Search Results (2,623)

Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Increasing evidence indicates that alterations in glycosylation and glycan-binding proteins, such as galectins, contribute substantially to colorectal carcinogenesis. We review the current knowledge on the role of known human galectins in CRC to provide up-to-date summaries, focusing on their involvement in tumor initiation, progression, invasion, angiogenesis, immune evasion, and treatment resistance, integrating molecular mechanisms with diagnostic, prognostic, and therapeutic perspectives. Methods: We searched for “colorectal cancer” and “Galectin”, “Galectin-X” and “colorectal cancer”, and “Gal-X” and “colorectal cancer” (X denotes the number of the respective galectin) in PubMed, ScienceDirect, Scopus, and Web of Science databases. All records were screened for relevance by the authors. Results: We summarize the expression patterns of individual galectins in colorectal tissues and circulation, their involvement in oncogenic signaling pathways, and their interactions with the tumor microenvironment. Furthermore, we critically evaluate the available evidence regarding their diagnostic, prognostic, and therapeutic potential. Conclusions: Although galectin-1 and galectin-3 are the most extensively investigated galectins, accumulating evidence suggests that galectin-4, galectin-8, and galectin-9 also play important context-dependent roles in CRC progression and immune regulation. However, methodological heterogeneity and limited clinical validation currently preclude the implementation of galectins as standalone biomarkers in routine practice. Future research should focus on standardized multicenter studies, clarification of context-dependent galectin functions, and the development of galectin-targeted therapies. A deeper understanding of galectin biology may facilitate the development of novel multimarker diagnostic approaches and personalized therapies for CRC patients. Full article

Extracellular vesicles (EVs), including exosomes and microvesicles, are nanoscale membrane-enclosed particles that transfer proteins, lipids, mRNAs, and microRNAs between cells. The same communication system is now being developed in two apparently opposing settings: mesenchymal stem/stromal cell (MSC)-derived EVs are explored as cell-free regenerative therapeutics, whereas tumor-derived EVs can promote metastasis, immune evasion, and treatment resistance while also serving as liquid-biopsy biomarkers. Rather than treating these studies separately, this review compares them along shared mechanistic axes: producer-cell identity and state, luminal cargo, membrane and surface composition (including the biomolecular corona), dose and administration route, biodistribution, and recipient-cell context. This cross-field perspective shows that angiogenesis, immunomodulation, matrix remodeling, and tissue tropism are not intrinsically regenerative or oncogenic; their consequences depend on where, how, and to which cells EV signals are delivered. We review EV biology and MISEV2023-aligned nomenclature, examine bidirectional regenerative and cancer-associated functions, and survey engineering strategies for cargo loading and surface modification together with plant-derived exosome-like nanovesicles. We further compare EVs with lipid nanoparticles, adeno-associated viruses, polymers, and virus-like particles, and discuss how engineering can improve potency and targeting while increasing manufacturing and characterization complexity. Finally, we address tumor-related safety considerations for regenerative EVs and the unresolved biological, technical, manufacturing, and regulatory questions that must be addressed for clinical translation. Full article

Bisphenol A (BPA) is a non-persistent industrial chemical widely used in the production of polycarbonate plastics and epoxy resins. Due to its mass production and versatility, BPA is ubiquitous in environmental matrices, leading to human exposure through ingestion, dermal contact, and inhalation. As a known endocrine-disrupting chemical (EDC) with estrogenic activity, BPA exposure has been associated with reproductive, metabolic, immune, oncogenic, and developmental effects. Mechanistically, BPA is reported to exert its toxic effects via multiple pathways, including alterations in epigenetic microRNA (miRNA) expression. miRNAs are endogenous non-coding RNA molecules that regulate gene expression by targeting mRNAs, thereby influencing a wide range of cellular and metabolic pathways involved in development and disease. Importantly, this review consolidates evidence suggesting that the biological effects of BPA may, in part, be mediated through miRNA-driven epigenetic modifications, affecting numerous downstream proteins and signaling pathways. Altered miRNA expression induced by BPA exposure is implicated in diverse health outcomes, including reproductive dysfunction, oncogenesis, metabolic disorders, and neurodevelopmental abnormalities. Notably, BPA exposure predominantly results in the upregulation of specific miRNAs, such as miR-21 and miR-146a, although tissue-specific and sex-dependent variations are evident. In this review, we provide a comprehensive overview of human, in vivo, and in vitro studies investigating BPA-induced miRNA dysregulation and its associated biological effects. Full article

