Search Results (995)

Objectives: This review examines the role of oxidative stress in the survival, apoptosis, and therapy resistance of head and neck squamous cell carcinoma (HNSCC) cells, with a focus on how redox imbalance influences tumour progression and treatment outcomes. Methods: A literature search was conducted in Scopus using the keywords head and neck squamous cell carcinoma, oxidative stress, reactive oxygen species (ROS), and antioxidant systems. Articles published in English were included, without restrictions on publication year. Reviews, clinical studies, and experimental research addressing oxidative stress mechanisms in HNSCC were considered, while non-English papers and studies unrelated to HNSCC were excluded. Key Findings: ROS exhibit dual effects in HNSCC, promoting tumour growth and DNA damage while also inducing apoptosis through molecular interactions. Elevated ROS contribute to drug resistance by inhibiting apoptosis, altering autophagy, and enhancing proliferation. Cancer cells counteract this via adaptive antioxidant responses involving transcriptional regulation and upregulation of enzymatic defences. Major risk factors for HNSCC—alcohol, tobacco, and high-risk HPV infection—disrupt redox homeostasis, underscoring the central role of oxidative stress in both carcinogenesis and therapy response. Conclusions: Oxidative stress plays a context-dependent role in HNSCC progression and treatment resistance. Targeting redox-regulatory pathways may provide therapeutic benefit. This review synthesizes recent insights on ROS-mediated mechanisms, highlighting potential strategies for improving HNSCC management beyond existing literature. Full article

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across tumour types, limiting the assessment of CDH17 as a biomarker or therapeutic target for Wnt pathway in cancer. In this study, we systematically review and meta-analyse the relationship between CDH17 and Wnt/β-catenin signalling in human cancers and evaluate whether CDH17 modulation affects tumour behaviour through Wnt-related mechanisms. Our search of Medline, Web of Science and Scopus identified five studies examining CDH17 expression in the Wnt/β-catenin pathway in vitro and in vivo. All five studies identified CDH17 as a key driver of canonical Wnt signalling, directly influencing cancer progression in hepatocellular carcinoma (HCC), gastric cancer (GC), and colorectal cancer (CRC). Meta-analysis (MA) showed that CDH17 inhibition consistently reduced Wnt/β-catenin downstream T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activity (MD = −1.32, 95% CI: −1.64 to −0.99, p < 0.00001). Narrative synthesis found that CDH17 suppression decreased total and nuclear β-catenin, phosphorylated glycogen synthase kinase-3 beta (GSK-3β), and cyclin D1 while increasing tumour suppressors, retinoblastoma (Rb) and p53/p21. These changes were associated with reduced proliferation, colony formation, migration, invasion and cell cycle arrest. In vivo, CDH17 suppression resulted in 80–95% tumour growth suppression (Mean Difference (MD) = −96.67, 95% CI: [−144.35, −48.98], p < 0.0001), with immunohistochemistry confirming cytoplasmic β-catenin sequestration and lower cyclin D1 levels. Collectively, these findings show CDH17 as a critical upstream effector sustaining Wnt/β-catenin signalling, cancer progression, tumour proliferation, stem cell properties, and metastasis, and support CDH17 inhibition as a promising therapeutic target across multiple cancer types. Full article

