Search Results (494)

Tumor-associated glycosylation is a defining hallmark of cancer, exerting profound effects on multiple aspects of tumor biology. This phenomenon arises from the central role of glycosylation in a wide range of cellular processes and its inherently diverse structural complexity. In cancer cells, aberrant glycosylation often results in the modification of glycoconjugate structures, leading to alterations in cell surface architecture that disrupt cellular homeostasis and signaling pathways. These changes can enhance tumor cell proliferation, invasion, and metastasis by modulating cell adhesion, receptor activation, and intracellular communication. Beyond its direct impact on cancer cells, tumor-associated glycosylation plays a pivotal role in shaping the tumor microenvironment. Aberrant glycan structures influence immune cell infiltration by altering antigen presentation and immune checkpoint interactions, contributing to immune evasion. Additionally, these modifications regulate angiogenesis by affecting endothelial cell function and promoting the formation of aberrant vasculature, which supports tumor growth and metastasis. Glycosylation also mediates tumor–stroma interactions, influencing extracellular matrix remodeling and fibroblast activation, further enhancing cancer progression. This interplay between cancer-associated glycan modifications and their functional roles in tumorigenesis presents a promising therapeutic approach. Unlike conventional treatments, glycan-targeting therapies confer high tumor specificity, operate independently of canonical immune checkpoint targets, and help mitigate immune cell exhaustion. This review explores commonly dysregulated glycan motifs implicated in tumorigenesis and delves into their mechanistic contributions to cancer pathogenesis. We then highlight emerging opportunities for therapeutic intervention, including the development of glycan-targeted therapies and biomarker-driven strategies for cancer diagnosis and treatment. We also outline where glycan-targeted agents (e.g., desialylating biologics, glycomimetics, and anti-glycan mAbs) can complement checkpoint blockade and potentially overcome immune escape. Full article

Ovarian cancer is the deadliest gynecologic cancer, mainly because it is often diagnosed late and resists standard treatments. The tumor microenvironment (TME) plays a major role in disease progression and therapy failure. Two key components of the TME, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), create conditions that facilitate tumor growth and immune evasion. CAFs are highly diverse and originate from sources like fibroblasts and stem cells. They support cancer by remodeling the extracellular matrix, promoting angiogenesis, and releasing cytokines and growth factors that aid tumor survival. TAMs, which are usually in an M2 state, also promote metastasis and suppress immune responses by secreting immunosuppressive molecules. Together, CAFs and TAMs interact with cancer cells to activate pathways such as the TGF-β, IL-6, and PI3K/AKT pathways, which drive resistance to therapy. New treatments aim to block these interactions by targeting CAFs and TAMs through depletion, reprogramming, or pathway inhibition, often combined with immunotherapy. Advances such as single-cell sequencing and spatial transcriptomics now enable more precise identification of CAF and TAM subtypes, enabling more targeted therapies. This review summarizes their roles in epithelial ovarian cancer and explores how targeting these cells could improve outcomes. Full article

Background: Triple-negative breast cancer (TNBC) is more likely to metastasise to the lungs than other breast cancer (BrCa) types, yet the molecular interactions within the tumour microenvironment (TME) at secondary sites remain poorly understood. Methods: This pilot study aimed to explore the metabolic crosstalk between MDA-MB-231 TNBC cells and MRC-5 lung fibroblasts within a co-culture system to replicate the lung metastatic TME. Co-cultures were also treated with Vitamin D or Vitamin E to evaluate the effects of these nutraceuticals on the metabolic crosstalk between TNBC cells and fibroblasts. Results: Our findings demonstrate that co-culture induced the activation of fibroblasts into cancer-associated fibroblasts (CAFs), evidenced by increased α-SMA and FAP expression. Metabolic profiling revealed that TNBC cells in co-culture displayed increased expression of enzymes associated with oxidative phosphorylation (OXPHOS) and glutamine metabolism, while fibroblasts exhibited a metabolic profile consistent with glycolysis and lactate metabolism. Vitamin D inhibited lactate metabolism and HIF-1α expression in fibroblasts while suppressing TCA cycle activity in cancer cells, suggesting a potential role in disrupting oncogenic metabolic crosstalk. Conversely, Vitamin E treatment was associated with increased expression of TCA cycle and oxidative metabolism-related markers in BrCa cells without significantly affecting fibroblast glycolysis. Such differential metabolic responses may contribute to metabolic heterogeneity within the tumour microenvironment. Conclusions: These results provide valuable insights into the metabolic dynamics of TNBC metastases in the lung TME and demonstrate that Vitamins D and E exert distinct effects on metabolic crosstalk between cancer cells and fibroblasts. These findings may have significant implications for the potential supplementation of Vitamins D and E in patients with metastatic TNBC and justify further in-depth analysis. Full article