Gastric Cancer (GC) is characterized by remarkable biological heterogeneity, reflected by the continuous expansion of biomarkers with diagnostic, prognostic, predictive, and therapeutic relevance. However, most reviews organize these biomarkers according to signaling pathways or individual molecular alterations, often overlooking the interconnected biological processes and functional states that shape gastric carcinogenesis and tumor evolution. This review proposes a biology-oriented conceptual framework that interprets GC biomarkers through five fundamental biological questions capturing interconnected biological capabilities and tumor states: preservation of gastric lineage identity, acquisition of stem cell-like properties, epithelial–mesenchymal transition, immune evasion, and dependence on actionable oncogenic pathways. Within each biological domain, biomarkers were critically selected and comparatively evaluated according to their biological significance, pathological applicability, translational relevance, and clinical utility. Core biomarkers central to each biological process are discussed alongside complementary biomarkers that further refine biological interpretation and clinical stratification. Rather than presenting another comprehensive catalogue of molecular alterations, this review integrates current evidence into a coherent framework linking tumor biology with diagnostic pathology and precision oncology. By emphasizing biological capabilities rather than isolated molecular pathways, this approach provides a practical perspective for biomarker interpretation and establishes a conceptual foundation for future multimarker strategies in GC. Full article

Cancer remains a highly complex and heterogeneous disease, causing major morbidity and mortality worldwide despite advances in diagnosis and treatment. The hallmarks of cancer enlighten the biological mechanisms supporting tumourigenesis and malignant evolution, while helping to identify potential therapeutic targets. Medical cannabis has mostly been used in oncology for supportive care, but increasing preclinical evidence suggests interference with cancer-related signalling pathways. This narrative review summarizes the current evidence on cannabinoids, in particular the phytocannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), framing their prospective anticancer effects in the hallmarks of cancer. Preclinical studies imply that CBD exerts antiproliferative effects by modulating oncogenic signalling pathways, including EGFR, PI3K/AKT, RAS/RAF/ERK, mTOR and Wnt/β-catenin, while also influencing tumour suppressor pathways involving p53, p21 and p27, causing cell cycle arrest. CBD has additionally been shown to promote programmed cell death via mitochondrial dysfunction and autophagy, altering cancer metabolism as well. Furthermore, CBD has shown anti-invasive and antiangiogenic properties and also appears to modulate immune responses and interactions with the tumour microenvironment, including emerging links with the microbiome. Overall, cannabinoids exhibit biologically plausible antitumour activity across multiple cancer hallmarks and may present promising candidates for combination therapeutic strategies. Nonetheless, the current evidence remains predominantly preclinical, and robust translational studies and clinical trials are needed to clarify their pharmacokinetic and pharmacodynamic profiles, determine their clinical efficacy and safety while assessing their potential integration into multimodal cancer treatment. Full article

Transcriptomic profiling reproducibly resolves pancreatic ductal adenocarcinoma (PDAC) into two prognostically divergent tumour-intrinsic programmes—classical/progenitor and basal-like/squamous—accompanied by a separable stromal axis; additional proposed classes are strongly influenced by low tumour cellularity and generalise poorly across datasets. Rather than cataloguing these programmes, this review synthesises evidence that they behave as plastic cell states and proposes an integrative developmental framework for interpreting that plasticity, rather than claiming its discovery. The framework combines a normal-pancreas developmental reference frame, the regulation of state by lineage transcription factors, epigenetic remodelling, oncogenic (KRAS) dosage, stromal instruction, and treatment pressure, and a testable notion of spatial disorganisation. Throughout, we separate robust prognostic evidence—basal-like assignment and low GATA6 expression are consistently associated with worse outcome—from predictive claims: predictive utility remains unproven because no completed prospective trial has assigned treatment according to classical–basal subtype and demonstrated improved clinical outcome from that strategy, and existing signals derive from retrospective or observational analyses. The proposition that the classical–basal spectrum reflects a spatially disordered redeployment of the normal duct’s luminal–basal hierarchy is presented as a hypothesis requiring validation in independent atlases rather than as established biology. We define the falsifiable experiments needed to test the framework and its clinical implications. Full article

Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, cellular context and biased coupling to G-protein αq (Gαq), G-protein α12/13 (Gα12/13) and β-arrestin. PAR-2 is best understood not as a simple inflammatory receptor but as a proteolytic rheostat that converts diverse coagulation, inflammatory, microbial and stromal protease inputs into distinct oncogenic programmes. Colorectal cancer and pancreatic ductal adenocarcinoma provide complementary models: in colorectal cancer, PAR-2 links mucosal inflammation and coagulation to proliferation, metastatic competence and resistance to epidermal growth factor receptor (EGFR)-targeted therapy, whereas in pancreatic cancer, it is embedded in a tissue-factor-rich desmoplastic microenvironment that promotes invasion, immune exclusion and chemoresistance. Therapeutic strategies suggested by this framework include direct and biased PAR-2 modulators, upstream protease and factor Xa (FXa) inhibition, statin repurposing and activated-fragment biomarkers such as the PAR-2 activation neoepitope (PRO-PAR2). These strategies must be applied under biomarker guidance, since PAR-2 blockade may benefit inflammation-dominant tumours yet prove counterproductive where PAR-2 sustains antitumour immunity. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

Liquid biopsy, the analysis of tumor-derived material in blood, saliva, and other body fluids, is increasingly explored for the diagnosis, surveillance, and molecular characterization of head and neck squamous cell carcinoma (HNSCC). Its performance, however, is not uniform across the disease, and the reason is fundamentally molecular. human papillomavirus (HPV)-positive oropharyngeal cancers carry viral oncogenes that are absent from the host genome and therefore provide a near ideal, tumor specific circulating marker, whereas HPV-negative tumors are driven by a heterogeneous somatic landscape that offers no single universal target. In this narrative review, we adopt a molecular perspective. We first examine the biological origin of circulating tumor DNA and of the other analytes that liquid biopsy can interrogate including circulating tumor HPV DNA, viral transcripts, microRNAs, extracellular vesicles, and methylation signatures. We then consider how analytical platforms, from droplet digital PCR to next generation and ultrasensitive whole-genome sequencing, translate these molecules into measurements. Only afterward do we discuss the clinical questions, organized by clinical objective rather than by individual study: diagnosis and early detection, prognosis and risk stratification, treatment response monitoring, minimal residual disease and surveillance, and biomarker guided de-escalation in HPV-positive disease. Twelve registered clinical trials, involving approximately 1183 patients, are presented as illustrations of these questions. We close on the biological and technical gaps that still separate promising signals from clinical practice, and on the multi analyte and dynamic strategies most likely to bridge them. At present, liquid biopsy should be regarded as a complementary tool rather than as a replacement for established clinicopathological assessment. Full article

Colorectal cancer, especially the microsatellite-stable subtype, which accounts for 85% to 95% of cases, resists immune checkpoint inhibitors largely due to metabolic reprogramming in the tumor microenvironment. Lactate has evolved from a waste product into a central immunosuppressive regulator. Oncogenic KRAS and BRAF mutations drive aerobic glycolysis, causing glucose deprivation and massive lactate accumulation in the tumor microenvironment. Lactate suppresses immunity through three parallel mechanisms. It signals via GPR81 to recruit polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and inhibit T-cell function. It contributes to histone H3K18 lactylation, which silences effector genes including IFN-γ and GZMB while upregulating PD-L1 expression. It also acidifies the microenvironment to pH 6.0–6.5, directly impairing NK and T-cell activity. Concurrent lipid abundance stabilizes the MCT4 lactate exporter, forming a bidirectional feed-forward loop that amplifies lactate effects. Spatial metabolic heterogeneity creates distinct immune battlefields, with a supportive ‘metabolic oasis’—a concept proposed in this review—at the invasive front and a deeply immunosuppressive core. Thus, lactate acts as an epigenetic and signaling hub that bridges oncogenic mutations, metabolic competition and immune evasion. Targeting lactate metabolism through LDHA or MCT4 inhibition, modulation of histone lactylation, or disruption of lactate-lipid crosstalk, when combined with classical immune checkpoint blockade and guided by spatial biomarkers, offers a promising strategy to overcome immunotherapy resistance in this challenging subtype. Full article

