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Cells
Special Issues
Molecular Mechanisms of Tumor Pathogenesis
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Molecular Mechanisms of Tumor Pathogenesis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 20 June 2025 | Viewed by 9323

Special Issue Editors

Dr. Saverio Candido

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Guest Editor
1 Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
2 Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
Interests: oncology; melanoma; bioinformatics; immunotherapy; ferroptosis; DNA methylation; tumor microenvironment; cancer biomarkers; cancer treatment response
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro Lavoro

E-Mail
Guest Editor
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Interests: oncology; epigenetics; computational biology; ferroptosis; genomics; translational medicine; drug resistance; tumor microenvironment; microbiota

Special Issue Information

Dear Colleagues,

The molecular mechanisms underlying tumor initiation and progression are complex and multifaceted, involving a wide range of genetic, epigenetic and environmental factors. Although the precise mechanisms may vary depending on the tumor context, several common features have been identified that are involved in cancer development. As widely reported in the literature, both somatic and germline mutations play a critical role in tumor pathogenesis by oncogene activation or the silencing of tumor suppressor genes. Similarly, epigenetic alterations (e.g., DNA methylation, histone modifications and non-coding RNA regulation) may affect the key genes leading to the dysregulation of different signaling transduction pathways and loss of regulatory mechanisms of crucial biological processes, including cell growth, differentiation and DNA repair. In this field, recent advances in molecular biology technologies have led to the identification of the key molecular drivers of tumorigenesis and cancer progression, paving the way for the development of personalized medicine. Therefore, understanding these molecular mechanisms is mandatory to identify potential therapeutic targets, improving the management and clinical outcome of cancer patients.

This Special Issue aims to provide an overview of the recent advances into the molecular mechanisms involved in tumor pathogenesis, providing a new starting point for the development of new cancer treatment options. This Special Issue will contain original research articles, including in silico studies, and in vitro and in vivo experiments, as well as literature reviews.

We look forward to your contributions.

Dr. Saverio Candido
Dr. Alessandro Lavoro
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. Cells 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 2700 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.

Keywords

  • cancer
  • therapeutic targets
  • biomarkers
  • epigenetics
  • DNA methylation
  • microRNAs
  • somatic mutations
  • germline mutations
  • chromatin remodeling
  • histone modifications

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Published Papers (5 papers)

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Research

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15 pages, 2356 KiB  
Article
Knockdown of Keratin 6 Within Arsenite-Transformed Human Urothelial Cells Decreases Basal/Squamous Expression, Inhibits Growth, and Increases Cisplatin Sensitivity
by Nelofar Nargis, Donald A. Sens and Aaron A. Mehus
Cells 2024, 13(21), 1803; https://doi.org/10.3390/cells13211803 - 31 Oct 2024
Viewed by 1340
Abstract
Urothelial carcinoma (UC) is prevalent, especially in elderly males. The high rate of recurrence, treatment regime, and follow-up monitoring make UC a global health and economic burden. Arsenic is a ubiquitous toxicant that can be found in drinking water, and it is known [...] Read more.
Urothelial carcinoma (UC) is prevalent, especially in elderly males. The high rate of recurrence, treatment regime, and follow-up monitoring make UC a global health and economic burden. Arsenic is a ubiquitous toxicant that can be found in drinking water, and it is known that exposure to arsenic is associated with UC development. Around 25% of diagnosed UC cases are muscle-invasive (MIUC) which have poor prognosis and develop chemoresistance, especially if tumors are associated with squamous differentiation (SD). The immortalized UROtsa cell line is derived from normal human urothelium and our lab has malignantly transformed these cells using arsenite (As3+). These cells represent a basal subtype model of MIUC and the tumors derived from the As3+-transformed cells histologically and molecularly resemble clinical cases of the basal subtype of MIUC that have focal areas SD and expression of the basal keratins (KRT1, 5, 6, 14, and 16). Our previous data demonstrate that KRT6 protein expression correlates to areas of SD within the tumors. For this study, we performed a lentiviral knockdown of KRT6 in As3+-transformed UROtsa cells to evaluate the effects on morphology, gene/protein expression, growth, colony formation, and cisplatin sensitivity. The knockdown of KRT6 resulted in decreased expression of the basal keratins, decreased growth, decreased colony formation, and increased sensitivity to cisplatin, the standard treatment for MIUC. The results of this study suggest that KRT6 plays a role in UC cell growth and is an exploitable target to increase cisplatin sensitivity for MIUC tumors that may have developed resistance to cisplatin treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)
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14 pages, 2836 KiB  
Article
Identification of Poliovirus Receptor-like 3 Protein as a Prognostic Factor in Triple-Negative Breast Cancer
by Gian Marco Leone, Katia Mangano, Salvatore Caponnetto, Paolo Fagone and Ferdinando Nicoletti
Cells 2024, 13(15), 1299; https://doi.org/10.3390/cells13151299 - 3 Aug 2024
Viewed by 1888
Abstract
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate [...] Read more.
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)
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Review