Background/Objectives: Cancer-associated fibroblasts (CAFs) are key stromal mediators of breast tumor progression and therapy resistance. Carvacrol, a dietary monoterpenic phenol, exhibits antiproliferative activity in cancer cells, but its effects on primary human breast CAFs remain unclear. This study aimed to determine whether carvacrol selectively induces mitochondria-related apoptotic signaling in breast CAFs while sparing normal fibroblasts (NFs). Methods: Primary fibroblast cultures were established from invasive ductal carcinoma tissues (CAFs, n = 9) and nonmalignant breast tissues (NFs, n = 5) and validated by α-SMA and FAP immunofluorescence. Cells were exposed to 400 μM carvacrol. Apoptosis was assessed by TUNEL assay and BAX/BCL-XL Western blotting. Changes in signaling pathways were evaluated by analyzing PPARα/NF-κB, sirtuin (SIRT1, SIRT3), autophagy-related markers (LAMP2A, p62), and matrix metalloproteinases (MMP-2, MMP-3). In silico molecular docking and 100-ns molecular dynamics simulations were performed to examine interactions between carvacrol and caspase-3 and caspase-9. Results: Carvacrol induced a pronounced, time-dependent apoptotic response in CAFs, with TUNEL-based viability declining to approximately 10% of control levels by 12 h and a marked increase in the BAX/BCL-XL ratio. In contrast, NFs exhibited minimal TUNEL positivity and no significant change in BAX/BCL-XL. In CAFs, but not NFs, carvacrol reduced PPARα expression and NF-κB nuclear localization, increased SIRT1 and SIRT3 levels, selectively suppressed MMP-3 while partially normalizing MMP-2, and altered autophagy-related markers (decreased LAMP2A and accumulation of p62), consistent with autophagic stress and possible impairment of autophagic flux. Computational analyses revealed stable carvacrol binding to caspase-3 and caspase-9 with modest stabilization of active-site loops, supporting caspase-dependent, mitochondria-related apoptosis. Conclusions: Carvacrol selectively targets breast cancer-associated fibroblasts by inducing mitochondria-related apoptotic signaling while largely sparing normal fibroblasts. This effect is accompanied by coordinated modulation of PPARα/NF-κB, sirtuin, autophagy, and MMP pathways. These findings support further evaluation of carvacrol as a microenvironment-directed adjunct in breast cancer therapy. Full article

