Search Results (327)

Skeletal muscle regeneration depends on coordinated transitions of muscle stem cells (MuSCs), also known as satellite cells, from quiescence through activation and proliferative expansion to differentiation and fusion, while self-renewal replenishes the quiescent MuSC pool within a dynamically remodeled niche. Fibroblast growth factor (FGF) signaling regulates these transitions, but its effects vary as MuSCs and their niche change across regenerative stages. FGF output is shaped by ligand availability and extracellular presentation, fibroblast growth factor receptor (FGFR) isoform expression and coreceptor availability, receptor trafficking, intracellular feedback, and the state of the responding cell. Following acute injury, FGF inputs can support MuSC activation and expansion; signaling is subsequently reconfigured during differentiation, fusion, self-renewal, and return to quiescence. Aging-associated regenerative decline, chronic injury and dystrophic remodeling, denervation, and metabolic dysfunction disrupt this coordination and can uncouple FGF activity from productive repair. Rhabdomyosarcoma provides a distinct malignant context in which the FGF network is rewired to sustain oncogenic myogenic cell states. Here, we integrate molecular, cellular, and niche-level evidence across these settings to explain why FGF signaling produces divergent outcomes and to clarify how cellular context and timing should inform therapeutic modulation. Full article

Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence. Full article

Background: Fibroblast Growth Factor Receptor 3 (FGFR3) mutations are common and clinically relevant alterations in bladder cancer, with implications for diagnosis, monitoring, and patient selection for targeted therapies. Tissue-based testing is often limited by sample availability, invasiveness, and the need for repeated sampling. This study aimed to develop and analytically validate a sensitive double drop-off droplet digital polymerase chain reaction (ddPCR) assay for simultaneous detection of four FGFR3 hotspot mutations in tissue and liquid biopsy samples. Methods: The assay targeted four FGFR3 mutations (S249C, R248C, Y373C, G370C) using reference probes that generate a constant fluorescence signal and wild-type-specific drop-off probes that lose binding when a mutation is present, thereby distinguishing wild-type double-positive droplets from mutant droplets with reduced drop-off fluorescence. Analytical validation was performed using synthetic mutant oligonucleotides, wild-type genomic DNA, and cell-free DNA (cfDNA) from healthy donors (HDs). Specificity, limit of blank (LOB), limit of detection (LOD), and assay precision were evaluated. Performance was compared with next-generation sequencing (NGS) in formalin-fixed paraffin-embedded (FFPE) tissue DNA. FGFR3 mutations were also assessed in matched plasma and urinary cfDNA from bladder cancer patients. Results: The assay demonstrated clear cluster separation, no cross-reactivity, and reliable detection of all mutations down to 0.2% mutant allele frequency (MAF). Strong agreement was observed with a mutation-specific singleplex ddPCR assay for S249C. Concordance with NGS in tissue DNA was 74.2%, with ddPCR identifying additional low-abundance mutations not reported by NGS. FGFR3 mutations were detected in plasma and urinary cfDNA, with complete concordance between matched plasma and urine samples. Conclusions: This ddPCR assay provides a rapid, sensitive, and cost-effective method for detecting clinically relevant FGFR3 mutations and may complement sequencing-based approaches for molecular monitoring using tissue, plasma, and urine specimens. Full article

Soft tissue sarcomas are malignant neoplasms originating from mesenchymal cells. In cats, there are two groups: inoculation site-associated sarcomas (ISSs) and non-inoculation site-associated sarcomas (NISSs). The aim of this study was to investigate the immunoexpression of metalloproteinases (MMPs) 2 and 9, tissue inhibitors (TIMPs) 1 and 2, and the main molecules related to angiogenesis and vascular count in both sarcoma groups; compare their expression; and evaluate their association with angiogenesis. Both tumor groups expressed all the molecules evaluated. A positive correlation was detected between MMP-2 and angiogenic factors in both ISSs and NISSs. MMP-9 expression correlated positively with MMP-2 in both groups. TIMP-1 correlated with both MMP and with angiogenic factors in ISS. Fibroblast growth factor receptor 2 (FGFR-2) expression was higher in NISS. Studying the pathways that regulate angiogenesis in these neoplasms is crucial for identifying ways to intervene and limit neoplastic progression, thereby developing new therapeutic approaches. Full article

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined. Materials and Methods: A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction. Results: A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations. Conclusions: FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver. Full article