Differentiated thyroid carcinoma is a morphologic diagnosis, not a direct measure of preserved thyroid function. Although most papillary, follicular, and oncocytic thyroid carcinomas retain architectural or cytologic features of follicular-cell derivation, a clinically important subset loses the molecular machinery required for effective iodine transport, organification, and radioiodine therapy. This functional divergence is central to the biology of radioiodine-indifferent and radioiodine-refractory thyroid cancer. This review examines the role of oncogenic MAPK/ERK signaling as a principal regulator of thyroid lineage suppression and therapeutic failure. Aberrant activation of the RAF–MEK–ERK axis, most prominently through BRAF^V600E, RAS alterations, and receptor tyrosine kinase fusions, does more than promote proliferation. It reshapes follicular-cell identity by repressing thyroid-lineage transcriptional programs and silencing iodine-handling genes, including SLC5A5/NIS, TPO, TG, TSHR, SLC26A4, and related components of the iodine metabolic transcriptome. This repression is mediated through coordinated transcriptional, epigenetic, and post-transcriptional mechanisms involving lineage transcription factors such as PAX8, NKX2-1, and FOXE1; chromatin-modifying programs including histone deacetylation and PRC2/EZH2-associated repression; DNA methylation; and non-coding RNA networks. Importantly, ERK-driven functional dedifferentiation is not always a fixed terminal state. Preclinical models and early clinical trials demonstrate that pharmacologic inhibition of the MAPK pathway can restore iodine avidity in selected radioiodine-refractory tumors, creating the theranostic basis for redifferentiation therapy. Iodine-124 PET/CT and lesion-level dosimetry have shown that restored iodine uptake can be measured diagnostically and then exploited therapeutically with iodine-131. However, clinical translation remains limited by inter- and intratumoral heterogeneity, incomplete durability of response, adaptive pathway reactivation, persistent epigenetic repression, tumor microenvironmental influences, and the absence of standardized dosimetric thresholds. We propose that advanced follicular-cell-derived thyroid cancers should be understood along a functional differentiation continuum rather than through morphology alone. Within this framework, radioiodine refractoriness reflects not merely treatment failure, but a therapeutically interrogable state of lineage suppression. Refinement of redifferentiation therapy will require genotype-informed patient selection, functional imaging, standardized dosimetry, rational combination strategies, and prospective trials capable of distinguishing true restoration of radioiodine therapeutic efficacy from the antiproliferative effects of kinase inhibition alone. Full article

Kaempferol, a naturally occurring dietary flavonoid abundantly found in various fruits and vegetables, has garnered significant attention due to its diverse pharmacological properties, most notably its potent anticancer activity. In the orchestration of cancer pathogenesis, the PTEN/PI3K/AKT/mTOR signaling cascade plays a pivotal role, where aberrant activation or dysregulation of this pathway drastically accelerates tumor cell proliferation, survival, and metabolic reprogramming, thereby driving tumorigenesis. Moreover, non-coding microRNAs (miRNAs) have emerged as key modulators involved in regulating this pathway, functioning as either oncogenes or tumor suppressors to determine cancer cell fate. Previous studies have demonstrated that kaempferol and its derivatives, owing to their molecular structures, suppress the PI3K/AKT/mTOR signaling pathway either directly or indirectly, thereby playing a critical role in inhibiting cancer cell proliferation. Hence, this comprehensive review elucidates the therapeutic potential of kaempferol and its derivatives, focusing specifically on their molecular mechanisms in modulating the PTEN/PI3K/AKT/mTOR pathway. Furthermore, this review highlights the crosstalk between kaempferol and the specific miRNAs targeting these signaling components in various cancer types. Full article