Background and Objectives: To evaluate the prognostic value of the Clinical–Pathologic Stage–Estrogen receptor status and Grade (CPS+EG) staging system, which combines clinical staging, pathological staging, oestrogen receptor (ER) status, and tumour grade in predicting survival outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving neoadjuvant therapy (NACT). Materials and Methods: A retrospective review was performed on 245 female breast cancer patients who received anti-HER2 therapy alongside NACT at the Medical Oncology Department of Kartal Dr Lütfi Kırdar City Hospital, University of Health Sciences, from April 2012 to June 2024. The CPS+EG score was calculated using the MD Anderson Cancer Centre neoadjuvant treatment response calculator. Patients were categorised into two groups based on their CPS+EG score < 3 and ≥3. The primary outcomes assessed were disease-free survival (DFS) and overall survival (OS). Kaplan–Meier and log-rank tests were utilised for time-to-event analysis; Cox regression was used for multivariate analysis. A significance level of ≤0.05 was considered. Results: The median age of the patient cohort was 51 years (range: 27–82 years). Among these patients, 183 (74.6%) had a CPS+EG score less than 3, while 62 (25.3%) exhibited a score of 3 or higher. The median follow-up duration was 37.6 months. The pathological complete response (pCR) rate across the entire cohort was 51.8%. Specifically, the pCR rate was 56.3% in the group with CPS+EG scores below 3, and 38.7% in those with scores of 3 or higher (p = 0.017). Patients with CPS+EG scores less than 3 demonstrated superior overall survival (OS), which reached statistical significance in univariate analysis. Multivariate analysis identified the CPS+EG score as an independent prognostic factor for both overall survival and disease-free survival (DFS), with hazard ratios of 0.048 (95% CI: 0.004–0.577, p = 0.017) and 0.35 (95% CI: 0.14–0.86, p = 0.023), respectively. Conclusions: The CPS+EG score is an independent and practical prognostic marker, particularly for overall survival, in patients with HER2-positive breast cancer who have received neoadjuvant therapy. Patients with a CPS+EG score < 3 have higher pCR rates and survival rates. When used in conjunction with pCR, it can improve risk categorisation and contribute to the individualisation of adjuvant strategies in the post-neoadjuvant period. Due to its ease of calculation and lack of additional costs, this score can be instrumental in clinical practice for identifying high-risk patients. Our findings support the integration of the CPS+EG score into routine clinical decision-making processes, although prospective validation studies are necessary. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy with poor clinical outcomes. microRNA-7-5p (miR-7-5p) has been described as both a tumour suppressor and an oncomiR depending on the tissue context, but its role in HNSCC remains unclear. This study aimed to clarify the clinical significance and biological function of miR-7-5p in HNSCC by integrating data from multiple sources. Methods: A systematic review of the literature was conducted to identify studies analysing miRNA expression in human head and neck tissues. A meta-analysis of individual patient data from Gene Expression Omnibus (GEO), ArrayExpress, and The Cancer Genome Atlas (TCGA) was performed to assess miR-7-5p expression in tumours and normal tissues, and its associations with clinical parameters and prognostic outcomes. Bioinformatics analyses were used to predict miR-7-5p target genes, classify hub genes, and perform gene ontology enrichment analysis. MicroRNA in situ hybridisation (miRNA ISH) and real-time quantitative PCR (RT-qPCR) were conducted on tissue samples, HNSCC cell lines, and an in vitro model of oral oncogenesis to validate miR-7-5p expression patterns. Results: miR-7-5p was significantly upregulated in tumours compared to normal tissues and associated with larger tumour size, HPV-negative status, poor disease-specific survival, and shorter progression-free intervals. Bioinformatics analysis highlighted miR-7-5p target genes enriched in pathways related to cell growth, survival, and tumourigenesis. Despite evidence supporting the anti-cancer role of exogenous miR-7-5p in preclinical models, the observed endogenous upregulation in tumours suggests that miR-7-5p expression may represent a compensatory or stress-responsive mechanism during tumourigenesis, rather than acting as a primary oncogenic driver. Conclusions: This study provides new insights into the complex role of miR-7-5p in HNSCC, supporting its potential as both a biomarker and a therapeutic target. Understanding the context-specific functions of miR-7-5p is essential for its development as an RNA-based therapeutic in HNSCC. Full article

Survival rates for those with metastatic osteosarcoma (OS) have not improved over the last four decades. It is imperative that novel approaches to treating and curing OS be sought. We, therefore, turned our attention to Brusatol (Bru), a naturally occurring Nrf2 inhibitor reported to elicit anti-cancer effects in a multitude of tumour models. Importantly there is emerging evidence that Nrf2 is implicated in chemoradiotherapy resistance in OS and that inhibiting Nrf2 may represent a desirable route to treating OS. Surprisingly, using the human OS cell line, MG63, we actually found that Bru promoted cell growth. Compared to control, normoxic cultures, the application of Bru (50 nM) over 3 days led to an increase in cell number by approximately 1.7-fold. A similar outcome occurred for cells under hypoxic conditions, although the extent of cell growth was significantly less at around 1.3-fold. Furthermore, Bru prevented MG63 differentiation in response to co-treatment with the calcitriol analogue, EB1089, and the lipid growth factor, lysophosphatidic acid. The extent of inhibition was profound at approximately 2.8-fold. The application of the Nrf2 activator, dimethyl fumarate, did not rescue these phenotypes. Whilst Bru has shown promise in other cancer models, it would appear, from our findings, that this agent may not be suitable for the treatment of OS. Full article

