Search Results (1,269)

In the tumor microenvironment, various immune and stromal cells, such as fibroblasts and vascular endothelial cells, contribute to tumor growth and progression by interacting with cancer cells. Tumor-associated macrophages (TAMs) have attracted attention as major players in the tumor microenvironment. The origin of TAMs is believed to be the infiltration of monocytes derived from bone marrow progenitor cells into tumor tissues and their differentiation into macrophages, whereas tissue-resident macrophages derived from yolk sacs have recently been reported. TAMs infiltrating tumor tissues act in a tumor-promoting manner through immunosuppression, angiogenesis, and the promotion of cancer cell invasion. Reflecting the nature of TAMs, increased TAM invasion and TAM-specific gene expression in tumor tissues may be the new biomarkers for cancer. Moreover, new therapeutic strategies targeting TAMs, such as transformation into immunostimulatory macrophages, suppression of TAM infiltration, and promotion of phagocytosis, are being investigated, and many clinical trials are underway. As the origin and function of TAMs are further elucidated, TAM-targeted therapy is expected to become a new option for the immunotherapy of various cancers, including oral cancers. Full article

Repeated UV exposure, air pollution, and toxins promote skin oxidative stress. ROS destroy macromolecules, changing cellular mechanisms and signaling cascades. Inflammation and injury to skin cells degrade function and accelerate aging, causing wrinkles, firmness loss, and dermatological disorders. Gymnema inodorum (GI) contains phytochemical antioxidants such polyphenols and triterpenoids that lower ROS and strengthen skin. GI extracts (GIEs) have never been examined for their effects on dermal skin fibroblasts’ oxidative stress and intracellular cytoprotective mechanisms. In this study, GIEs were prepared as a water extract (GIE0) and ethanol extracts with concentrations ranging from 20% to 95% v/v (GIE20, GIE40, GIE60, GIE80, and GIE95). These extracts were assessed for phytochemical content, antioxidant capacity, and free radical scavenging efficacy. The results were compared to a commercially available native Gymnema extract (NGE) obtained from Gymnema sylvestre. During principal component analysis (PCA), the most effective extracts were identified and subsequently evaluated for their ability to mitigate oxidative stress in fibroblasts. Cytoprotective effects of GIE and NGE against H₂O₂-induced human dermal fibroblast injury were investigated by cell viability, intracellular ROS production, and signaling pathways. GIE0, GIE80, GIE95, and NGE were the best antioxidants. By preserving ROS balance and redox homeostasis, GIE and NGE reduce fibroblast inflammation and oxidative stress-induced damage. Decreased ROS levels reduce MAPK/AP-1/NF-κB and PI3K/AKT/NF-κB signaling pathways, diminishing inflammatory cytokines. In conclusion, GIE and NGE have antioxidant and anti-inflammatory capabilities that can reduce H₂O₂-induced fibroblast oxidative stress and damage, thereby preventing skin aging and targeting cancer-associated fibroblasts. Full article

Objective: This study aims to identify clinically relevant lactylation-related biomarkers in chronic obstructive pulmonary disease (COPD) and investigate their potential mechanistic roles in COPD pathogenesis. Methods: Differentially expressed genes (DEGs) were identified from the GSE21359 dataset, followed by weighted gene co-expression network analysis (WGCNA) to detect COPD-associated modules. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine–recursive feature elimination (SVM–RFE) algorithms were applied to screen lactylation-related biomarkers, with diagnostic performance evaluated through the ROC curve. Candidates were validated in the GSE76925 dataset for expression and diagnostic robustness. Immune cell infiltration patterns were exhibited using EPIC deconvolution. Single-cell transcriptomics (from GSE173896) were processed via the ‘Seurat’ package encompassing quality control, dimensionality reduction, and cell type annotation. Cell-type-specific markers and intercellular communication networks were delineated using the ‘FindAllMarkers’ package and the ‘CellChat’ R package, respectively. In vitro validation was conducted using a cigarette smoke extract (CSE)-induced COPD model. Results: Integrated transcriptomic approaches and multi-algorithm screening (LASSO/Boruta/SVM–RFE) revealed carbonyl reductase 1 (CBR1) and peroxiredoxin 1 (PRDX1) as core COPD biomarkers enriched in oxidation–reduction and inflammatory pathways, with high diagnostic accuracy (AUC > 0.85). Immune profiling and scRNA-seq delineated macrophage and cancer-associated fibroblasts (CAFs) infiltration with oxidative-redox transcriptional dominance in COPD. CBR1 was significantly upregulated in T cells, neutrophils, and mast cells; and PRDX1 showed significant upregulation in endothelial, macrophage, and ciliated cells. Experimental validation in CSE-induced models confirmed significant upregulation of both biomarkers via transcription PCR (qRT-PCR) and immunofluorescence. Conclusions: CBR1 and PRDX1 are lactylation-associated diagnostic markers, with lactylation-driven redox imbalance implicated in COPD progression. Full article

