Search Results (280)

Oral squamous cell carcinoma (OSCC) accounts for most head-and-neck cancers, and effective biological adjuvants remain limited. Gingival mesenchymal stem cells (GMSCs) exhibit anti-tumour paracrine activity, but the underlying molecular mechanisms and their relevance in patient cohorts remain incompletely understood. Consensus apoptosis–reactive oxygen species (ROS) effectors were identified through integrated transcriptomic analyses of TCGA-HNSC and three GEO cohorts. Candidate genes were evaluated in primary OSCC cells exposed to GMSC-conditioned medium or indirect Transwell co-culture. Findings were further examined using patient-cohort validation, single-cell ligand–receptor analysis, pathway and transcription-factor activity inference, and drug-repurposing approaches. Computational analyses identified an apoptosis–ROS network centred on BAX, BCL2, CASP3, CASP9, NOX1, and GPX1. Indirect GMSC co-culture reduced intracellular ROS, increased early apoptosis, and induced G2/M accumulation, whereas conditioned medium produced inconsistent effects, suggesting a requirement for live bidirectional paracrine signalling. BAX was the only consistently up-regulated effector. The axis demonstrated concordant differential expression across independent HPV-negative OSCC cohorts but was not independently prognostic under leakage-free cross-validation or external validation. Pathway analyses supported ROS suppression, apoptosis activation, and altered stromal–tumour communication. Drug-repurposing analyses identified HSP90 inhibitors and the FDA-approved TOP2 inhibitor mitoxantrone as candidate therapeutic agents. GMSC paracrine activity targets a biologically interpretable apoptosis–ROS axis in OSCC that is reproducibly expressed across patient cohorts but does not constitute an independent prognostic biomarker. The identified therapeutic candidates warrant further experimental investigation. Full article

T1 high-grade (T1HG) urothelial carcinoma of the bladder presents a persistent clinical challenge: despite uniform high-risk classification under EAU guidelines, BCG failure and disease progression rates range from 10% to 40% across published series. Standard clinicopathological variables do not adequately explain this heterogeneity. Three pathological parameters evaluable from routine TURBT specimens—T1 substaging by lamina propria invasion depth, tumour budding at the invasion front, and E-cadherin (CDH1) immunohistochemistry—share a common mechanistic basis in CDH1-driven partial epithelial-to-mesenchymal transition and may refine escalation-oriented risk stratification without requiring additional tissue or molecular testing. We conducted a narrative critical review of PubMed/MEDLINE (January 2000–February 2026; 28 included studies) to evaluate the quantitative evidence for each parameter, with emphasis on reproducibility and BCG-specific outcome data. T1 substaging carries the strongest evidence: pooled progression HR 3.29 (95% CI 2.39–4.51) across 36 studies (n = 6781), with BCG failure of 41% vs. 21% in a centralised BCG-treated registry cohort of 264 patients on multivariable analysis. Tumour budding shows consistent adverse associations in BCG-treated pT1 NMIBC; zero progression was observed in the low-budding subgroup in the only available BCG-specific full-text cohort. CDH1 IHC is directionally supportive but limited by scoring heterogeneity (I² = 63%). All three parameters are mechanistically coherent and assessable from routine TURBT slides. Prospective validation with pre-specified thresholds and standardised scoring protocols is required before clinical implementation can be recommended. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC), the predominant malignant subtype of kidney cancer, is the leading cause of death among renal cell carcinoma patients. Although a subset of ccRCC patients benefit from select immune checkpoint inhibitors (ICIs), prognosis remains poor. While PD-1 and PD-L1 have been extensively studied, the prevalence and distribution of other immune checkpoints (ICs) and their relationship with epithelial-to-mesenchymal transition (EMT) remain poorly characterised. Here, we investigated the interplay between twenty ICs and EMT markers and assessed their combined prognostic relevance in ccRCC patients. Methods: Transcriptomic profiling and integrated bioinformatic analyses were performed, including differential expression, correlation analyses, survival analyses, forest plot analyses, ROC curve evaluation, and OncoPrint visualisation, complemented by analysis of single-cell RNA sequencing data, immunohistochemistry, and multiplex secretory IC (LegendPlex) assays. Results: Transcriptomic profiling of over 500 ccRCC tumours versus normal kidney tissue revealed dysregulation of ICs, particularly LAG3 and NT5E. Notably, expression of ICs, including LAG3 and NT5E, was associated with poor overall survival in 415 ccRCC patients. ICs that synergised with the EMT phenotype provided improved prognostic discrimination compared to individual ICs. Correlation analyses, single-cell RNA sequencing, and immunohistochemistry demonstrated an association between EMT-associated tumours and expression of LAG3 and NT5E. ROC analysis indicated modest prognostic performance of LAG3 and NT5E. Conclusions: Collectively, this study identifies an EMT–IC axis in ccRCC and demonstrates its relevance to tumour biology and patient outcomes, highlighting LAG3 and NT5E as potential prognostic markers and therapeutic targets that warrant further investigation. Full article

Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and natural killer cell-derived extracellular vesicles (NK-EVs) modulate cisplatin responsiveness in endometrial cancer cells (RL95-2 and HEC-1A). MSC-EVs and NK-EVs were isolated and characterised using nanoparticle tracking analysis, scanning electron microscopy, and EV marker profiling. MSC-EVs and NK-EVs reduced RL95-2 and HEC-1A cell viability in a dose-dependent manner, with MSC-EVs exhibiting substantial effects at lower particle concentrations. In a cisplatin-resistant HEC-1A (HEC-1A DDP-R) model, MSC-EVs were associated with greater reductions in cell viability under cisplatin treatment conditions, whereas NK-EVs showed comparatively modest effects. Mechanistic analyses demonstrated altered expression of apoptosis- and cell cycle–related proteins, including increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels and reduced cyclin A and cyclin D1 expression following MSC-EV treatment. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry demonstrated increased apoptotic cell populations after MSC-EV treatment, with MSC-EV + DDP co-treatment resulting in the highest apoptotic fraction in chemoresistant HEC-1A cells. Collectively, these findings indicate that MSC-EVs are associated with altered cellular responses to cisplatin in chemoresistant endometrial cancer cells, accompanied by changes in apoptosis-related protein expression, apoptotic cell populations, and cell-cycle regulators. Further investigation is required to determine their mechanistic role and therapeutic potential in overcoming chemoresistance. Full article

The family of uterine mesenchymal neoplasms is diverse in etiology and clinical impact. While histomorphology remains central to diagnostic classification, numerous biomarkers have been developed to aid in refining diagnoses and informing optimal treatment strategies. Indeed, a growing number of neoplasms are being primarily classified on the basis of key pathognomonic genetic events, and this number is expected to continue expanding as access to next-generation sequencing rapidly democratizes. Moreover, several quantitative biomarker tests have been developed to aid in the prognostic stratification of tumours with ambiguous morphologic features, providing critical insights to clinicians seeking optimal oncologic management while minimizing unnecessary treatment morbidity. In this review, we discuss key advances in the utilization of biomarkers for diagnostic classification, prognostication, and the prediction of response to targeted therapeutics in uterine mesenchymal neoplasms, with the aim of highlighting the most clinically impactful biomarkers used by pathologists to enhance the clinical care of patients. Full article

