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Current Research on Cancer Biology and Therapeutics: Third Edition

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: 20 October 2025 | Viewed by 8039

Special Issue Editor

Prof. Dr. Rafael Coveñas Rodríguez

E-Mail Website
Guest Editor
Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neuroscience of Castilla and León (INCYL), University of Salamanca, c/Pintor Fernando Gallego 1, 37007 Salamanca, Spain
Interests: cancer and anticancer peptides; substance P/neurokinin-1 receptor system; neurokinin-1 receptor antagonists
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer caused 10 million deaths in 2020 and remains a major health problem worldwide. Surgery, chemotherapy, and radiotherapy are the current cancer treatments, but unfortunately, their results are in many cases unsatisfactory. The development of promising cancer research fields (new cytostatics, stem cells, and the human genome) has not been translated into better perspectives for many cancer patients. To improve the diagnosis and treatment of tumors, novel specific anticancer strategies showing enhanced antitumor effects and decreased toxicity must be explored.

Cancer cells evade the immune system and show resistance to anticancer therapies, leading to cancer cell proliferation, survival, invasion, and metastasis. These mechanisms, as well as angiogenesis, are regulated by different ligands, receptors, and intracellular cascades that regulate the genetic/protein machinery of cancer cells; thus, anticancer drugs must specifically block these cellular events. This has opened up new research lines for exploring new therapeutic strategies focused on targetable molecules. Accordingly, the main aim of this Special Issue is to increase knowledge about potential targetable molecules involved in previous mechanisms such as peptides, signal transduction molecules, transcription factors, kinases, DNA damage repair enzymes, and epigenetic regulatory proteins. Thus, new antiproliferative, antimetastatic, and antiangiogenic strategies are welcome, as well as apoptotic inducers, signal transduction inhibitors, cytotoxic peptide conjugate-based cancer therapy, gene expression modulators, hormone therapies, and peptide receptor radionuclide therapy. Studies focused on the function–structure relationships between ligands and receptors for the design and synthesis of new and more effective anticancer compounds are also welcome.

I hope that this Special Issue opens the door to developing promising molecular targets, blocking tumor development, and developing new compounds capable of specifically destroying tumor cells. New anticancer strategies targeting tumor-specific molecular derangements must serve to improve the diagnosis and treatment of tumors and increase the cure rate and quality of life of cancer patients.

Prof. Dr. Rafael Coveñas Rodríguez
Guest Editor

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Keywords

  • antiangiogenic
  • anticancer therapy
  • antimetastatic
  • apoptosis
  • antiproliferative
  • cancer
  • peptides
  • signaling molecules
  • transcription factors
  • tumor

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Published Papers (7 papers)