Since cancer is often linked to the aging process, the importance of cellular senescence in cancer has come under the spotlight. While senescence in cancer cells can serve as a natural barrier against cancer due to its proliferation arrest, its secretory phenotypes and alterations in the surface proteome can paradoxically promote or suppress tumor progression. Senescent cancer-associated fibroblasts, endothelial cells, and immune cells can also contribute to cancer promotion. During therapeutic interventions for cancer, not only their therapeutic effects, but also therapy-induced senescence may have an impact on cancer outcomes. Senotherapeutics, therapy targeting senescent cells, have been reported as novel cancer therapy in recent studies, and the combination of senescence induction and senotherapeutics has been increasingly recognized. Although some clinical trials of senotherapeutic drugs for cancer with or without senescence-inducible therapy are ongoing, there is as yet no satisfactory clinical application. With further research into targeting senescence in oncology, it is expected that senotherapeutics, particularly in combination with senescence-inducing therapy, will become a novel therapeutic strategy. Full article

The tumor microenvironment (TME) has a substantial impact on the progression of gastric cancer. Collagen, the most abundant protein in the extracellular matrix (ECM), forms a dense physical barrier that regulates anti-tumor immunity in the TME. It is a significant regulator of the signaling pathways of cancer cells, which are responsible for migration, proliferation, and metabolism. ECM proteins, particularly remodeling enzymes and collagens, can be modified to increase stiffness and alter the mechanical properties of the stroma. This, in turn, increases the invasive potential of tumor cells and resistance to immunotherapy. Given the dynamic nature of collagen, novel therapeutic strategies have emerged that target both collagen biosynthesis and degradation, processes that are essential for addressing ECM stiffening. This review delineates the upregulation of the expression and deposition of collagen, as well as the biological functions, assembly, and reorganization that contribute to the dissemination of this aggressive malignancy. Furthermore, the review emphasizes the importance of creating 3D in vitro models that incorporate innovative biomaterials that avoid the difficulties of traditional 2D culture in accurately simulating real-world conditions that effectively replicate the distinctive collagen microenvironment. Ultimately, it investigates the use of decellularized ECM-derived biomaterials as tumor models that are designed to precisely replicate the mechanisms associated with the progression of stomach cancer. Full article

The Tumour Microenvironment (TME) is pivotal for melanoma progression and contributes to therapy resistance. While dermal cell involvement is well established, the role of epidermal cells remains less defined. To explore the contribution of Normal Human Keratinocytes (NHKs) to melanoma biology, we investigated the modification of gene and protein expression of NHKs exposed to melanoma-conditioned medium or maintained in a co-culture system. The analysis focused on pathways related to proliferation, inflammation, Extracellular Matrix (ECM) remodelling, and cell adhesion. Due to the well-documented melanoma–fibroblast crosstalk, Normal Human Fibroblasts (NHFs) and Cancer-Associated Fibroblasts (CAFs) were used as comparative references. Keratinocyte gene expression changes under the influence of melanoma secretome only partially overlapped with those of NHFs and CAFs, indicating cell-type-specific responses. Exposure to melanoma-conditioned medium induced the upregulation of bFGF, CXCL-16, TIMP-2, and E-cadherin in NHKs, alongside downregulating TGF-β and MMP-9. Although bFGF is a recognized pro-tumorigenic factor, the modulation of CXCL-16, TIMP-2, and TGF-β may reflect a protective response. Notably, under co-culture conditions, NHKs exhibited a pronounced pro-inflammatory and ECM-remodelling phenotype, characterized by elevated production of cytokines (IL-1α, IL-1β, and IL-8) and ECM-degrading enzymes (MMP-7, 9, 12, and 13), indicative of a pro-tumoral feature. Collectively, these findings underscore an active role for NHKs in melanoma initiation and progression. Full article

Cancer-associated fibroblasts (CAFs) restructure collagen hydrogels via actomyosin-driven fibril bundling and crosslinking, increasing polymer density to generate mechanical stress that accelerates tumor proliferation. Conventional hydrogel models lack spatial heterogeneity, thus obscuring how localized stiffness gradients regulate cell cycle progression. To address this, we developed a collagen hydrogel-based microtissue platform integrated with programmable microstrings (single/double tethering), enabling real-time quantification of gel densification mechanics and force transmission efficiency. Using this system combined with FUCCI cell cycle biosensors and molecular perturbations, we demonstrate that CAF-polarized contraction increases hydrogel stiffness (350 → 775 Pa) and reduces pore diameter (5.0 → 1.9 μm), activating YAP/TAZ nuclear translocation via collagen–integrin–actomyosin cascades. This drives a 2.4-fold proliferation increase and accelerates G1/S transition in breast cancer cells. Pharmacological inhibition of YAP (verteporfin), actomyosin (blebbistatin), or collagen disruption (collagenase) reversed mechanotransduction and proliferation. Partial rescue upon CYR61 knockdown revealed compensatory effector networks. Our work establishes CAF-remodeled hydrogels as biomechanical regulators of tumor growth and positions gel-based mechanotherapeutics as promising anti-cancer strategies. Full article