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24 pages, 2130 KiB  
Review
The Role of RAC2 and PTTG1 in Cancer Biology
by Katarzyna Rakoczy, Natalia Szymańska, Jakub Stecko, Michał Kisiel, Jakub Sleziak, Agnieszka Gajewska-Naryniecka and Julita Kulbacka
Cells 2025, 14(5), 330; https://doi.org/10.3390/cells14050330 - 23 Feb 2025
Viewed by 687
Abstract
Several molecular pathways are likely involved in the regulation of cancer stem cells (CSCs) via Ras-associated C3 botulinum toxin substrate 2, RAC2, and pituitary tumor-transforming gene 1 product, PTTG1, given their roles in cellular signaling, survival, proliferation, and metastasis. RAC2 is a member [...] Read more.
Several molecular pathways are likely involved in the regulation of cancer stem cells (CSCs) via Ras-associated C3 botulinum toxin substrate 2, RAC2, and pituitary tumor-transforming gene 1 product, PTTG1, given their roles in cellular signaling, survival, proliferation, and metastasis. RAC2 is a member of the Rho GTPase family and plays a crucial role in actin cytoskeleton dynamics, reactive oxygen species production, and cell migration, contributing to epithelial–mesenchymal transition (EMT), immune evasion, and therapy resistance. PTTG1, also known as human securin, regulates key processes such as cell cycle progression, apoptosis suppression, and EMT, promoting metastasis and enhancing cancer cell survival. This article aims to describe the molecular pathways involved in the proliferation, invasiveness, and drug response of cancer cells through RAC2 and PTTG1, aiming to clarify their respective roles in neoplastic process dependencies. Both proteins are involved in critical signaling pathways, including PI3K/AKT, TGF-β, and NF-κB, which facilitate tumor progression by modulating CSC properties, angiogenesis, and immune response. This review highlights the molecular mechanisms by which RAC2 and PTTG1 influence tumorigenesis and describes their potential and efficacy as prognostic biomarkers and therapeutic targets in managing various neoplasms. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)
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37 pages, 7538 KiB  
Review
Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review
by Innokenty M. Mokhosoev, Dmitry V. Astakhov, Alexander A. Terentiev and Nurbubu T. Moldogazieva
Cells 2024, 13(23), 1958; https://doi.org/10.3390/cells13231958 - 26 Nov 2024
Cited by 3 | Viewed by 2929
Abstract
Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. Findings: In our review article, we discuss recent data evidencing that [...] Read more.
Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. Findings: In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug–drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. Conclusions: The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)
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24 pages, 1463 KiB  
Review
Vulnerability of Antioxidant Drug Therapies on Targeting the Nrf2-Trp53-Jdp2 Axis in Controlling Tumorigenesis
by Ying-Chu Lin, Chia-Chen Ku, Kenly Wuputra, Deng-Chyang Wu and Kazunari K. Yokoyama
Cells 2024, 13(19), 1648; https://doi.org/10.3390/cells13191648 - 3 Oct 2024
Cited by 1 | Viewed by 1632
Abstract
Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes [...] Read more.
Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes associated with problems including tumor resistance or dose-limiting toxicity in host animals and patients. These problems are often caused by the imbalance between the levels of oxidative stress-induced reactive oxygen species (ROS) and the redox efficacy of antioxidants. Increased ROS levels, because of abnormal function, including metabolic abnormality and signaling aberrations, can promote tumorigenesis and the progression of malignancy, which are generated by genome mutations and activation of proto-oncogene signaling. This hypothesis is supported by various experiments showing that the balance of oxidative stress and redox control is important for cancer therapy. Although many antioxidant drugs exhibit therapeutic potential, there is a heterogeneity of antioxidation functions, including cell growth, cell survival, invasion abilities, and tumor formation, as well as the expression of marker genes including tumor suppressor proteins, cell cycle regulators, nuclear factor erythroid 2-related factor 2, and Jun dimerization protein 2; their effectiveness in cancer remains unproven. Here, we summarize the rationale for the use of antioxidative drugs in preclinical and clinical antioxidant therapy of cancer, and recent advances in this area using cancer cells and their organoids, including the targeting of ROS homeostasis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)
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