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Research

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15 pages, 2524 KiB  
Article
Disparate Roles of Cell–Cell Contact and Cytokine Secretion in an In Vitro Model of the Seminoma Microenvironment
by Patrick Fruth, Juliane Luft, Lucas Klaus, Tobias J. Legler, Holger M. Reichardt and Fabian A. Gayer
Int. J. Mol. Sci. 2025, 26(13), 6173; https://doi.org/10.3390/ijms26136173 - 26 Jun 2025
Viewed by 290
Abstract
Type II testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men and are classified into seminomas and non-seminomatous subtypes. Seminomas are known for their highly pro-inflammatory tumor microenvironment (TME) with abundant immune cell infiltration. While previous work has [...] Read more.
Type II testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men and are classified into seminomas and non-seminomatous subtypes. Seminomas are known for their highly pro-inflammatory tumor microenvironment (TME) with abundant immune cell infiltration. While previous work has demonstrated that the seminoma-derived cell line TCam-2 induces immune cell activation in co-culture and undergoes phenotypic changes itself, the underlying mechanisms remained unclear. To explore the role of direct cell–cell interaction and the effects mediated by soluble mediators such as cytokines, we conducted co-culture experiments of TCam-2 cells with purified human T cells or monocytes, including Transwell assays and treatments with IL-6, TNFα, or their respective blocking antibodies Tocilizumab and Adalimumab. In this way, we found that immune cell activation, indicated by enhanced secretion of pro-inflammatory cytokines and an upregulation of activation markers, strongly depended on direct physical contact between both cell types. Nonetheless, we also unveiled the role of soluble mediators in both immune cell activation and promoting a shift in TCam-2 cells from a seminoma-like phenotype to a more dedifferentiated phenotype, suggesting that cytokines critically shape the TME. These observations highlight the complexity of tumor–immune interactions in the seminoma microenvironment, offering new insight into immune-driven dynamics in TGCTs. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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18 pages, 1687 KiB  
Article
Synthesis of Novel Podophyllotoxin–Benzothiazole Congeners and Their Biological Evaluation as Anticancer Agents
by Pramukti Nawar Rai’dah, Zuzanna Molęda, Aleksandra Osińska, Armand Budzianowski, Izabela Młynarczuk-Biały and Zbigniew Czarnocki
Int. J. Mol. Sci. 2025, 26(13), 6033; https://doi.org/10.3390/ijms26136033 - 24 Jun 2025
Viewed by 394
Abstract
A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence [...] Read more.
A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence or presence of the ester group, showed the strongest cytotoxic effect towards all tested cancer cell lines with the IC50 0.68–2.88 µM. In addition, it was demonstrated that these compounds inhibit cancer cell proliferation by inducing G2/M phase arrest in HeLa cells. The structure–activity relationship was analyzed and it confirmed the importance of the core structural features like a dioxolane ring and free-rotating trimethoxyphenyl group for cytotoxicity. Moreover, the R configuration of the ester group at the C-8′ position proved to be substantial since its epimer was inactive. The molecular docking studies revealed that the most potent compounds have a different binding mode to β-tubulin than podophyllotoxin; however, the benzothiazole fragment docked in a similar location as the trimethoxyphenyl group of podophyllotoxin, exhibiting similar hydrophobic interactions. These findings clearly indicate that podophyllotoxin–benzothiazole derivatives could be addressed for further pharmacological studies in anticancer research. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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16 pages, 9727 KiB  
Article
Teratoma Development in 129.MOLF-Chr19 Mice Elicits Two Waves of Immune Cell Infiltration
by Lucas Klaus, Sybille D. Reichardt, Maria Neif, Lutz Walter, Fabian A. Gayer and Holger M. Reichardt
Int. J. Mol. Sci. 2024, 25(23), 12750; https://doi.org/10.3390/ijms252312750 - 27 Nov 2024
Viewed by 1119
Abstract
Teratomas are a highly differentiated type of testicular germ cell tumors (TGCTs), the most common type of solid cancer in young men. Prominent inflammatory infiltrates are a hallmark of TGCTs, although their compositions and dynamics in teratomas remain elusive. Here, we reached out [...] Read more.
Teratomas are a highly differentiated type of testicular germ cell tumors (TGCTs), the most common type of solid cancer in young men. Prominent inflammatory infiltrates are a hallmark of TGCTs, although their compositions and dynamics in teratomas remain elusive. Here, we reached out to characterize the infiltrating immune cells and their activation and polarization state by using high-throughput gene expression analysis of 129.MOLF-Chr19 mice that spontaneously develop testicular teratomas. We showed that inconspicuous testes without any apparent alterations in size or morphology can be clustered into three groups based on their expression of stemness and immune genes, supporting a model in which initial oncogenic transformation elicits a first wave of T-cell infiltration. Moderately and severely enlarged tumorous testes then displayed a progressive infiltration with T cells, monocytes/macrophages, and B cells. Importantly, T cells seem to adopt an inactive state caused by an overexpression of immune checkpoint molecules and the polarization of monocytes/macrophages to an anti-inflammatory phenotype. Our findings are supported by the analysis of metabolic gene expression, which unveiled alterations indicative of tumor growth and immune cell infiltration. Collectively, testicular teratomas, at least in mice, are characterized by a diverse inflammatory infiltrate containing T cells that putatively become inactivated, allowing the tumors to further grow. We believe that these findings may provide a rationale for the development of new immunomodulatory therapies for TGCTs. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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Review