The areca nut (AN) is chewed by approximately 600 million people worldwide. Among AN chewers, ~5% develop oral submucosal fibrosis (OSF), a progressive fibrotic disorder of the oral cavity. OSF is characterized by subepithelial fibrosis and mucosal rigidity, leading to restricted mouth opening, difficulty in mastication, deglutition, and speech. These impairments severely compromise oral hygiene and routine dental care, diminishing patients’ quality of life. At least 4% of OSF patients develop oral cancer. The prevalence of OSF correlates with AN chewing, particularly when accompanied by other risk factors such as tobacco use. The International Agency for Research on Cancer has identified chronic chemical and mechanical irritation of the oral mucosa from AN chewing as a major cause of OSF. The active chemical ingredients of AN include alkaloids such as arecoline, flavonoids, and tannins. Of these, arecoline is considered the most potent fibrogenic agent. In vitro, arecoline induces cultured fibroblasts to differentiate into highly contractile α-smooth muscle actin (α-SMA)-expressing myofibroblasts, the effector cells of fibrosis, and to express profibrotic markers and mediators, including transforming growth factor-β 1 (TGF-β1) and cellular communication network factor 2 (CCN2), which is associated with malignant progression of OSF. In vivo, mice exposed to AN extract or arecoline show submucosal collagen accumulation and myofibroblast differentiation, concomitant with upregulated pro-fibrotic gene (TGF-β1, Col1A1, α-SMA) expression. Although myofibroblasts can be seen in OSF patient-derived samples, substantial disease heterogeneity exists, which has thus far hindered the generation of high-quality data necessary to gain insights into underlying mechanisms and disease progression. Consequently, treatment options for OSF are limited and primarily symptomatic. Collectively, evidence from human and animal studies establishes OSF as an AN-induced fibrotic disorder and underscores the urgent need for mechanism-focused research to identify reliable diagnostic markers and therapeutic targets to address its growing global burden. Full article

Cancer-associated fibroblasts (CAFs) constitute a heterogeneous population of cells within the tumor microenvironment and are associated with cancer development and drug resistance. The absence of a universal classification for CAFs hinders their research and therapeutic targeting. To define CAF phenotypes, we developed patient-derived cell cultures of breast cancer (BC) and validated and characterized four distinct CAF subtypes (S1–S4) by Costa’s classification. Three out of five primary cell cultures of BC demonstrated different functional features rather than fixed cellular states due to the plasticity of the CAF phenotype. CAF crosstalk with cancer cells supported their survival in the presence of anticancer drugs. Based on the analysis of the cytotoxic effect of doxorubicin, cisplatin and tamoxifen, it was demonstrated that CAF-S4 and CAF-S1 cells were sensitive to the action of all drugs investigated, despite the fact that they possessed different mechanisms of action. CAF-S2 cells exhibited the highest level of resistance to the antitumour agents. Homotypic and heterotypic spheroids with CAFs could be used to model the fibrotic area of BC in vitro. The patient-derived cell cultures of CAFs formed spheroids. Hypoxia-activated CAF-S4 have been shown to stimulate the metastatic potential of triple-negative BC cells in a heterotypic spheroid model. Consequently, this study could be a starting point for the development of novel therapeutic strategies that target CAFs and their interactions with cancer cells. Full article

Cancer has recently been proposed as a type of channelopathy due to the aberrant expression of various ion channels. Voltage-gated potassium (K⁺) channels (VGKCs) are notably upregulated during tumor proliferation, while voltage-gated sodium (Na⁺) channels are predominantly associated with the invasive stage of cancer progression. Among these, the Kv10.1 channel has been found to be overexpressed in breast cancer, making it a promising therapeutic target. 4-Aminopyridine (4-AP), a non-selective voltage-gated potassium channel blocker, has emerged as a potential novel agent for breast cancer treatment. In this study, we aimed to elucidate the mechanism of action of 4-aminopyridine in breast cancer cells. To investigate the involvement of various cell death pathways, cycloheximide (CHX) (a paraptosis inhibitor), Z-VAD-FMK (a pan-caspase inhibitor), and 2-Aminoethoxydiphenyl borate (2-APB) (a phosphoinositide 3-kinase [PI3K] inhibitor) were employed. Experiments were conducted using the MCF-7 human breast cancer cell line and the L929 mouse fibroblast cell line as a healthy control. Assessments included cell viability assays, intracellular calcium (Ca²⁺) and K⁺ concentration measurements, and plasma membrane potential analysis. Our findings aim to contribute to the understanding of the therapeutic potential and cellular effects of VGKC blockers, particularly 4-aminopyridine, in breast cancer treatment strategies. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

