Search Results (13,506)

Obesity is associated with chronic adipose dysfunction characterized by oxidative stress, inflammation, senescence, and fibrosis, which can promote tumor progression. In prostate cancer, periprostatic adipose tissue may directly influence the prostate microenvironment. Radiation therapy is widely used in prostate cancer, but radiation-induced adipose dysfunction in obesity and its impact on the prostate microenvironment remain poorly understood. In the present study, we investigated the impact of obese and irradiated obese adipose microenvironments on prostate stromal remodeling, as well as the activation of prostate fibroblasts mediating prostate cancer progression. We utilized a high-fat diet obesity model with localized adipose irradiation in animal and in vitro studies using obese and irradiated obese adipocytes. Prostates from obese and irradiated obese mice exhibited epithelial hyperplasia, increased stromal activation markers, oxidative damage, and senescence. Interestingly, radiation maintained the obesity-induced pathological behavior in the prostate, rather than elevating it. The conditioned media from obese and irradiated obese adipocytes induced stromal activation markers, senescence, extracellular H₂O₂ production, pro-survival signaling, and inflammation. Notably, the only significant changes observed with the addition of radiation to obesity were enhancement of fibrosis-associated features and infiltration of CD4⁺ T cells. Functionally, prostate myofibroblasts or senescent fibroblasts promoted prostate cancer migration and induced epithelial-to-mesenchymal transition and elevated pro-tumorigenic pathways. Cytokine profiling identified elevated levels of CXCL10 and CXCL11 from myofibroblasts, and pharmacological inhibition of CXCR3 significantly reduced prostate cancer migration, implicating this signaling axis in activated fibroblast-driven tumor-promoting crosstalk. Collectively, these findings demonstrate obesity-associated adipose dysfunction reprograms the prostate microenvironment toward a pro-tumorigenic state, while radiation sustains rather than markedly amplifies these pathological changes, identifying obese adipose-stromal crosstalk and the CXCL10/CXCL11-CXCR3 axis as potential therapeutic targets to inhibit prostate cancer progression. Full article

Hepatocellular carcinoma (HCC) is an aggressive liver cancer requiring reliable biomarkers, while current approaches are limited by high-dimensional data and complex nonlinear gene interactions. In this study, differentially expressed genes were identified and fed to a deep autoencoder to reduce dimensionality, capture nonlinear interactions, and extract informative latent features. Predictive gene features were selected through mutual information (MI) ranking and LASSO regression and subsequently evaluated using logistic regression (LR), random forest (RF), and support vector machine (SVM) classifiers with 5-fold cross-validation (CV). The top 50 genes underwent enrichment analyses. Protein–protein interaction (PPI) networks were constructed to identify hub genes, followed by gene–drug interaction, transcription factor analysis, and survival validation. Enrichment analysis highlighted critical pathways involved in metabolic, signaling, and cell-cycle, and viral carcinogenesis. CV showed stable and high performance across classifiers (accuracy = 0.969, F1 ≈ 0.97), with RF and SVM achieving the highest AUC values (~0.983 and ~0.982). Independent tests showed excellent performance, with RF achieving perfect performance (1.0) across all evaluation metrics, confirming high feature discriminative power. Survival analysis showed that hub genes, including HSP90AB1, TUBA1B, PKM, H2AZ1, YWHAZ, ACLY, RAN, ILF2, KPNA2, and TXNRD1, were significantly associated with poor prognosis (HR > 1.5, p < 0.05), correlating with reduced overall, relapse-free, and disease-specific survival in HCC. The integrative novel framework effectively identifies biologically relevant biomarkers, providing insights into HCC mechanisms and potential targets for precision therapy. Full article