Breast cancer is the most common malignancy and leading cause of cancer-related mortality among women worldwide. Oestrogen receptor (ER)-positive disease accounts for the majority of cases, where endocrine and targeted therapies have substantially improved survival. Nevertheless, resistance to therapy remains inevitable, emphasising the need for precision strategies informed by molecular profiling. The molecular landscape of ER-positive breast cancer is increasingly complex, characterised by diverse genomic alterations driving resistance and progression. Advances in next-generation sequencing and circulating tumour DNA (ctDNA) technologies enable the dynamic assessment of tumour heterogeneity and clonal evolution, informing prognostication and guiding biomarker-driven therapy. Uniquely, this review integrates molecular phenotyping with clinical treatment algorithms for advanced ER-positive breast cancer, providing a practical framework to translate genomic insights into patient care. Key genomic alterations and targeted strategies with demonstrated clinical benefit, including oral selective ER degraders (SERDs) and PI3K/AKT/mTOR inhibitors in selected biomarker populations, are highlighted. Emerging targets, such as human epidermal growth factor 2 (HER2) mutations, and the potential of ctDNA monitoring to detect resistance and guide therapeutic escalation are also discussed. Incorporating molecular profiling, as recommended by international guidelines, into routine clinical decision making can personalise therapy and optimise patient outcomes. Addressing real-world challenges, including cost and accessibility, will be critical to achieving equitable implementation of precision oncology for patients with ER-positive breast cancer worldwide. Full article

Mechanistic cancer models can encapsulate beliefs about the main factors influencing tumour growth. In recent decades, many different types of dynamic models have been used for this purpose. The integration of a model’s differential equations yields a simulation of the behaviour of the system over time, thus enabling tumour progression to be predicted. A requisite for the reliability of these quantitative predictions is that the model is structurally identifiable and observable, i.e., that it is theoretically possible to infer the correct values of its parameters and state variables from time course data. In this paper, we show how to analyse these properties of tumour growth models using a well-established methodology, which we implemented previously in an open-source software tool. To this end, we provide an account of 20 published models described by ordinary differential equations, some of which incorporate the effect of interventions including chemotherapy, radiotherapy, and immunotherapy. For each model, we describe its equations and analyse their structural identifiability and observability, discussing how they are affected by the experimental design. We provide computational implementations of these models, which enable readily reproducing results. Our results inform about the possibility of inferring the parameters and state variables of a given model using a specific measurement setup, and, together with the corresponding methodology and implementation, they can be used as a blueprint for analysing other models not included here. Thus, this paper serves as a guide to select the most appropriate model for each application. Full article

Chimeric compounds represent a promising strategy in cancer therapy by simultaneously targeting multiple pathways responsible for tumour growth and survival. Their structure comprises two or more pharmacophores connected through suitable chemical linker. These dual or multi-functional drugs can interact with several biological targets for a more pronounced pharmacological effect. In order to identify new multi-targeting agents with anticancer efficacy, we designed and synthesised a series of novel multi-functional molecules by covalently linking antitumor compounds dichloroacetate (DCA) and Nutlin-3a. The design was aimed at addressing two critical events in cancer: (1) the Warburg effect and (2) the dysregulations of protein p53 pathway, both of which are directly linked to the predominant survival and aggressive proliferation of malignant cells. DCA reactivate oxidative phosphorylation by inhibiting mitochondria pyruvate dehydrogenase kinase (PDK), thereby unlocking the Warburg metabolism of cancer cells and its antiapoptosis state. Concurrently, Nutlin-3a restores the protective function of the “genome guardian” p53 protein, by blocking its antagonist oncoprotein E3 ligase MDM2. Chimeric compounds were obtained using a chemoenzymatic multi-step procedure that included a key lipase-catalysed asymmetric reaction. Biological evaluation of the synthesised Nutlin-DCA chimeras in a panel of three cancer cell lines demonstrated promising results in vitro. Specifically, compounds rac-19a, rac-19b, rac-20a, rac-20b and enantioenriched 20a caused a statistically significant reduction in cell viability at micromolar concentrations. These findings suggest that targeting both the Warburg effect and the p53 pathway with a single molecule is a viable approach for future cancer therapeutic development. Full article