Cellular senescence is closely connected with cancer progression, recurrence, and metastasis. Senotherapy aims to soothe the harmful effects of senescent cells either by inducing their apoptosis (senolytic) or by suppressing the senescence-associated secretory phenotype (SASP) (senomorphic). Fisetin, a well-studied senotherapeutic drug, was selected for this study to evaluate its efficiency when delivered in a liposomal formulation. The experiment evaluated the impact of liposome-encapsulated fisetin on senescent cells induced by doxorubicin (DOX) from two cell lines: WI-38 (normal lung fibroblasts) and A549 (lung carcinoma). Senescence was characterized by SA-β-galactosidase (SA-β-gal) activity, proliferation, morphology, and secretion of pro-inflammatory interleukin 6 (IL-6) and interleukin 8 (IL-8). Due to fisetin’s hydrophobic nature, it was encapsulated in liposomes to enhance cellular delivery. Cellular uptake studies confirmed that the liposomes were effectively internalized by both senescent cell types. Treatment with fisetin-loaded liposomes revealed a lack of senolytic effects but showed senomorphic activity, as evidenced by a significant reduction in IL-6 and IL-8 secretion in senescent cells. The liposomal formulation enhanced fisetin’s therapeutic efficacy, showing comparable results even at the lowest tested concentration. Full article

Lung cancer is one of the most common cancers and the leading cause of cancer-related death worldwide. Despite advancements, the overall survival rate for lung cancer remains between 10% and 20% in most countries. However, recent progress in diagnostic tools and therapeutic strategies has led to meaningful improvements in survival outcomes, highlighting the growing importance of personalized management based on accurate disease assessment. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has become essential in the management of lung cancer, serving as a key imaging modality for initial diagnosis, staging, treatment response assessment, and follow-up evaluation. Recent developments in radiomics and artificial intelligence (AI), including machine learning and deep learning, have revolutionized the analysis of complex imaging data, enhancing the diagnostic and predictive capabilities of FDG PET/CT in lung cancer. However, the limitations of FDG, including its low specificity for malignancy, have driven the development of novel oncologic radiotracers. One such target is fibroblast activation protein (FAP), a type II transmembrane glycoprotein that is overexpressed in activated cancer-associated fibroblasts within the tumor microenvironment of various epithelial cancers. As a result, FAP-targeted radiopharmaceuticals represent a novel theranostic approach, offering the potential to integrate PET imaging with radioligand therapy (RLT). In this review, we provide a comprehensive overview of FDG PET/CT in lung cancer, along with recent advances in AI. Additionally, we discuss FAP-targeted radiopharmaceuticals for PET imaging and their potential application in RLT for the personalized management of lung cancer. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Background/Objectives: After diagnosis, it is common for women with breast cancer to gain weight, which is associated with worse clinical outcomes. However, traditional measures such as body weight, BMI, and waist circumference do not detect key changes in body composition, such as fat redistribution or muscle loss. The objective of this exploratory study was to assess the evolution of body composition and muscle strength after one year of treatment, and their relationship with metabolic biomarkers. Methods: Prospective observational study in newly diagnosed breast cancer patients. Body composition was assessed using bioelectrical impedance analysis (BIA) and ultrasound (US); muscle strength was measured by handgrip dynamometry. Biomarkers analyzed included glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), total cholesterol (and its fractions), triglycerides, C-reactive protein (CRP), 6-interleukin (IL-6), vitamin D, myostatin, and fibroblast growth factor 21 (FGF-21). Results: Sixty-one women (mean age 58 years) were included. After one year, fat mass and related parameters significantly increased, while skeletal muscle mass and muscle strength decreased. Sarcopenic obesity prevalence rose from 1.16% to 4.9%. No significant changes were found in biomarkers, but positive correlations were observed between fat parameters and insulin, HOMA-IR, and triglycerides, and negative correlations with HDL-cholesterol. Conclusions: BIA and US can detect unfavorable changes in body composition that are not reflected in conventional measurements. At one year post-diagnosis, women showed increased fat accumulation, muscle loss, and reduced strength, even without significant metabolic biomarker changes. Further research is warranted to elucidate the long-term clinical implications of these findings and the external validity in larger cohorts. Full article