Focused ultrasound (FUS) comprises a diverse group of non-invasive, non-ionizing acoustic technologies that have evolved from tools for localized tissue destruction into platforms capable of influencing complex biological processes. In oncology, growing evidence suggests that the effects of focused ultrasound extend beyond direct tumor treatment to include modulation of the tumor microenvironment and anti-tumor immunity. This review examines the major FUS modalities currently under investigation for cancer therapy, including high-intensity focused ultrasound (HIFU), intrinsic threshold histotripsy, boiling histotripsy, shock-scattering histotripsy, and low-intensity focused ultrasound (LIFU), with emphasis on the distinct physical mechanisms that underlie their biological effects. Although these modalities differ in how they interact with tissue, they share the capacity to alter tumor biology through changes in antigen availability, inflammatory signaling, and immune cell activity. These responses have been associated with enhanced immune recognition of tumors, remodeling of immunosuppressive microenvironments, and improved therapeutic responsiveness in preclinical and emerging clinical studies. As interest in focused ultrasound continues to expand, understanding the relationship between modality-specific bioeffects and downstream immune outcomes has become increasingly important. Collectively, the literature highlights focused ultrasound as a versatile therapeutic platform capable of linking precise local intervention with broader biological and immunological consequences, supporting its continued development as both a tumor-directed and immune-modulating strategy in cancer therapy. Full article

Regulatory CD4+ T cells (Tregs) are essential for immune tolerance, tissue repair, and control of inflammation, but functional human Tregs cannot be identified reliably by a single protein. This targeted narrative review evaluates protein-level and proteomics-supported Treg signatures with explicit attention to species, sample source, analytical platform, validation strategy, and intended use. Primary human LC-MS/MS studies reveal pathway-level differences involving T-cell receptor signaling, metabolism, lysosomal activity, and lineage protection, whereas murine proteomic studies provide mechanistic candidates such as Themis1 but do not establish human biomarkers. CyTOF, functional single-cell protein profiling, spatially resolved protein imaging, and multi-omics further resolve phenotypic and tissue heterogeneity. Established CD25high/CD127low/FOXP3-based panels support enrichment and phenotyping; CTLA-4, ICOS, TIGIT, GITR, PD-1, chemokine receptors, suppressive enzymes, metabolic proteins, and emerging candidates report functional or tissue states but are not Treg-exclusive. Cancer currently provides the strongest tissue-level and prognostic evidence, whereas data in healthy aging, cardiovascular and metabolic disease, osteoarthritis, and neurodegeneration remain heterogeneous and mainly exploratory. Across contexts, validated diagnostic sensitivity, specificity, reference ranges, prospective clinical utility, and inter-laboratory reproducibility are largely absent. Treg immunoproteomics is therefore best regarded as a discovery and stratification framework rather than a standardized clinical diagnostic test. Full article

Cell signaling, and the biochemical reactions underlying it, are complex phenomena fundamental for control of cellular behavior in response to the incentives present in the cell’s direct environment. It is crucial for coordination of cell activities such as growth, differentiation, metabolism, and death. The aim of this review is to present mathematical and computational models of biochemical reactions and cell signaling pathways in an educational and comprehensive way, outlining broad aspects of modeling such as differential equations, and artificial intelligence and machine learning approaches. This review also discusses potential applications of mathematical and computational models of cell signaling and biochemical reactions in fields such as systems biology, personalized medicine (i.e., cancer treatment, neurodegenerative disease treatment), and identification of drug targets. Full article

Background/Objectives: Isorhamnetin is a naturally occurring flavonoid with reported antioxidant, anti-inflammatory, and anticancer properties. Although its biological activities have been extensively investigated, its effects on ovarian cell physiology remain insufficiently characterized. This study aimed to evaluate the influence of isorhamnetin on the viability, steroid hormone secretion, apoptosis, and growth factor signalling in human ovarian cell lines representing both non-tumour and tumour phenotypes. Methods: Human granulosa (HGL5), granulosa tumour (COV434), and epithelial ovarian carcinoma (OVCAR-3) cell lines were treated with isorhamnetin at concentrations of 5–80 μg/mL for 24 h. Cell viability was determined using the AlamarBlue^TM assay. The secretion of progesterone, 17β-estradiol, and the presence of transforming growth factor β2 (TGF-β2), transforming growth factor β receptor 2 (TGFBR2), and apoptosis-inducing factor (AIF) was quantified by enzyme-linked immunosorbent assay (ELISA). Results: Isorhamnetin significantly reduced cell viability in a dose-dependent manner, with tumour cell lines exhibiting greater sensitivity than non-tumour granulosa cells. A significant decrease in viability was observed in OVCAR-3 cells from 10 μg/mL onward, whereas COV434 cells showed significant reductions at concentrations of 20 μg/mL and higher. In contrast, HGL5 cell viability was significantly affected only at the highest concentration (80 μg/mL). No significant changes were detected in the secretion of progesterone, 17β-estradiol, TGF-β2, or TGFBR2 in any of the examined cell lines. A significant reduction in AIF production was observed only in HGL5 cells treated with 80 μg/mL isorhamnetin. Conclusions: Isorhamnetin preferentially decreased the viability of ovarian tumour cells while exerting only limited effects on non-tumour granulosa cells, indicating preferential cytotoxic activity toward malignant ovarian cells. The absence of significant changes in steroid hormone production and TGF-β suggests that its antiproliferative effects involve molecular pathways that were not investigated in the present study. These findings support further investigation of isorhamnetin as a potential natural compound for ovarian cancer prevention or adjunctive therapy. Full article

