant DNA methylation has been shown to be a fingerprint characteristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted in both the tumor area (N = 27) and the adjacent tumor-free (NAT) area (N = 15). We found 78,935 differentially methylated CpG sites (DMCs) (FDR < 0.05), 42,888 hypomethylated and 36,047 hypermethylation showing overall hypomethylation. Gene ontology and KEGG analysis of differentially methylated genes showed significant enrichment in developmental genes, as well as in genes involved in metabolic processes and the cell cycle, such as the TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB as the most epigenetically dysregulated gene, hypomethylated and downregulated in CRC (both with p < 0.001) and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated in a dose-dependent manner, suggesting a potential role in CRC. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as indicators of malignant potential, with adverse effects associated with disease origin and progression in CRC. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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18 pages, 2384 KB

Open AccessArticle

Distinctive Features of Extracellular Vesicles Present in the Gastric Juice of Patients with Gastric Cancer and Healthy Subjects

by Gleb Skryabin, Adel Enikeev, Anastasiia Beliaeva, Sergey Galetsky, Dmitry Bagrov, Andrey Moiseenko, Anna Vnukova, Oiatiddin Imaraliev, Ivan Karasev and Elena Tchevkina

Int. J. Mol. Sci. 2025, 26(12), 5857; https://doi.org/10.3390/ijms26125857 - 18 Jun 2025

Viewed by 704

Abstract

Extracellular vesicles (EVs) are key mediators of intercellular communication and play a vital role in cancer progression. While EVs in the blood are well-studied, those in local body fluids, such as gastric juice (GJ), remain underinvestigated. Previously, we first characterized GJ-derived EVs and demonstrated their potential for gastric cancer (GC) screening. Here, we conducted a detailed morphological analysis of GJ-EVs using cryo-electron microscopy, identifying both typical and atypical EV subtypes, and categorized their relative abundances. A subsequent comparison of the size distribution of GJ-derived EVs by nanoparticle tracking analysis revealed significant differences between samples obtained from GC patients (n = 40) and healthy subjects (n = 25). Additionally, the mean EV sizes differed significantly according to the presence of the tetraspanin protein CD9. Furthermore, the ratio of CD9-positive to CD9-negative EV samples differed between cancer patients and healthy donors. These data suggest that GJ contains distinct subpopulations of EVs that vary in size and CD9 expression, as well as EVs with certain types of atypical morphology. The identification of discrepancies in EV size and the presence of CD9 between GJ from cancer patients and healthy individuals offers potential avenues for the identification of new GC markers. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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28 pages, 14266 KB

Open AccessArticle

Identification of CDK1 as a Biomarker for the Treatment of Liver Fibrosis and Hepatocellular Carcinoma Through Bioinformatics Analysis

by Jiayi Qin and Zhuan Li

Int. J. Mol. Sci. 2025, 26(8), 3816; https://doi.org/10.3390/ijms26083816 - 17 Apr 2025

Cited by 1 | Viewed by 1565

Abstract

Cyclin-dependent kinase 1 (CDK1) has emerged as a critical regulator of cell cycle progression, yet its role in liver fibrosis-associated hepatocellular carcinoma (LF-HCC) remains underexplored. This study aimed to systematically evaluate CDK1’s prognostic significance, immune regulatory functions, and therapeutic potential in LF-HCC pathogenesis. Integrated bioinformatics approaches were applied to multi-omics datasets from GEO, TCGA, and TIMER databases. Differentially expressed genes were identified through enrichment analysis and protein–protein interaction networks. Survival outcomes were assessed via Kaplan–Meier analysis, while immune cell infiltration patterns were quantified using CIBERSORT. Molecular docking simulations evaluated CDK1’s binding affinity with pharmacologically active compounds (alvocidib, seliciclib, alsterpaullone) using AutoDock Vina. CDK1 demonstrated significant overexpression in LF-HCC tissues compared to normal controls (p < 0.001). Elevated CDK1 expression correlated with reduced overall survival (HR = 2.41, 95% CI:1.78–3.26, p = 0.003) and advanced tumor staging (p = 0.007). Immune profiling revealed strong associations between CDK1 levels and immunosuppressive cell infiltration, particularly regulatory T cells (r = 0.63, p = 0.001) and myeloid-derived suppressor cells (r = 0.58, p = 0.004). Molecular docking confirmed high-affinity binding of CDK1 to kinase inhibitors through conserved hydrogen-bond interactions (binding energy ≤ −8.5 kcal/mol), with alvocidib showing optimal binding stability. This multimodal analysis establishes CDK1 as both a prognostic biomarker and immunomodulatory regulator in LF-HCC pathogenesis. The enzyme’s dual role in driving tumor progression and reshaping the immune microenvironment positions it as a promising therapeutic target. Computational validation of CDK1 inhibitors provides a rational basis for developing precision therapies against LF-HCC, bridging translational gaps between biomarker discovery and clinical application. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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Review