We propose a life-expectancy pay-off function (LEP) for determining optimal cancer treatment within a control theory framework. The LEP averages life expectancy over all future outcomes, outcomes that are determined by key events during therapy such as tumour elimination (cure) and patient death (including treatment related mortality). We analyse this optimisation problem for tumours treated with chemotherapy using tumour growth models based on ordinary differential equations. To incorporate tumour elimination we draw on branching processes to compute the probability distribution of tumour population extinction. To demonstrate the approach, we apply the LEP framework to simplified one-compartment models of tumour growth that include three possible outcomes: cure, relapse, or death during treatment. Using Pontryagin’s maximum principle (PMP) we show that the best treatment strategies fall into three categories: (i) continuous treatment at the maximum tolerated dose (MTD), (ii) no treatment, or (iii) treat-and-stop therapy, where the drug is given at the MTD and then halted before the treatment (time) horizon. Optimal treatment strategies are independent of the time horizon unless the time horizon is too short to accommodate the most effective (treat-and-stop) therapy. For sufficiently long horizons, the optimal solution is either no treatment (when treatment yields no benefit) or treat-and-stop. Patients, thus, split into an untreatable class and a treatable class, with patient demographics, tumour size, tumour response, and drug toxicity determining whether a patient benefits from treatment. The LEP is in principle parametrisable from data, requiring estimation of the rates of each event and the associated life expectancy under that event. This makes the approach suitable for personalising cancer therapy based on tumour characteristics and patient-specific risk profiles. Full article

Bladder cancer (BCa) is one of the most diagnosed cancers worldwide. It is classified as non-muscle-invasive (NMIB), confined to the mucosa, and muscle-invasive (MIB), extended to deeper layers or formed metastases. The poor outcomes associated with MIBC indicate the urgent need for candidate biomarkers to improve treatment strategies. Molecular characterisation of both NMIBC and MIBC, and especially the classification of tumours into molecular subtypes, could provide the development of novel therapeutics in high-risk muscle-invasive bladder cancer. A few studies have focused on pathways implicated in MIBC, including growth factors, DNA–RNA modifying enzymes and the differential roles played by the NOTCH receptors. NOTCH1 has been revealed as a tumour suppressor; in contrast, NOTCH2 and NOTCH3 have demonstrated an oncogenic role in BCa. Recent reports have found that NOTCH2 and NOTCH3 are associated with poor prognosis. Moreover, inhibiting these NOTCH receptors effectively restrained BCa growth and metastasis, suggesting the potential value of targeting NOTCH as a promising therapeutic strategy for bladder cancer. Given the crucial role of the NOTCH pathway, we will discuss the different predictive value of the four NOTCH receptors and the potential of NOTCH-combined therapy in BCa. Full article

In light of the growing significance of molecular biomarkers in central nervous system tumours, in this study, we aimed to comprehensively and quantitatively analyze the mRNA expression levels of DJ-1 (Parkinsonism-associated deglycase 7, PARK7), GDF15 (Growth Differentiation Factor 15), and MFGE8 (Milk Fat Globule-EGF Factor 8 Protein) in glioma and meningioma tissues and to thoroughly evaluate the associations between these gene expression profiles and clinicopathological parameters. Real-time PCR (qRT-PCR) analyses performed on tumour tissues obtained from a total of 27 glioma and 18 meningioma patients revealed that these three genes exhibited significantly elevated expression compared to control samples. Despite their different cellular origins, statistically significant positive correlations were observed between the expression levels of DJ-1, GDF15, and MFGE8 and both tumour grade and the Ki-67 proliferation index (Ki-67 Pi) in both glioma and meningioma cases, indicating that higher gene expression is associated with increased tumour aggressiveness in both tumour types. Receiver operating characteristic (ROC) curve analyses further confirmed the diagnostic and prognostic potential of these genes. Additionally, protein–protein interaction networks involving the target genes were characterised, providing valuable insights into their molecular mechanisms. These findings suggest that DJ-1, GDF15, and MFGE8 may play a role in the aggressiveness, invasion, and proliferation of gliomas and meningiomas. Moreover, integrating these genes as molecular biomarkers into tumour classification systems may provide a foundation for the development of personalised and targeted therapeutic strategies, although further studies are needed to support this. Full article