Pancreatic ductal adenocarcinoma frequently metastasises to the liver, although the mechanisms underlying hepatic pre-metastatic niche formation remain unclear. Small extracellular vesicles mediate tumour–host communication and may drive hepatic microenvironment reprogramming. This study investigated the effects of pancreatic ductal adenocarcinoma-derived small extracellular vesicles on extracellular matrix remodelling and epithelial–mesenchymal transition-related plasticity in hepatic cells. Small extracellular vesicles were isolated from pancreatic ductal adenocarcinoma cell lines (MIAPaCa-2, PANC-1) and from the serum of 25 patients, characterized, and administered to hepatic stellate (LX-2) and hepatocyte-like (HEPA-RG) cells. Cell viability and migration were evaluated by functional assays, morphology by scanning electron microscopy, and molecular changes by RT-PCR, Western blotting, and immunofluorescence. In LX-2 cells, small extracellular vesicles exposure increased metabolic activity, adhesion, and migration, while inducing morphological and molecular changes associated with extracellular matrix remodelling, including reduced collagen type I alpha 2 chain, vimentin, and E-cadherin expression. In HEPA-RG cells, viability was minimally affected, whereas migration and EMT-related plasticity were enhanced. Patient-derived small extracellular vesicles induced similar but less pronounced effects. Overall, pancreatic ductal adenocarcinoma-derived small extracellular vesicles induced early hepatic microenvironmental remodelling, supporting a potential role for tumour–liver crosstalk in pre-metastatic niche-associated processes, highlighting tumour–liver crosstalk as a potential therapeutic target. Full article

Background/Objectives: The tumour immune microenvironment (TIME) critically influences colorectal cancer (CRC) progression and therapeutic response, yet mechanisms shaping immune phenotypes remain unclear. Mucin-type O-glycosylation regulates tumour–immune interactions at the cell surface. Methods: We analysed O-glycosylation activity in 988 colorectal cancer (CRC) tumours derived from three independent cohorts: The Cancer Genome Atlas (TCGA-CRC, n = 534), the Clinical Proteomic Tumour Analysis Consortium (CPTAC2-CRC, n = 106), and the Sidra–Leiden University Medical Center (Sidra-LUMC, n = 348). O-glycosylation activity was quantified using a transcriptomic gene signature and single-sample gene set enrichment analysis (ssGSEA). Tumours were stratified into high and low O-glycosylation groups based on the median score, and associations with immune phenotypes, genomic alterations, and tumour functional states were assessed. Results: High O-glycosylation tumours exhibited an immune-desert phenotype with reduced immune-inflamed (p = 3.65 × 10⁻¹⁰) and immune-excluded (p = 0.0070) signatures alongside increased immune-desert scores (p = 0.0049) and reduced Siglec signalling (p = 8.14 × 10⁻⁵). O-glycosylation was associated with genomic stability, including lower TP53 mutation frequency (p = 0.0056), reduced aneuploidy (p = 0.0116), and decreased fraction of genome altered (p = 0.0309). High O-glycosylation tumours also showed upregulation of multidrug resistance programmes and reduced epithelial–mesenchymal transition (p = 0.0141) and proliferation (p = 0.0294). Conclusions: O-glycosylation defines a CRC subtype characterised by immune exclusion, genomic stability, and multidrug resistance, highlighting its potential as a biomarker and therapeutic target. Full article

Ovarian cancer (OC) remains one of the most lethal gynaecological malignancies, which is mainly due to late diagnosis, high frequency of metastasis, and the risk of developing resistance to systemic therapy. In recent years, exosomes—small extracellular vesicles (EVs) secreted by cancer cells and components of the tumour microenvironment (TME)—have been identified as potential mediators of OC progression. Exosomes participate in intercellular communication and enable the transfer of RNA, proteins, and lipids. These vesicles may modulate the immune response, promote angiogenesis, remodel the extracellular matrix, and drive epithelial–mesenchymal transitions. Exosomes also appear to play a role in the development of drug resistance via direct transfer of resistance factors or indirect modification of TME. In this review article, we summarise current knowledge on the biological role of exosomes in OC pathogenesis. We also discuss their possible diagnostic, prognostic, and therapeutic relevance. The properties and composition of exosomes make them promising noninvasive liquid biomarkers and convenient carriers for anticancer drugs. However, to fully exploit their potential, further large-scale preclinical and clinical studies are required, which should focus primarily on standardising research methods and assessing the safety and efficacy of exosome-based diagnostic and therapeutic methods. Full article