Background/Objectives: Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer (NSCLC), is frequently diagnosed at advanced stages with distant metastasis, underscoring the need for effective prognostic biomarkers. Fibroblast growth factor 2 (FGF2), a multifunctional regulator, has shown to play contradictory roles in cancer progression. Methods: We analyzed three independent Gene Expression Omnibus (GEO) datasets (GSE19804, GSE18842, and GSE19188) to identify consistently dysregulated genes in LUAD. Functional enrichment (GO, KEGG, and cancer hallmark analysis), protein–protein interaction (PPI) network construction, and hub gene prioritization were performed using public bioinformatic tools. Survival analyses were conducted via the Kaplan–Meier Plotter. The expression of FGF2 was validated across multiple platforms, including TCGA, CPTAC, TNMplot, LCE, and the Human Protein Atlas. Functional assays (Transwell migration and wound healing) demonstrated that exogenous FGF2 significantly suppressed LUAD cell motility in vitro. Results: A total of 949 differentially expressed genes (DEGs) were commonly identified across datasets, with enrichment in cell adhesion and metastasis-related pathways. Among the 11 hub genes identified, FGF2 was consistently downregulated in LUAD tissues across all datasets and stages. Higher FGF2 expression was associated with longer overall and progression-free survival. In vitro, FGF2 treatment significantly suppressed the migration and wound healing abilities of LUAD cell lines. Conclusions: FGF2 is downregulated in LUAD and inversely associated with metastatic progression and poor prognosis. The observed reduction in cancer cell motility upon FGF2 treatment in vitro, together with its expression pattern, supports a potential tumor-suppressive role and suggests that FGF2 may serve as a candidate non-invasive biomarker for monitoring LUAD metastasis. Full article

Schiff bases are widely studied for their biological activities, yet structure–activity relationships governing their anticancer potential remain insufficiently understood. In this work, eight structurally diverse imine derivatives (A–H) were evaluated for their cytotoxic, biochemical, and biomolecular interactions in human cancer cells. Their antiproliferative effects were assessed in HeLa, A549, and LS174T cell lines, with MRC-5 fibroblasts used as a non-malignant control. Cytotoxicity screening identified three compounds (A, B, and F) with the highest potency, prompting further mechanistic investigation. Cell cycle analysis revealed G1 arrest and accumulation of sub-G1 populations for all three derivatives, with compound B additionally increasing S-phase content and compound F inducing G2/M arrest. All compounds reduced intracellular ROS levels and caused significant DNA damage at subtoxic concentrations. Western blot analysis demonstrated downregulation of HIF-1α and PDK3, suggesting disruption of hypoxia-associated metabolic signaling. Fluorescence quenching experiments showed strong binding of the active compounds to bovine serum albumin (K_a ≈ 10⁶ M⁻¹), and molecular docking supported stable interactions near tryptophan-adjacent binding regions. Collectively, these findings indicate that selected Schiff bases exert multi-target anticancer activity by modulating oxidative stress, DNA integrity, cell-cycle progression, and metabolic adaptation pathways, warranting further investigation of their therapeutic potential. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) exhibits high immune infiltration yet remains clinically aggressive. Although immune checkpoint blockade benefits a subset of patients, the molecular programs enabling concurrent immune activation and immune evasion in TNBC are not fully defined. This study aimed to identify TNBC-specific tumor-intrinsic and tumor-extrinsic molecular features that may explain this paradox. Methods: Publicly available single-cell RNA-sequencing data from primary breast tumors were analyzed to characterize subtype-specific transcriptional programs across epithelial and stromal compartments. Tumor-intrinsic findings were independently validated using bulk transcriptomic and clinical data from the METABRIC cohort. Tumor microenvironment remodeling was evaluated using multiplexed tissue imaging of TNBC tumors. Functional analyses were done included Gene Ontology enrichment, Hallmark gene set enrichment analysis, and SERPINB3-centered protein–protein interaction network analysis using STRING. Results: Single-cell analysis identified SERPINB3 as a TNBC-enriched epithelial gene relative to ER+ and HER2+ tumors. This subtype-restricted pattern was validated in the METABRIC cohort and associated with pathways related to epithelial–mesenchymal transition, interferon signaling, and antigen presentation. TNBC tumors also displayed a humoral immune signature characterized by B-cell and plasmablast enrichment, as well as ectopic immunoglobulin gene expression in cancer-associated fibroblasts, endothelial cells, and myeloid populations. Multiplex imaging revealed coordinated associations between immune suppression, stromal activation, and tumor proliferation. Network analysis placed SERPINB3 within interconnected immune-regulatory and stromal signaling modules. Conclusions: Together, these data indicate that TNBC exhibits co-existing immune activation and immune-suppressive features. The identified epithelial and stromal signatures represent candidate biomarkers that may inform future studies of immune regulation and therapeutic stratification in TNBC. Full article