Angiogenesis is a fundamental biological process involved in the formation of new blood vessels from the pre-existing vascular network. In addition to physiological processes, angiogenesis is also implicated in pathological conditions such as tumour growth and metastatic progression. Research on marennine, a water-soluble blue-green pigment produced by the marine diatom Haslea ostrearia, has highlighted various promising biological activities. In vivo studies have suggested the potential of marennine in cancer treatment. However, these studies were conducted with crude extracts, the exact composition of which remained poorly defined. In this context, our study aimed to explore the effects of marennine on angiogenesis and tumour proliferation by using a Precipitated Extracellular Marennine (PEMn) extract. Our results confirmed the antiproliferative properties of PEMn on several cancer cell lines associated with angiogenic tumours. We then analysed its impact on the key steps of the angiogenic process, including Endothelial Colony-Forming Cells (ECFCs) proliferation, migration, and tubulogenesis. In parallel, we investigated the underlying mechanisms of its action, notably by assessing its effects on cell cycle regulation, senescence, and apoptosis. PEMn significantly inhibited tumour cell proliferation, induced ECFC senescence and apoptosis, impaired migration and tubulogenesis, and downregulated VEGFR-1 expression, highlighting its potential as a novel marine-derived antiangiogenic compound. These findings provide deeper insights into the mechanisms of action of marennine, identifying this bioactive natural compound as a novel bioactive compound in cancer treatment. Full article

Background: It remains unclear whether metformin, a widely used antidiabetic medication, has any influence on the survival outcomes or treatment-related toxicities of radiotherapy in cancer patients. Given metformin’s potential anti-cancer properties, including its ability to inhibit tumour growth through the modulation of cellular metabolism and enhancement of radiosensitivity, its impact on radiotherapy outcomes warrants thorough investigation. This study aimed to evaluate the impact of metformin on survival and adverse events among cancer patients receiving radiotherapy. Methods: Database searches were conducted in MEDLINE, EMBASE, Web of Science, Scopus, and PubMed (2000–2025) to retrieve studies of adults with cancer treated with radiotherapy and concurrent metformin. Metformin users were compared with non-users. The pooled overall survival rate was presented in terms of odds ratio (OR) and 95% confidence interval (95%CI). Diabetic subgroup analyses and meta-regression by cancer type were conducted. ORs and 95%CIs of radiotherapy-related adverse events were presented by cancer type. Results: This study identified 25 articles. The pooled overall survival rate showed no significant difference between metformin users and non-users across subgroups (ORs: 1.00–1.77). Conflicting survival trends were observed for prostate, oesophageal, and non-small cell lung cancer across diabetic conditions. Metformin users with breast cancer exhibited a significantly lower risk of heart failure (OR: 0.72; 95%CI: 0.56–0.94) and heart events (OR: 0.72; 95%CI: 0.59–0.88). Conclusions: Metformin did not significantly impact overall survival but may reduce heart-related adverse events in breast cancer patients based on limited data. Further research is needed on cancer types and diabetic conditions. Full article