The phenotypic plasticity of epithelial cells along the epithelial–mesenchymal (E-M) axis, or epithelial–mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour metastasis. This review article investigates the potential interplay between hyperglycaemia-induced metabolic stress and EMT in the context of therapeutic resistance. The study examines a complex, multifaceted network of molecular mechanisms regulating EMT, including specialised transcription factors and signalling pathways as well as growth factors, integrins, and matrix metalloproteinases in various epithelial carcinomas. Emerging findings have demonstrated the existence of EMT hybrid states along the continuum, possessing heightened metastatic potential and distinctive metabolic signatures that play critical roles in the development of therapeutic resistance in cancer cells. Hyperglycaemia has been particularly highlighted for its potential to promote EMT-driven therapeutic resistance through various interconnected mechanisms. Elevated glucose levels induce the increased production of reactive oxygen species (ROS), activation of EMT-promoting transcription factors, and a metabolic shift towards glycolysis. This hyperglycaemic stress involves upregulation of glucose transporters and glycolytic enzymes, creating feed-forward loops that support drug efflux mechanisms and help maintain the mesenchymal phenotype. Clinical data also indicate that hyperglycaemia in OSCC patients is associated with more advanced tumour stages, more extended hospital stays, less effective treatments, and higher rates of local recurrence and distant metastasis. Overall, these insights reveal a deleterious feed-forward loop in which hyperglycaemia promotes EMT-driven therapeutic resistance, with the strongest clinical evidence in oral squamous cell carcinoma (OSCC) and supportive data from pancreatic and breast cancers. Although glycaemic control represents a promising low-risk adjunctive approach, its clinical benefit remains to be validated in prospective interventional studies. Full article

Background: Tumour glycosylation regulates immune modulation and progression, but whether the CRC sialylome—the complete repertoire of sialylated glycans—defines a biologically distinct subtype remains unclear. We investigated how the “sugar code” shapes CRC biology, immunity, and therapeutic response. Methods: Transcriptomic data from three CRC cohorts (TCGA, Sidra-LUMC, and CPTAC-2; n = 988) were batch-corrected and integrated. Single-sample gene set enrichment analysis (ssGSEA) quantified sialyltransferase expression, sialic acid metabolism, EMT, MDR mechanisms, immune phenotypes, and Siglec-associated transcriptional signatures. GSEA, gene ontology enrichment analysis (GOEA), and drug ontology enrichment analysis (DOEA) characterised pathways and identified drug response-associated transcriptional signatures. Results: High sialylome activity defined a genomically stable but clinically advanced CRC subset enriched for left-sided tumours, mucinous histology, MSI, and BRAF mutations. At the transcriptional level, Sialyl-High tumours were associated with a mesenchymal, stromal-remodelling programme accompanied by reduced proliferative activity. They demonstrated enrichment of vesicular trafficking-related pathways alongside reduced representation of canonical efflux-associated programmes. Critically, the sialylome was associated with Siglec-related immune signatures, with sialylated glycan-related gene expression correlating with Siglec receptor expression (CD33 and SIGLEC7/9/10), consistent with an immune-inflamed yet structurally excluded microenvironment. DOEA identified selective enrichment of drug-response signatures related to sialic acid metabolism inhibitors (oseltamivir and Neu5Ac) and glycocalyx-disrupting agents (ginsenosides and soyasaponins). Conclusions: The CRC sialylome is associated with tumour phenotypic variation, including immune-excluded states linked to Siglec-associated transcriptional signatures and patterns consistent with non-canonical drug resistance programmes. These findings position the “sugar code” as a central organising principle in CRC and identify glycan-directed therapies as a promising strategy for the targeting of this aggressive subtype. Full article