Background: Hypoxia-inducible factor-1α (HIF-1α) is a well-known transcriptional regulator that mediates a broad spectrum of cellular responses to hypoxia, including angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. These activities can be achieved by upregulation of numerous genes, such as vascular endothelial growth factors, fibroblast growth factors, and platelet-derived growth factors, which are involved in the growth regulation of normal tissues and solid tumors. Notably, HIF-1α-mediated regulation of the solid tumor’s microenvironment effectively modulates tumor sensitivity to anticancer therapies and thereby can contribute to disease progression. Methods: The study was performed on breast, lung and prostate cancer cell lines. Protein expression was examined by western blotting. Antitumor activity of 2-ANPC was measured by syngeneic 4T1 breast cancer mouse model. Results: We show here that a 2-aminopyrrole derivative (2-amino-1-benzamido-5-(2-(naphthalene-2-yl)-2-oxoethylidene)-4-oxo-4,5-dihydro-1-H-pyrrole-3-carboxamide—2-ANPC), previously shown as a potent microtubule-targeting agent, effectively downregulates HIF-1α expression in a broad spectrum of cancer cell lines, including breast, lung, and prostate cancer. The downregulation of HIF-1α expression in 2-ANPC-treated cancer cells was due to enhanced proteasome-mediated degradation, whereas the proteasome inhibitor MG-132 effectively reversed this downregulation. 2-ANPC’s potency in downregulating HIF-1α was also shown in vivo by using the 4T1 breast cancer syngraft model. Importantly, this 2-aminopyrrole derivative also downregulated the expression of vascular endothelial growth factor receptors 1 and 3 (VEGFR1 and 3) in 4T1 tumors, which correlated with decreased tumor weight and size. As expected, an increase in apoptotic (i.e., cleaved caspase-3-positive) cells was detected in 4T1 tumors treated with 2-aminopyrrole derivative. Lastly, using various computational tools, we identified four potential binding sites for 2-ANPC to interact with HIF-1α, HIF-1β, and the p300 complex. Conclusions: Collectively, we show here, for the first time, that HIF-1α is a novel molecular target for the 2-aminopyrrole derivative (2-ANPC), thereby illustrating it as a potential scaffold for the development of potent chemotherapeutic agents with anti-angiogenic activity. Full article

The tumor microenvironment (TME) plays an important role in the development, progression, and treatment response of pediatric cancers, yet remains less elucidated compared to adult malignancies. Pediatric tumors are unique with a low mutational burden, an immature immune landscape, and unique stromal interactions. The resultant “cold” immune microenvironments limits the effectiveness of conventional immunotherapies. This review summarizes the key cellular and non-cellular components of the pediatric TME—including T cells, NK cells, tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix remodeling, angiogenesis, and hypoxia—and describes how these elements shape tumor behavior and therapy resistance. The role of TME in common pediatric cancers like leukemia, lymphoma, neuroblastoma, brain tumors, renal tumors, and sarcomas is discussed. Emerging therapeutic strategies targeting immune checkpoints, macrophage polarization, angiogenic pathways, and stromal barriers are discussed. Full article

DNA damage resulting from oxidative stress plays a major role in cancer formation. Despite DNA damage, the inability of cells to enter apoptosis due to irregularities in apoptotic protein levels and the induction of their proliferation as a result of the increase in polyamine levels causes the development and progression of cancer. The anticancer effects of Rhus coriaria L. extracts on lung cancer, colon cancer and fibroblast cell lines were determined by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). Total antioxidant status (TAS) was analyzed with a commercial kit. The expression levels of genes related to apoptosis and the polyamine pathway in lung and colon cancer cell lines were analyzed by a Real-time Polymerase Chain Reaction (RT-PCR) device. Rhus coriaria L. extracts were found to have anticancer effects selectively on A549 and HT-29 cancer lines. It has also been shown that Rhus coriaria L. extracts have strong antioxidant capacity and can inhibit the Xanthine Oxidase (XO) enzyme in a dose-dependent manner. Afterwards, the interactions of the molecules in extracts of Rhus coriaria L. against various proteins such as colon cancer protein (PDB ID: 3DTC and 4UYA) lung cancer protein (PDB ID: 4ZXT and 5ZMA) were examined, and their activities were compared. MM/GBSA methods of the molecule with the best docking score are calculated as binding free energy. Full article