Gastrointestinal symptoms (GI) (abdominal pain, vomiting, and diarrhea) during the febrile phase of dengue (less than 5 days from fever onset) might indicate prominent innate immune responses. Serum and feces samples from cases with GI symptoms versus those without GI symptoms (n = 20 per group) were analyzed. From these, only the neutrophil extracellular traps (NETs), serum fibroblast growth factor (FGF) 21, and fecal microbiome analyses, but not the routine parameters, endotoxemia, or serum cytokines, were higher in the GI cases than in the non-GI cases. From the in vitro experiments, both lipopolysaccharide (LPS) and the dengue virus (DENV) upregulated the FGF receptor 1 (FGFR1) and cytokines in hepatocytes (HepG2) and THP-1-differentiated macrophages. Meanwhile, LPS and DENV induced NETs in isolated neutrophils from healthy volunteers. Only the starvation protocol, but not LPS or DENV, enhanced supernatant FGF-21 from hepatocytes. Incubation of recombinant FGF-21 in LPS + DENV-activated cells (hepatocytes, macrophages, and neutrophils) attenuated inflammation, as determined by supernatant cytokines and NETs. Hence, abdominal symptoms in dengue during the febrile phase indicate prominent innate immune responses, as detected by NETs and FGF-21 (an acute-phase protein), implying significant hepatic stress with a possible counteracting anti-inflammation. Full article

Fibroblast growth factor receptor 2 (FGFR2) inhibitors such as pemigatinib are targeted therapies for cholangiocarcinoma with FGFR2 alterations. While generally well tolerated, they are associated with unique adverse events. Calciphylaxis, a potentially fatal vascular calcification disorder, is a rare complication. We present a 43-year-old woman with metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 fusion who developed calciphylaxis after seven months of pemigatinib therapy. Despite drug discontinuation, antibiotics, and multidisciplinary supportive care, she deteriorated rapidly and died from sepsis and advanced disease. Histopathological analysis confirmed dermal and vascular calcifications consistent with calciphylaxis. This case highlights the importance of early recognition of cutaneous lesions in patients on FGFR inhibitors. Prompt cessation of therapy, management of metabolic derangements, and consideration of sodium thiosulfate may be lifesaving. Full article

Recurrent genetic and chromosomal aberrations drive multiple myeloma (MM) pathogenesis. Among these, the t(4;14) translocation leads to overexpression of fibroblast growth factor receptor 3 (FGFR3) and is associated with poor prognosis. However, therapeutic approaches directly targeting FGFR3-driven myeloma progression remain limited. Here, we investigated the single-agent activity of ponatinib, a multikinase inhibitor, in MM. KMS18 and U266 myeloma cell lines were treated with ponatinib, and apoptosis induction, as well as VEGF and IL-6 secretion, was assessed. RNA sequencing of MM cells revealed pathway alterations induced by ponatinib treatment, which were subsequently validated by Western blot analysis. In vivo, mice inoculated with 5T33 myeloma cells received ponatinib, and survival was monitored. Notably, ponatinib exerted potent single-agent antimyeloma activity in an FGFR3-dependent manner by inducing apoptosis and suppressing VEGF and IL-6 secretion through inhibition of JAK/STAT, PI3K/AKT, and MAPK signaling. In vivo administration prolonged survival in myeloma-bearing mice. Collectively, our findings demonstrate the therapeutic efficacy of ponatinib in FGFR3-expressing MM beyond selective FGFR3 inhibition, suggesting that concurrent suppression of multiple signaling pathways is a critical mechanism of action. These results highlight the therapeutic potential of combined FGFR3-targeted strategies in multiple myeloma and provide a rationale for further clinical investigation. Full article

Fibroblast growth factor receptor 2b (FGFR2b) has become an increasingly important therapeutic target in gastric and gastroesophageal junction cancer, particularly with the clinical development of FGFR2b-directed antibody therapy. However, its translation into routine treatment selection is not straightforward. FGFR2b is usually assessed as a protein biomarker by immunohistochemistry, and a positive result may reflect different biological situations depending on staining intensity, percentage of positive tumor cells, sample type and spatial distribution. In addition, FGFR2b protein expression, FGFR2 amplification, transcript-level activity and true pathway dependency are related but not interchangeable. This review examines FGFR2b-positive gastric cancer from the perspective of biomarker reliability rather than target presence alone. We discuss the biological basis of FGFR2b targeting, the reasons for variability in reported positivity rates, the implications of intratumoral and inter-lesion heterogeneity, the current clinical evidence for FGFR2b-directed and broader FGFR-targeted approaches, and the emerging challenges of safety, resistance and treatment sequencing. Particular attention is given to the gap between detecting FGFR2b and identifying tumors in which this target is sufficiently expressed, representative and biologically relevant to guide therapy. We also consider how FGFR2b should be interpreted alongside HER2, CLDN18.2, immune biomarkers and other receptor tyrosine kinase alterations. As FGFR2b-directed strategies move forward, their success will depend not only on drug efficacy, but also on standardized testing, careful reporting, and selective reassessment when disease biology changes. FGFR2b therefore offers a useful model for how protein biomarkers can be developed in gastric cancer: not as isolated positive-or-negative labels, but as clinically interpreted variables within a changing therapeutic landscape. Full article