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide, and metabolic reprogramming is increasingly recognized as an important feature of its progression. Among these changes, fatty acid metabolism (FAM) has drawn growing attention because it supports energy supply, membrane synthesis, redox balance, and stress adaptation in tumor cells. CRC cells can increase fatty acid uptake, activate de novo synthesis, adjust fatty acid oxidation (FAO), and alter lipid droplet (LD) dynamics according to metabolic demand. These processes are strongly influenced by the hypoxic tumor microenvironment. Under hypoxic conditions, signaling pathways centered on hypoxia-inducible factors (HIFs) reshape lipid uptake, synthesis, oxidation, and storage, allowing CRC cells to maintain survival and adapt to limited oxygen and nutrient availability. Increasing evidence suggests that this metabolic shift is closely linked to invasion, metastasis, stem-like behavior, and resistance to therapy. In this review, we provide an integrated overview of the hypoxia–FAM axis in CRC. We first summarize the major steps of FAM reprogramming, then highlight how hypoxia reshapes these processes through HIF-dependent and related pathways. We also discuss FAM crosstalk with stromal and immune cells, experimental models, and metabolic heterogeneity between primary CRC and liver metastases. Finally, we discuss therapeutic strategies targeting FAM and hypoxia-associated signaling in CRC. Full article

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Background: Cancer cells live in a dynamic and favorable ecosystem conducive to their growth and survival, known as the tumor microenvironment (TME). The TME is replete with various proinflammatory cell types that mediate crosstalk via the secretion of cytokines and chemokines to facilitate tumor growth and development. One cardinal proinflammatory cytokine that is present in the TME is interleukin-1 (IL-1). IL-1 promotes tumor angiogenesis and cancer cell metastasis; thus IL-1 receptor antagonist (IL-1Ra) is of clinical interest. Our lab previously reported that chronic exposure to exogenous IL-1 can select for cancer cells that evolve insensitivity to IL-1 signaling, thus rendering IL-1-targeting therapies, like IL-1Ra, irrelevant. While immune cells are the primary source of TME IL-1, cancer cells can also produce and secrete IL-1 to engage in autocrine and/or paracrine signaling. In this context, cancer cell exposure to multiple other sources of exogenous IL-1 beyond autocrine production might also amplify extrinsic IL-1 signaling in these cells, but the consequences of sustained amplified IL-1 signaling on the regulation, function, and therapeutic response of these cancer cells need to be explored. Methods: Using the IL-1-secreting 5637 bladder cancer (BlCa) cell line, we generated chronic IL-1 sublines by spiking the growth medium with additional IL-1α or IL-1β chronically for 6 months. Once established, we assessed subline acute IL-1 sensitivity, paracrine signaling and response to IL-1Ra. Results: Following chronic exposure to elevated exogenous IL-1 levels, the 5637 BlCa cell line retains sensitivity to acute IL-1 and IL-1Ra and maintains the ability to induce IL-1-dependent endothelial cell activation, which is reversed with IL-1Ra. These data suggest that for cancer cells that engage in cell autonomous IL-1 signaling, sustained extrinsic IL-1 exposure does not dampen IL-1 or IL-1Ra sensitivity, supporting the context-dependent use of IL-1 antagonists as rational therapeutics in both acute and chronic inflammatory TMEs. Full article