Background: Malignant ovarian tumours are most often detected at an advanced stage, when peritoneal dissemination across abdominal organs is already present. Metastasis in ovarian cancer arises from complex interactions between cancer cells and diverse components of the tumour microenvironment (TME), including extracellular matrix elements, fibroblasts, adipocytes, mesenchymal cells and leukocytes. This dynamic niche drives tumour progression, invasiveness and immunosuppression through cytokine- and chemokine-mediated signalling. A deeper understanding of these interactions may enable targeted modulation of the TME and help limit metastatic spread. Methods: In this study, using immunoenzymatic assays and a computational digital twin—a mechanistic, ODE-based in silico model that replicates key cellular and microenvironmental processes—we investigated whether and how caffeic acid phenethyl ester (CAPE) influences TME activation, cytokine and growth factor levels, and extracellular matrix remodelling. Results: Our findings show that CAPE modulates both pro- and antitumourigenic signalling pathways across immune, stromal and hypoxia-related axes, suggesting its potential to reshape the ovarian cancer microenvironment and improve therapeutic outcomes in this challenging malignancy. Conclusions: Taken together, these results indicate that CAPE may serve as a multifaceted modulator capable of simultaneously targeting tumour cells and their microenvironment, offering a promising avenue for enhancing therapeutic strategies in ovarian cancer. Full article

Understanding how genetic risk variants contribute to respiratory diseases requires mapping genome-wide association study (GWAS) signals to disease-relevant cell types and states within the human lung. Here, we integrated GWAS summary statistics for ten major respiratory diseases, including asthma, COPD, idiopathic pulmonary fibrosis (IPF), COVID-19, and lung cancer, using a large-scale single-cell transcriptomic dataset of more than 523,000 cells from the Human Lung Cell Atlas. Applying the single-cell Disease Relevance Score (scDRS) framework, we systematically identified shared and disease-specific cellular associations across four major compartments, namely epithelial, immune, endothelial, and stromal. We found that alveolar type II (AT2) cells represent a central susceptibility hub for asthma, COPD, and COVID-19, whereas disease-specific risk enrichment was observed in subpopulations such as CCL3⁺ alveolar macrophages in COVID-19 and adventitial fibroblasts in asthma. Importantly, subclustering revealed substantial heterogeneity within cell types, with distinct transcriptional programs underlying differential disease associations. For example, AT2 subclusters exhibited divergent susceptibility patterns to asthma versus COVID-19, reflecting immune-interacting versus antiviral states. Our results provide a systematic single-cell framework for linking genetic risk to the cellular architecture of the human lung and uncover both shared and disease-specific mechanisms underlying respiratory disease susceptibility. Full article