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39 pages, 1623 KiB  
Review
Bispecific Antibodies in Solid Tumors: Advances and Challenges
by Khine Swe Shan, Saba Musleh Ud Din, Shivani Dalal, Teresita Gonzalez, Misha Dalal, Pablo Ferraro, Atif Hussein and Michel Vulfovich
Int. J. Mol. Sci. 2025, 26(12), 5838; https://doi.org/10.3390/ijms26125838 - 18 Jun 2025
Viewed by 1446
Abstract
Bispecific antibodies (BsAbs) have shown potential in cancer treatment and have become a rapidly growing field in cancer immunotherapy. Unlike monoclonal antibodies with two identical binding sites, BsAbs simultaneously bind two distinct epitopes on the same or different antigens, allowing for a range [...] Read more.
Bispecific antibodies (BsAbs) have shown potential in cancer treatment and have become a rapidly growing field in cancer immunotherapy. Unlike monoclonal antibodies with two identical binding sites, BsAbs simultaneously bind two distinct epitopes on the same or different antigens, allowing for a range of mechanisms of action, including engaging immune cells to kill cancer cells and blocking signaling pathways. Despite regulatory approvals for hematological malignancies in the last decade, their clinical success in solid malignancies has been lacking until recently. There are currently five BsAbs approved by the FDA in the United States for solid tumors—amivantamab, tarlatamab, tebentafusp, zanidatamab and zenocutuzumab—and two BsAbs approved in China—cadonilimab and ivonescimab. Currently, several BsAbs are under clinical development for solid tumors, but are mostly in early phase I and II trials. This review provides an overview of the basic mechanism of action of BsAbs, current FDA-approved BsAbs, and current BsAbs under clinical development, their challenges in clinical use, the management of toxicities, and future directions. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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27 pages, 2090 KiB  
Review
Peptidergic Systems and Neuroblastoma
by Manuel Lisardo Sánchez and Rafael Coveñas
Int. J. Mol. Sci. 2025, 26(8), 3464; https://doi.org/10.3390/ijms26083464 - 8 Apr 2025
Viewed by 627
Abstract
The peptidergic systems are involved in neuroblastoma. Peptides (angiotensin II, neuropeptide Y, neurotensin, substance P) act as oncogenic agents in neuroblastoma, whereas others (adrenomedullin, corticotropin-releasing factor, urocortin, orexin) exert anticancer effects against neuroblastoma. This plethora of peptidergic systems show the functional complexity of [...] Read more.
The peptidergic systems are involved in neuroblastoma. Peptides (angiotensin II, neuropeptide Y, neurotensin, substance P) act as oncogenic agents in neuroblastoma, whereas others (adrenomedullin, corticotropin-releasing factor, urocortin, orexin) exert anticancer effects against neuroblastoma. This plethora of peptidergic systems show the functional complexity of the mechanisms regulated by peptides in neuroblastoma. Peptide receptor antagonists act as antineuroblastoma agents since these compounds counteracted neuroblastoma cell growth and migration and the angiogenesis promoted by oncogenic peptides. Other therapeutic approaches (signaling pathway inhibitors, focal adhesion kinase inhibitors, peptide receptor knockdown, acetic acid analogs) that also counteract the beneficial effects mediated by the oncogenic peptides in neuroblastoma are discussed, and future research lines to be developed in neuroblastoma (interactions between oncogenic and anticancer peptides, combination therapy using peptide receptor antagonists and chemotherapy/radiotherapy) are also suggested. Although the data regarding the involvement of the peptidergic systems in neuroblastoma are, in many cases, fragmentary or very scarce for a particular peptidergic system, taken together, they are quite promising with respect to potentiating and developing this research line with the aim of developing new therapeutic strategies to treat neuroblastoma in the future. Peptidergic systems are potential and promising targets for the diagnosis and treatment of neuroblastoma. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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14 pages, 953 KiB  
Review
AhR and STAT3: A Dangerous Duo in Chemical Carcinogenesis
by Marco Minacori, Sara Fiorini, Monia Perugini, Annamaria Iannetta, Giorgia Meschiari, Silvia Chichiarelli, Fabio Altieri, Pier Giorgio Natali and Margherita Eufemi
Int. J. Mol. Sci. 2025, 26(6), 2744; https://doi.org/10.3390/ijms26062744 - 18 Mar 2025
Viewed by 1049
Abstract
Human chemical carcinogenesis is a multistage process where chemicals or their metabolites cause irreversible changes in normal cell physiology, eventually leading to uncontrolled proliferation, transforming a normal cell into a cancerous one. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic [...] Read more.