It is well known that genetic variants contribute to cellular sensitivity to chemotherapeutic agents and ionizing radiation (IR). The aim of this study was to identify single nucleotide polymorphisms (SNPs) and genes associated with the spectrum of normal cellular sensitivity of lymphoblastoid cell lines (LCLs) towards ionizing radiation and mitomycin C (MMC). In the first step, we determined the viability of LCLs established from male participants of the Berlin Aging Study II (BASE-II) aged ≥62 years following treatments with increasing doses of IR (n = 137 cell lines) or MMC (n = 140 cell lines) using the alamarBlue assay. Results from intra-experimental triplicates and three independent experiments for each cell line and treatment were used to calculate the area under the curves (AUCs) representing the specific sensitivity to IR and MMC of each LCL. The data from these experiments were subsequently used as outcomes in genome-wide association studies (GWASs). In addition, we calculated polygenic risk scores (PGS) from UK Biobank GWAS results for four cancer-related phenotypes and assessed the extent to which the variance in the IR and MMC sensitivity is explained by these PGS. The GWAS analyses revealed one variant, rs74728080, located in CDH13 on chromosome 16, to show genome-wide significant (p < 5 × 10⁻⁸, ß = 2.81) association with cellular viability after treatment with IR. In the GWAS on MMC sensitivity the most interesting signal was elicited by SNP rs113978558 in an intron of the PLD5 gene on chromosome 1 (p = 9.232 × 10⁻⁸; ß = 1.44). Several other SNPs with statistically suggestive (i.e., p < 1 × 10⁻⁵) evidence of association with IR or MMC sensitivity were identified. PGS calculations from GWAS of four cancer-related traits in UKB explained ~5% and ~3% of phenotypic variance in IR- and MMC-induced cell viability, respectively. The genome-wide significant association of rs74728080 with IR sensitivity and the location of this variant in CDH13 is interesting and functionally highly plausible given its known involvement in oxidative stress response and function as a tumor suppressor. Taken together, our novel data suggest that CDH13 may be genuinely involved in regulating cellular IR sensitivity. Full article

Calcium signaling is a fundamental regulator of cell physiology, controlling proliferation, differentiation, migration, metabolism, gene expression, and cell death. In cancer, these signaling pathways are extensively remodeled to generate spatially and temporally restricted Ca²⁺ signals that support malignant progression while avoiding calcium-induced cytotoxicity. PMCAs traditionally regarded as high-affinity calcium extrusion pumps, have recently emerged as multifunctional regulators of compartmentalized calcium signaling. In addition to maintaining low cytosolic Ca²⁺ concentrations, PMCA isoforms organize specialized signaling microdomains by interacting with receptors, ion channels, scaffold proteins, and downstream signaling molecules, thereby selectively modulating calcium-dependent pathways involved in tumor growth and metastasis. Accumulating evidence demonstrates that PMCA isoforms exert distinct, context-dependent functions in cancer. PMCA1 primarily contributes to basal calcium homeostasis but has also been implicated in tumor progression, angiogenesis, and regulation of the tumor immune microenvironment. PMCA2 promotes survival and oncogenic signaling in HER2-positive breast cancer through stabilization of receptor signaling complexes. PMCA3 has been linked mainly to endocrine tumors and selected malignancies, although mechanistic evidence remains limited. PMCA4 exhibits the greatest functional diversity, acting either as a tumor suppressor or a promoter depending on the cancer type by regulating localized calcium signaling, cell migration, invasion, differentiation, and interactions with oncogenic signaling networks. This review summarizes current advances in the structural biology, regulation, and signaling functions of PMCA isoforms, with particular emphasis on their emerging roles in cancer biology. We also discuss the potential of PMCAs as prognostic biomarkers and therapeutic targets, highlighting the importance of isoform-specific strategies for targeting calcium signaling in cancer. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited therapeutic options for patients at high risk of disease recurrence and metastasis. The cyclic nucleotide-degrading enzyme, phosphodiesterase 10A (PDE10), that hydrolyzes both cAMP and cGMP has been previously reported to be expressed in multiple cancers and regulates key cellular signaling pathways involved in cancer cell proliferation, survival, and maintenance of stem cell-like properties. We found that PDE10 overexpression was associated with poor relapse-free survival of TNBC patients and identified its potential as a therapeutic target for TNBC using a novel inhibitor, ADT-030. Our results showed that ADT-030 inhibited the growth of TNBC cells, reduced colony-forming efficiency and enhanced the therapeutic efficacy of paclitaxel. A TNBC mouse model demonstrated that oral administration of ADT-030 significantly suppressed syngeneic tumor growth and enhanced the antitumor efficacy of paclitaxel. ADT-030 treatment altered differentially expressed genes (DEGs), signaling pathways, and cellular processes. Overall, our findings suggest that ADT-030, as a monotherapy or in combination with standard-of-care chemotherapy, may be an effective therapeutic approach for TNBC. Further studies are warranted to better understand the oncogenic role of PDE10 in TNBC and the mechanisms by which ADT-030 modulates the tumor microenvironment (TME) and enhances chemotherapy response. Full article