Objectives: Cancer is a multifactorial disease determined by several factors. Metabolic disorders such as obesity and diabetes significantly contribute to cancer risk by promoting chronic inflammation, insulin resistance, and hormonal dysregulation. Obesity and hyperglycaemia elevate insulin-like growth factor-1 (IGF-1) levels, driving oncogenic pathways such as PI3K/Akt/mTOR, which promote tumour proliferation and survival. Furthermore, cancer cells undergo metabolic reprogramming, characterised by increased reliance on glycolysis (Warburg effect), facilitating tumour growth and therapy resistance. Hence, body weight reduction and glycaemic control may represent potential strategies for cancer prevention and treatment. Irisin, a myokine secreted by skeletal muscle, plays a critical role in cellular metabolism and energy homeostasis. Emerging evidence suggests that irisin may exert tumour-suppressive effects by modulating key metabolic and oncogenic pathways. Methods: A systematic literature search identified studies investigating irisin’s effects in various cancer models. Results: In vitro, irisin exerts dose- and time-dependent anti-proliferative effects in a variety of cancer cell lines, primarily via PI3K/Akt/mTOR inhibition and AMPK activation, leading to cell cycle arrest and apoptosis. Additionally, irisin inhibits epithelial–mesenchymal transition, which suppresses cancer cell migration and invasion. However, conflicting findings, particularly in hepatocellular carcinoma, suggest tissue-specific responses. Similarly, clinical data regarding systemic and tumoural irisin levels remain inconsistent and appear to vary based on cancer type and stage. Conclusions: Irisin represents a promising therapeutic target due to its ability to modulate metabolic and oncogenic pathways. However, further research is needed to elucidate its clinical relevance and optimise its application as an adjunct to existing cancer therapies. Full article

Background: Phosphaturic mesenchymal tumours secreting fibroblast growth factor 23 (hereinafter referred to as FGF23+ PMT) are rare neoplasms that can cause hypophosphataemic osteomalacia, owing to excessive FGF23 production. Mast cells (MCs) play a key role in tumour biology by modulating proliferative activity of atypical cells, resistance to innate and acquired immunity, angiogenesis, and metastatic behaviour. However, MCs associated with FGF23+ PMT have not previously been investigated. This study, to our knowledge, is the first to characterise features of the tumour microenvironment through spatial phenotyping of the immune and stromal landscape, together with histotopographic mapping of intercellular MC interactions with other subcellular populations in FGF23+ PMT. Methods: Histochemical staining (haematoxylin and eosin, toluidine blue, Giemsa solution, picro-Mallory protocol, silver impregnation), as well as monoplex and multiplex immunohistochemical staining with spatial phenotyping, were performed to detect atypical FGF23-secreting cells, immune cells (CD3, CD4, CD8, CD14, CD20, CD38, CD68, or CD163), stromal components (CD31, α-SMA, or vimentin), and specific MC proteases (tryptase, chymase, or carboxypeptidase A3). Bioinformatics analysis using artificial intelligence technologies was applied for spatial profiling of MC interactions with tumour, immunocompetent, and stromal cells in the tumour microenvironment. Results: Bioinformatic analysis of the entire tumour histological section, comprising over 70,000 cells stained using monoplex and multiplex immunohistochemical protocols, enabled identification of more than half of the cell population. The most abundant were CD14+ (30.7%), CD163+ (23.2%), and CD31+ (17.9%) cells. Tumour-associated MCs accounted for 0.7% of the total pool of immunopositive cells and included both mucosal and connective tissue subpopulations, predominantly of the tryptase + chymase-CPA3-specific protease phenotype. This pattern reflected combined multidirectional morphogenetic processes in the patient’s FGF23+ PMT. More than 50% of MCs were colocalized with neighbouring cells of the tumour microenvironment within 20 μm, most frequently with monocytes (CD14+CD68+), M2 macrophages (CD68+CD163+), and endothelial cells (CD31+). In contrast, colocalization with atypical FGF23-secreting cells was rare, indicating minimal direct effects on tumour cell activity. Interaction with T lymphocytes, including CD8+, was also infrequent, excluding their activation and the development of antitumour effects. Mapping of MC histotopography validated the hypothesis of their inductive role in monocyte differentiation into M2 macrophages and probable polarisation of macrophages from M1 into M2, thereby contributing to slow tumour growth. MCs were further involved in extracellular matrix remodelling and participated in the formation of pro-osteogenic niches within the FGF23+ PMT microenvironment, leading to pathological osteoid development. Conclusions: This study demonstrated active MC participation in the evolution of the FGF23+ PMT microenvironment. The findings may be applied in translational medicine to develop novel algorithms for personalised therapy in patients with FGF23-secreting tumours, offering an alternative when surgical removal of the tumour is not feasible. Full article