Human chemical carcinogenesis is a multistage process where chemicals or their metabolites cause irreversible changes in normal cell physiology, eventually leading to uncontrolled proliferation, transforming a normal cell into a cancerous one. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that regulates cell proliferation, differentiation, apoptosis, angiogenesis, inflammation, and immune responses. Its aberrant activation triggers tumor progression by promoting the expression of oncogenic genes; thus, STAT3 is classified as an oncoprotein. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that responds to a wide variety of chemicals, including carcinogens like dioxins, inducing genes associated with detoxification, proliferation, and immune regulation. Recent reports show that AhR plays a critical role in cancer development and maintenance. AhR may interact with signaling pathways, like the STAT3 pathway, which mediates the carcinogenic effects of several pollutants. Various chemical agents, such as industrial waste and hydrocarbon compounds, can alter the expression or signaling activity of AhR and STAT3 pathways, leading to different types of cancers. Understanding the complex STAT3-AhR network in the regulation of chemical carcinogenesis could open new avenues for cancer prevention or treatment, particularly in personalized medicine, aiming to improve life expectancy and achieving a complete cure. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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19 pages, 1839 KiB  
Review
The Effects of Podophyllotoxin Derivatives on Noncancerous Diseases: A Systematic Review
by Piotr Strus, Karol Sadowski, Weronika Ploch, Adrianna Jazdzewska, Paulina Oknianska, Oliwia Raniszewska and Izabela Mlynarczuk-Bialy
Int. J. Mol. Sci. 2025, 26(3), 958; https://doi.org/10.3390/ijms26030958 - 23 Jan 2025
Cited by 2 | Viewed by 2374
Abstract
Podophyllotoxin (PPT) is commonly used for genital warts due to its antimitotic properties and relatively good accessibility since it can be extracted from plants in low-economy countries. However, due to relatively high toxicity, it cannot be used in a systematic way (intravenously). Thus, [...] Read more.
Podophyllotoxin (PPT) is commonly used for genital warts due to its antimitotic properties and relatively good accessibility since it can be extracted from plants in low-economy countries. However, due to relatively high toxicity, it cannot be used in a systematic way (intravenously). Thus, there is a need to find or create an equally effective derivative of PPT that will be less toxic. Natural PPT is a suitable and promising scaffold for the synthesis of its derivatives. Many of them have been studied in clinical and preclinical models. In this systematic review, we comprehensively assess the medical applications of PPT derivatives, focusing on their advantages and limitations in non-cancerous diseases. Most of the existing research focuses on their applications in cancerous diseases, leaving non-cancerous uses underexplored. To do that, we systematically reviewed the literature using PubMed, Embase, and Cochrane databases from January 2013 to January 2025. In total, 5333 unique references were identified in the initial search, of which 44 were included in the quantitative synthesis. The assessment of the quality of eligible studies was undertaken using the PRISMA criteria. The risk of bias was assessed using a predefined checklist based on PRISMA guidelines. Each study was independently reviewed by two researchers to evaluate bias in study design, reporting, and outcomes. Our analysis highlights the broad therapeutic potential of PPT derivatives, particularly in antiviral applications, including HPV, Dengue, and SARS-CoV-2 infections. Apart from their well-known anti-genital warts activity, these compounds exhibit significant anti-inflammatory, antimitotic, analgesic, and radioprotective properties. For instance, derivatives such as cyclolignan SAU-22.107 show promise in antiviral therapies, while compounds like G-003M demonstrate radioprotective effects by mitigating radiation-induced damage. To build on this, our review highlights that PPT derivatives, apart from anti-genital warts potential, exhibit four key properties—anti-inflammatory, antimitotic, analgesic, and radioprotective—making them promising candidates not only for treating viral infections such as HPV, Dengue, and SARS-CoV-2 but also for expanding their therapeutic potential beyond cancerous diseases. In conclusion, while PPT derivatives hold great potential across various medical domains, their applications in non-cancerous diseases remain limited by the scarcity of dedicated research. Continued exploration of these compounds is essential to unlock their full therapeutic value. Full article
(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Third Edition)
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