Fucosylation, the enzymatic addition of fucose residues to glycans, modulates receptor signalling and cellular identity in the intestinal epithelium. Its role as an integrative determinant of cancer cell fate in colorectal cancer (CRC) remains undefined. Transcriptomic and clinicopathological data from 976 CRC patients across three independent cohorts (TCGA-CRC, CPTAC2-CRC, Sidra-LUMC) were analysed. A curated fucosylation gene set was used to calculate tumour fucosylation scores. Associations with histogenetic status, genomic features, microenvironmental phenotypes, drug resistance programmes, and survival were evaluated using gene set enrichment analysis, multivariable Cox regression, and integrated molecular subtyping. High-fucosylation tumours exhibited elevated epithelial differentiation, MSI-H/BRAF-mutant enrichment, oxidative phosphorylation dominance, the complete absence of EMT and invasion programmes, and favourable prognosis (HR = 0.633, 95% CI: 0.470–0.853, p = 0.003). Low-fucosylation tumours demonstrated mesenchymal phenotypes, TP53 mutations, chromosomal instability, comprehensive multi-family RTK signalling, immune-excluded microenvironments, and poor outcomes. Distinct multidrug resistance programmes emerged: drug efflux in low-fucosylation tumours versus xenobiotic sensing, target bypass, and drug sequestration in high-fucosylation tumours. Tumour fucosylation status defines two fundamentally distinct CRC cell states with mutually exclusive engagement of invasion programmes, metabolic pathways, immune phenotypes, and resistance mechanisms. Fucosylation represents an independent prognostic biomarker and integrative determinant of cancer cell fate, with significant implications for risk stratification and personalised therapeutic strategies. Full article

Solitary fibrous tumour is an uncommon, predominantly benign tumour of mesenchymal origin, developing mainly in the thoracic cavity and on the pleural surface, although it has been reported in a wide variety of extrapleural sites. Its occurrence in the liver is particularly rare. We present the case of a 57-year-old woman in whom a large mass was identified in the left lobe of the liver, demonstrating inhomogeneous contrast enhancement without significant compression of the abdominal vessels. The lesion measured 170 mm in its greatest diameter and severely destroyed the surrounding liver parenchyma. SFT is characterised by haphazardly arranged ovoid and spindle-shaped cells with numerous mildly staghorn-like vessels lined by flattened endothelium. It typically shows NAB2–STAT6 gene rearrangement with CD34 and/or STAT6 positivity on immunohistochemistry. Since imaging methods are not specific regarding the nature of the lesion, pathological and immunohistochemical analyses are essential for establishing an accurate diagnosis and assessing differential diagnostic possibilities. Full article

Background: Uterine sarcomas are rare but highly aggressive mesenchymal malignancies associated with poor survival. Preoperative differentiation from benign leiomyomas remains a critical oncologic challenge, frequently resulting in unexpected postoperative diagnoses and potential tumour dissemination during morcellation. Reliable, accessible biomarkers to support preoperative risk assessment are lacking. This study evaluated whether CRP, a systemic inflammatory marker implicated in tumour biology, could aid in the preoperative identification of uterine sarcoma. Methods: This retrospective single-centre study included 39 patients with histologically confirmed uterine sarcoma and 39 patients with leiomyoma treated between 2010 and 2021. Preoperative serum CRP levels were compared between groups. As data were non-normally distributed, the Mann–Whitney U test was used for comparisons, and Spearman’s rank correlation was applied for association analyses. Results: Patients with sarcoma were significantly older than controls (56.2 ± 12.9 vs. 39.2 ± 6.7 years, p < 0.0001). Preoperative CRP levels were significantly higher in sarcoma patients compared with leiomyoma patients (26.4 ± 46.8 mg/L vs. 0.4 ± 1.6 mg/L; p < 0.001). Elevated CRP (>5 mg/L) was observed in 53.8% of sarcoma cases versus 2.6% of controls. Undifferentiated sarcomas demonstrated the highest CRP levels. CRP levels were not significantly associated with tumour aggressiveness. A moderate negative correlation between age and preoperative CRP was identified (r = −0.476, p = 0.029). Receiver operating characteristic analysis demonstrated a moderate discriminatory ability of preoperative CRP for differentiating uterine sarcoma from leiomyoma (AUC 0.751, 95% CI 0.668–0.834). Conclusions: Elevated preoperative CRP levels are significantly associated with uterine sarcoma and may enhance oncologic risk stratification prior to surgery. Integration of CRP into multimodal preoperative assessment algorithms could improve surgical planning and reduce the risk of inadvertent tumour dissemination. Prospective multicentre studies are required to validate its diagnostic performance and define clinically relevant cut-off values. Full article