Cellular senescence is one of the major risk factors for the onset and progression of chronic pulmonary diseases. Cellular senescence can be induced by diverse stressors, including genotoxic damage, oncogenic signaling, and therapeutic interventions. These senescent cells communicate via the release of multiple inflammatory molecules known as the Senescence-Associated Secretory Phenotype (SASP), which induces persistent low-grade inflammation and contributes to various chronic inflammatory lung diseases. This review summarizes the basic concepts of cell senescence, its hallmarks, SASP, and the mechanisms of cell senescence in the lung, and its consequences in the development and progression of chronic pulmonary diseases. Current therapeutic strategies include senolytics (e.g., BCL-2 family inhibitors and dasatinib–quercetin) and senomorphics that suppress SASP activity. Future directions in the development of cell- and stage-specific therapies are critical for targeting age-related lung disease with desired outcomes. Full article

Apoptosis is traditionally considered a definitive barrier against oncogenesis, as caspase activation typically eliminates damaged and genetically unstable cells. Here, we report that caspase-8, an initiator of extrinsic apoptosis, paradoxically promotes genetic instability and carcinogenesis following exposure to radiation. We observed that a substantial fraction of mammalian cells exposed to ionizing radiation can survive despite caspase-8 activation. This sublethal activation of caspase-8 facilitated persistent DNA damage, which was attenuated by the expression of a dominant-negative caspase-8 (C360A, Casp8DN) or short hairpin RNA (shRNA)-mediated knockdown of caspase-8 in mammalian cells. The facilitative role of caspase-8 in radiation-induced genomic instability was further validated in caspase-8 heterozygous mice. Moreover, inhibition of caspase-8 abolished iron-ion radiation-induced oncogenic transformation in both soft agar and nude mice. Mechanistically, sublethal caspase-8 activation promoted the nuclear translocation of mitochondrial endonuclease G and persistent DNA damage, accompanied by activation of non-canonical nuclear factor κB (NF-κB) signaling. Collectively, our findings demonstrate that caspase-8 can act as a causative driver of radiation-induced malignancy, challenging the dogma of caspases as universal anticancer barriers and providing important insights into the long-term health risks associated with space radiation and radiotherapy. Full article

Background/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare, highly aggressive form of pediatric myelodysplastic/myeloproliferative neoplasm characterized by molecular heterogeneity and constitutive activation of the RAS signaling pathway. This study aimed to characterize the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic potential of mutated epigenetic regulator genes in JMML. Methods: Tumor and matched buccal swab samples were collected from 35 JMML patients, and whole-exome sequencing was performed. Somatic variants were called with GATK-Mutect2 and annotated with ANNOVAR. maftools and OncodriveCLUST were used for mutational profiling, co-occurrence analysis, driver gene identification, and protein domain mapping. Drug–gene interactions were explored using DGIdb, mutational signatures for genes were characterized by MutationalPatterns, and functional enrichment analysis was performed by the clusterProfiler package. Results: A total of 28 variants were detected in epigenetic regulator genes, with missense mutations being the most common class of variants and a C>T nucleotide substitution pattern being the most frequent. EP300, SETD2, and DNMT3B were the genes most frequently altered, with 8.57% of cases each, followed by ASXL1, BCORL1, ATRX, KMT2A, and TET2 (5.71% each). Driver gene analysis identified ASXL1 as the top candidate driver gene, followed by BCORL1, EP300, and SETD2. Functional enrichment analysis revealed a high number of genes involved in chromatin organization, histone modification, transcriptional regulation, and oncogenic signaling pathways. The mutational signatures identified were SBS5-like, which are dominated by C>T and T>C transitions, indicating endogenous mutational processes. Analysis of drug–gene interactions revealed KMT2A, EP300, and ATRX as the most interconnected and potentially actionable therapeutic targets. Conclusions: This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis. Full article