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25 pages, 1749 KB

Open AccessReview

TGF-β Signaling in Cancer: Mechanisms of Progression and Therapeutic Targets

by Elżbieta Cecerska-Heryć, Adrianna Jerzyk, Małgorzata Goszka, Aleksandra Polikowska, Julita Rachwalska, Natalia Serwin, Bartosz Wojciuk and Barbara Dołęgowska

Int. J. Mol. Sci. 2025, 26(15), 7326; https://doi.org/10.3390/ijms26157326 - 29 Jul 2025

Viewed by 1136

Abstract

Transforming growth factor-β (TGF-β) is a key protein family member that includes activins, inhibins, and bone morphogenetic proteins (BMPs). It is essential in numerous biological processes, such as chemotaxis, apoptosis, differentiation, growth, and cell migration. TGF-β receptors initiate signaling through two primary pathways: the canonical pathway involving Smad proteins and non-canonical pathways that utilize alternative signaling mechanisms. When TGF-β signaling is disrupted, it has been shown to contribute to the development of various diseases, including cancer. Initially, TGF-β effectively inhibits the cell cycle and promotes apoptosis. However, its role can transition to facilitating tumor growth and metastasis as the disease progresses. Moreover, TGF-β drives cancer progression through epithelial–mesenchymal transition (EMT), modulation of factor expression, and evasion of immune responses. This complexity establishes the need for further research, particularly into pharmacological agents targeting TGF-β, which are emerging as promising therapeutic options. Current clinical and preclinical studies are making significant strides toward mitigating the adverse effects of TGF-β. This underscores the critical importance of understanding its underlying mechanisms to enhance treatment effectiveness and improve survival rates for cancer patients. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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15 pages, 715 KB

Open AccessReview

Genomic Predictive Biomarkers in Breast Cancer: The Haves and Have Nots

by Kate Beecher, Tivya Kulasegaran, Sunil R. Lakhani and Amy E. McCart Reed

Int. J. Mol. Sci. 2025, 26(15), 7300; https://doi.org/10.3390/ijms26157300 - 28 Jul 2025

Viewed by 620

Abstract

Precision oncology, also known as personalized oncology or precision medicine, is the tailoring of cancer treatment to individual patients based on the specific genetic, molecular, and other unique characteristics of their tumor. The goal of precision oncology is to optimize the effectiveness of cancer treatment while minimizing toxicities and improving patient outcomes. Precision oncology recognizes that cancer is a highly heterogeneous disease and that each patient’s tumor has a distinct genetic diversity. Precision medicine individualizes therapy by using information from a patient’s tumor in the context of clinical history to determine optimal therapeutic approaches and increasing numbers of drugs target specific tumor alterations. Several targeted therapies with approved companion diagnostics are commercially available, the haves of precision oncology, where predictive biomarkers guide clinical decision-making and improve outcomes. However, many therapies still lack clear biomarkers, the have nots, posing a challenge to fully realizing the promise of precision oncology. Herein, we describe the current state of the art for breast cancer precision oncology and highlight the therapeutic agents that require a more robust biomarker. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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28 pages, 939 KB

Open AccessReview

Targets for CAR Therapy in Multiple Myeloma

by Olga A. Bezborodova, Galina V. Trunova, Elena R. Nemtsova, Varvara A. Khokhlova, Julia B. Venediktova, Natalia B. Morozova, Maria S. Vorontsova, Anna D. Plyutinskaya, Elena P. Zharova, Peter V. Shegai and Andrey D. Kaprin

Int. J. Mol. Sci. 2025, 26(13), 6051; https://doi.org/10.3390/ijms26136051 - 24 Jun 2025

Viewed by 940

Abstract

Multiple myeloma (MM or plasma cell myeloma) is a heterogenous B-cell malignant tumor that typically exhibits a high recurrence rate, resistance to drugs, and molecular diversity of tumor subclones. Given the limited efficacy of standard therapy options, cellular immunotherapy featuring a chimeric antigen receptor (CAR) has proven tangible potential in treatment for relapsed and refractory forms of MM. The rational choice of a tumor target which shows high selectivity, stable expression, and biological significance is key to the successful implementation of CAR therapy. This review has summarized and analyzed data from the literature on biological properties, the features of expression, and the clinical development stages of CAR cell products for MM treatment which target BCMA, GPRC5D, FcRH5, SLAMF7, CD38, CD138, TACI, APRIL, CD19, TNFR2, CD44v6, CD70, NKG2D ligands, etc. Special focus is on strategic approaches to overcoming antigenic escape, such as multi-specific CAR constructs, logical activation sequences, and controlled safety systems. The analysis underscores the need for integrating the molecular selection of targets with cutting-edge bioengineering solutions as a key trend for raising the efficacy, stability, and safety of cellular therapy in the case of MM. Full article

(This article belongs to the Special Issue Advancements in Cancer Biomarkers)

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