Bladder cancer is a molecularly heterogeneous malignancy in which biomarker-driven therapies increasingly shape clinical management. Fibroblast growth factor receptor 3 (FGFR3) alterations and nectin-4 expression are key therapeutic targets, yet their integrated biological and clinical relevance remains unclear. A systematic search of PubMed, Scopus, and Cochrane Central was conducted from database inception to 22 February 2026 (PROSPERO: CRD420261309413). Studies reporting the prevalence of FGFR3 alterations and/or nectin-4 expression in bladder cancer were included. Proportions were pooled using a random-effects model with restricted maximum likelihood and Freeman–Tukey transformation. Heterogeneity was assessed with I² and Cochran’s Q. Fourteen studies (three randomized and 11 observational), including 3955 patients (mean age: 67.34 years), were analyzed. The pooled prevalence of FGFR3 alterations was 52% (95% CI: 23.33–80.12; I² = 99%), while that of nectin-4 expression was 78% (95% CI: 64.23–89.81; I² = 91%). FGFR3 prevalence varied significantly by disease stage, study design, and region, with higher rates in advanced/metastatic disease and randomized trials (p < 0.05). Nectin-4 expression was generally high across included studies, although interpretation was limited by the small number of studies and assay variability. Sensitivity analyses showed the stability of estimates; however, interpretation is limited by substantial heterogeneity. The observed prevalence estimates are strongly influenced by study design, biomarker selection, and assay variability, limiting their interpretation as true biological prevalence. These results should, therefore, be interpreted cautiously and viewed as descriptive rather than definitive estimates. Separate analyses of biomarker-enriched trials and unselected cohorts are necessary to obtain clinically meaningful estimates. Full article

Bladder cancer worldwide has seen a sharp rise, making it a significant global health concern. Recurrence monitoring is the main concern in treating the disease, and drug resistance follows suit. Treatment options include first-line medications, adjuvant therapy with BCG (Bacillus Calmette–Guérin) instillations, and combination therapies targeting the PD-1/PD-L1 axis. It has varying 5-year relative survival rates depending on the stage at diagnosis. Despite initial treatment success, resistance often develops, leading to relapse. Resistant to standard treatment is often due to immune landscape changes that are controlled by the most aberrant genes in bladder cancer, which also have a hold in the immune environment of the bladder. Dysregulation of FGFR3 (Fibroblast Growth Factor Receptor 3) in bladder cancer contributes to cell proliferation and metastasis. Simultaneously, the alterations in EGFR (Epidermal Growth Factor Receptor) regulation are linked to cell migration and resistance to treatment. FGFR3 in non-muscle invasive bladder cancer and EGFR in muscle-invasive bladder cancer are central elements in triggering various signaling pathways that contribute to chemoresistance. Concentrating the roles of both genes within the bladder tumour, they present opportunities not only as therapeutic targets but also as potential points of resistance and monitoring for recurrence. Exploring FGFR3 and EGFR to enhance treatment efficacy when combined with ICIs and developing markers into reliable diagnostic tools for recurrence, ultimately aiming for improved patient well-being, is the key aspect we propose to target from this narrative. Full article

Ameloblastoma is a common benign odontogenic tumor. Its etiology has been associated with dysregulation of the MAPK and SHH pathways, and new theories suggest that tumor stem cells (TSCs) and the epithelial–mesenchymal transition (EMT) are participants in their pathogenesis. Objective: To determine the immunohistochemical expression of SOX2 and CD44 as indicators of TSCs and the gene expression of vimentin, smooth muscle actin, and FGFR1 as indicators of the EMT in conventional, unicystic, and peripheral ameloblastoma. Materials and Methods: Conventional, unicystic, and peripheral ameloblastomas and dental follicles, as a control group, were analyzed by peroxidase immunohistochemistry assays for SOX2 and CD44 as TSC-related markers, and the EMT relationship was determined by RT-qPCR expression for vimentin (VIM), alpha smooth muscle actin (ACTA2), fibroblast growth factor receptor 1 (FGFR1), and GAPDH as a control. Results: The most affected anatomical site was the mandible, with an average age of 38.03 (±20.95) years. SOX2 and CD44 immunoexpression were significantly higher in conventional ameloblastoma. RT-qPCR results showed predominant non-significant expression of VIM, ACTA2, and FGFR1 in unicystic ameloblastoma compared to other ameloblastoma types. Conclusion: The significantly higher immunoexpression of SOX2 and CD44 in conventional subtypes could suggest a greater presence of TSCs, and predominant VIM, ACTA2, and FGFR1 gene expression in unicystic ameloblastoma could suggest the possibility of EMT processes related to cystic formation. More research on TSCs and the EMT is necessary to elucidate this finding. Full article