Neuroblastoma (NB) represents a paradigmatic developmental malignancy in which lineage specification, oncogenic signalling, and epigenetic regulation converge to define tumour behaviour. Among the molecular axes shaping NB heterogeneity, neurotrophin receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) and the p75NTR occupy a central position at the intersection between neuronal differentiation programs and malignant plasticity. While high TrkA and TrkC expression is associated with adrenergic identity, differentiation competence, and favourable clinical outcome, TrkB, frequently sustained by BDNF-driven autocrine loops, characterises mesenchymal-like, therapy-resistant states enriched in metabolic and inflammatory adaptations. Importantly, in NB, the dysregulation of neurotrophin signalling rarely arises from recurrent genetic alterations of neurotrophic tyrosine receptor kinase (NTRK) loci. Instead, Trk receptor expression is dynamically shaped by promoter methylation, polycomb repressive complex 2/Enhancer of Zeste homolog 2 (PRC2/EZH2)-dependent chromatin repression, MYCN-driven transcriptional silencing, enhancer rewiring, and microRNA-mediated control. These epigenetic mechanisms govern reversible transitions along the adrenergic–mesenchymal (ADRN–MES) continuum, enabling tumour cells to adapt to microenvironmental and therapeutic stress. Single-cell and spatial multi-omics approaches have further revealed that Trk-associated phenotypes are embedded within complex regulatory circuits integrating receptor tyrosine kinase (RTK) networks, cytokine signalling, metabolic remodelling, and stromal reinforcement. Here, we provide a comprehensive synthesis of the epigenetic and microenvironmental mechanisms regulating neurotrophin receptors in NB, with particular emphasis on how chromatin plasticity and cell-state transitions reshape Trk-dependent signalling outputs. We discuss advanced three-dimensional and organoid-based models that recapitulate niche-specific regulation of the Trk axis and evaluate emerging therapeutic strategies combining epigenetic modulators, differentiation-inducing agents, and RTK-targeted compounds. Understanding the temporal and spatial dynamics of Trk signalling may open new opportunities to therapeutically stabilise differentiation states and disrupt adaptive resistance programs in high-risk NB. Full article

This review evaluates the emerging role of circulating tumour cells (CTCs) as clinically meaningful, minimally invasive biomarkers for oral squamous cell carcinoma (OSCC). Despite advances in management, OSCC continues to demonstrate high morbidity and mortality, largely due to late diagnosis and the absence of validated biomarkers for early detection or real-time monitoring. Conventional diagnostic tools, tissue biopsy, and imaging provide only static snapshots and fail to capture tumour heterogeneity or evolving biological behaviour. CTCs offer a novel and significant opportunity to address these limitations. Key findings from recent studies highlight that CTC enumeration correlates with tumour burden, nodal metastasis, recurrence, and overall prognosis. Molecular and phenotypic characterisation further reveals dynamic traits such as epithelial–mesenchymal transition, stemness, and therapy resistance, providing insights into metastatic potential and treatment failure. Technological advances, including immunocytochemistry, microfluidic capture platforms, PCR-based assays, and next-generation sequencing, have enhanced the sensitivity and specificity of CTC detection and enabled detailed multi-omic profiling. Collectively, evidence suggests that integrating CTC analysis into OSCC clinical workflows could improve early detection, refine risk stratification, personalise therapeutic strategies, and support longitudinal monitoring of disease dynamics. As research progresses, CTC-based diagnostics represent a promising frontier in shifting OSCC management toward more precise, adaptive, and biologically informed care. Full article