Single-cell sequencing (scRNA-seq) has emerged as a pivotal technology for deciphering the complex cellular heterogeneity and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), positioning it as a critical tool for informing novel therapeutic strategies. This review explores how scRNA-seq reveals diverse cellular subpopulations and their functional roles within the PDAC TME, including malignant epithelial cells with transitional phenotypes, heterogeneous cancer-associated fibroblasts (CAFs), functionally distinct immune cells such as tumor-associated neutrophils (TANs) and macrophages (TAMs), and actively participating neural components like Schwann cells. These cellular constituents form specialized functional units that drive tumor progression, immune evasion, neural invasion, and therapy resistance through metabolic reprogramming, immunosuppressive signaling, and cellular plasticity. The review further examines technological advances in single-cell sequencing from 2023 to 2025, focusing on sample preprocessing innovations, multi-omics integration (combining transcriptomics with epigenomics and proteomics), spatial resolution enhancements, and customized computational tools that address PDAC-specific challenges. Clinically, single-cell sequencing enables precise cellular subtyping, identification of novel biomarkers, and development of personalized therapeutic approaches, including combination therapies targeting specific cellular subpopulations and their interactions. Despite these advances, significant challenges remain in standardizing clinical applications such as liquid biopsy for early detection and tumor microenvironment assessment for diagnostic staging, validating biomarkers like CLIC4, GAS2L1, Cytokeratins, Vimentin and N-cadherin in circulating tumor cells, and comprehensively integrating multi-omics data. Future research focusing on both technology refinement and biological validation will be essential for translating single-cell insights into improved diagnostic and therapeutic outcomes for pancreatic cancer. Full article

Renal cell carcinoma (RCC) features a complex tumor microenvironment, where cancer-associated fibroblasts (CAFs) play key roles in tumor progression, epithelial–mesenchymal transition (EMT), immune evasion, and resistance to treatment. This article updates our understanding of CAF origins, diversity, and functions in RCC, incorporating recent single-cell RNA sequencing (scRNA-seq) data that refine CAF subtypes. The paper explores the mechanistic interactions between CAFs and EMT, focusing on CAF-derived signaling pathways like TGF-β, IL-6/STAT3, HGF/c-MET, and Wnt/β-catenin, as well as extracellular-vesicle-mediated transfer of miRNAs and lncRNAs that promote metastatic behavior in RCC. It also addresses how CAF-driven remodeling of the extracellular matrix, metabolic changes, and activation of YAP/TAZ contribute to invasion and resistance to therapies, particularly in relation to tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint blockade. The review highlights emerging therapeutic strategies targeting CAFs, such as inhibiting specific signaling pathways, disrupting CAF–tumor cell communication, and selectively depleting CAFs. In conclusion, it identifies limitations in current CAF classification systems and proposes future research avenues to improve RCC-specific CAF profiling and exploit the CAF–EMT axis for therapeutic gain. Full article

Pancreatic cancer is characterized by an extensive fibrotic stroma largely driven by activated pancreatic stellate cells (PSCs)/fibroblasts, which also function to support tumor growth and metastasis. Cholecystokinin-B receptors (CCK-BRs) are expressed on pancreatic stellate cells (PSCs) and have emerged as a key regulator of PSC activation and tumor-stromal interactions. We hypothesized that disrupting CCK-BR function shifts PSCs to a more quiescent phenotype and reduces their pro-fibrotic and tumor-supportive activity to decrease growth of pancreatic cancer. Murine PSCs were genetically engineered with CRISPR-Cas9 to knockout the CCK-BR. In a series of experiments, the role of the CCK-BR expression was evaluated on cell migration, proliferation, differentially expressed genes, molecular signaling pathways, and in co-culture with murine pancreatic cancer epithelial cells. Next, primary human pancreatic stellate cells were treated with proglumide, a CCK-BR antagonist, to study the effects of pharmacologic blockade of the CCK-BR on cellular signaling and proliferative pathways by RNA sequencing. Knockout of the CCK-BR led to significant decreases in PSC activation and the ability to stimulate growth of pancreatic cancer cells in co-culture. Both genetic knockdown and pharmacologic blockade of the CCK-BR downregulated genes implicated in fibrosis, proliferation, fibroblast activation, and tumorigenesis, while genes implicated in apoptosis and tumor suppression were upregulated. Flow cytometry showed increased apoptosis markers in CCK-BR-knockout cells compared to controls. These experiments combine transcriptomic profiling with functional validation to provide a comprehensive analysis of how targeting CCK-BR interrupts the cross-communication between cancer cells and fibroblasts. Blockade or downregulation of the CCK-BR on pancreatic fibroblasts may provide a strategy to disrupt oncogenic signaling pathways and reprogram the tumor microenvironment. Full article