The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine therapies. The exact mechanisms behind this interaction are not fully understood; specific breast CAF subtypes have been linked to it, such as CAFs lacking the expression of the glycoprotein CD146 or maintaining the expression of CD63. Other proposed mechanisms include signaling pathways aberrantly activated in CAFs, epigenetic modifications mainly in the form of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), and paracrine signaling, all limiting endocrine modulation effectiveness. Strategies aiming to simultaneously target CAFs and endocrine signaling in luminal breast cancer are currently being developed. Fibroblast growth factor receptor (FGFR) targeting in combination with endocrine inhibition has already entered the clinical trial landscape. However, CAFs are a highly diverse and heterogeneous cell population, making their targeting complex and difficult to implement in clinical practice. Full article

Background/Objectives: Claudin-18.2 (CLDN18.2) has recently emerged as a therapeutic target in gastric cancer; however, its prognostic relevance in the neoadjuvant setting remains insufficiently defined. We evaluated the clinical significance of CLDN18.2 and fibroblast growth factor receptor 2b (FGFR2b) expression in patients with locally advanced gastric cancer treated with neoadjuvant therapy. Methods: This retrospective single-center study included 64 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy followed by curative surgery. Pretreatment endoscopic biopsy specimens were analyzed using immunohistochemistry to assess CLDN18.2 and FGFR2b expression. Survival outcomes were evaluated using Kaplan–Meier analysis and Cox proportional hazards regression models. Results: CLDN18.2 positivity was detected in 29.7% of patients and was not associated with baseline clinicopathological characteristics or pathological treatment response. However, CLDN18.2-positive tumors demonstrated significantly shorter relapse-free survival (median 19.0 vs. 36.6 months, p = 0.038) and overall survival (median 28.9 vs. 53.4 months, p = 0.005). In multivariable analysis, CLDN18.2 positivity remained an independent predictor of relapse-free survival. FGFR2b positivity was observed in 14.1% of patients and was evaluated descriptively due to limited case numbers. Conclusions: CLDN18.2 expression may represent a clinically relevant prognostic biomarker reflecting aggressive tumor biology in locally advanced gastric cancer treated with neoadjuvant therapy. Full article

Upper-tract urothelial carcinoma (UTUC) represents a biologically distinct and clinically challenging subset of urothelial malignancies, accounting for only 5–10% of urothelial cancers but carrying a disproportionately high risk of advanced disease and recurrence. Historically, management strategies for UTUC have been extrapolated from bladder cancer data, with limited prospective evidence specific to the upper urinary tract. However, recent years have witnessed an expanding number of UTUC-focused clinical trials that are reshaping treatment paradigms across localized, locally advanced, and metastatic disease states. This review examines the evolving landscape of clinical trials in UTUC, highlighting pivotal and ongoing studies that will inform contemporary management. We summarize evidence supporting perioperative systemic therapy, including neoadjuvant and adjuvant chemotherapy, and discuss the expanding role of immune checkpoint inhibitors in both perioperative and metastatic settings. Additionally, we review trials evaluating kidney-sparing approaches, intraluminal therapies, and novel drug-delivery platforms aimed at preserving renal function while maintaining oncologic control. Emerging trial designs incorporating molecular profiling, fibroblast growth factor receptor (FGFR)-targeted therapies, and biomarker-driven patient selection are also explored. Despite meaningful progress, significant gaps remain, including the underrepresentation of UTUC patients in large urothelial cancer trials, heterogeneity in risk stratification, and challenges in trial accrual for this rare disease. We conclude by outlining future directions for UTUC-specific clinical research, emphasizing the need for collaborative, multicenter trials, innovative endpoints, and integrated translational studies to further refine personalized treatment strategies. As the clinical trial ecosystem for UTUC continues to mature, these efforts hold promises for improving outcomes while balancing oncologic efficacy with renal preservation. Full article