Human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (Trop-2) are tumor-associated antigens widely overexpressed in multiple malignant tumors, which drive malignant proliferation, invasion, metastasis, and therapeutic resistance by activating key downstream signaling pathways. Antibody–drug conjugates (ADCs) targeting HER2 and Trop-2 leverage their antigen-specific binding capacity to achieve precise targeted delivery of cytotoxic drugs, representing a significant breakthrough in solid tumor therapy. This review systematically outlines the biological functions and carcinogenic mechanisms of HER2 and Trop-2, focusing on the latest research and development progress of related ADCs. We also summarize and analyze key clinical data and application prospects in breast cancer (BC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC), while also delving into the challenges and future directions within this field. Full article

Objectives: Fluorescence-guided surgery (FGS) targeting prostate-specific membrane antigen (PSMA) holds promise for improving surgical precision in prostate cancer. Since conjugation of fluorescent dyes to targeting vectors can substantially alter pharmacokinetic properties, we systematically evaluated a library of fluorescent dyes conjugated to a PSMA-617-derived scaffold incorporating sarcosine-based spacers to identify candidates with favorable biodistribution and optical profiles for clinical translation. Methods: Nineteen fluorescent dyes spanning NIR, large Stokes shift, and STED-compatible categories were conjugated to a dual-labeled PSMA-617-derived precursor (Glu-urea-Lys-2Nal-TXA-Sar₁₀-Lys(DOTA)-Sar₅-βAla; hereafter DP). Compounds were radiolabeled with ⁶⁸Ga or ¹⁷⁷Lu and characterized for serum stability, lipophilicity, binding affinity, and internalization in LNCaP^PSMA+ cells. In vivo pharmacokinetics were assessed in LNCaP xenograft-bearing BALB/c nu/nu mice by µPET/MRI (1 and 2 h p.i., 500 pmol ⁶⁸Ga), organ distribution (0.5, 1, and 2 h p.i., 60 pmol ¹⁷⁷Lu), and clinical-grade endoscopic fluorescence imaging. Results: All conjugates retained hydrophilic character (logD: −3.72 to −1.79), low nanomolar binding affinity (K_i: 18–87 nM), and high serum stability (94–100% intact at 24 h). Despite comparable in vitro properties, dye conjugation markedly influenced in vivo pharmacokinetics: tumor uptake at 2 h p.i. ranged from 1 to 23%ID/g and kidney accumulation from 3 to 82%ID/g. Visible-range dyes exhibited faster renal washout within the imaging window and higher tumor-to-background contrast than NIR fluorophores. Fluorescence signal intensity did not correlate with radiotracer-derived uptake, underscoring the importance of dye-specific photophysical properties. Conclusions: DP-12 (SulfoCy5), DP-15 (Alexa Fluor 647), and DP-18 (Tide Fluor 5WS) were identified as lead candidates combining favorable pharmacokinetics with strong fluorescence contrast, warranting further evaluation toward fluorescence-guided prostate cancer surgery. Full article

Breast cancer (BC) progression is strongly influenced by the extracellular matrix (ECM), whose remodelling regulates tumour growth, invasion, metastasis, immune modulation, and therapeutic response. Among ECM components, collagens have emerged as both structural proteins and active mediators of mechanotransduction, stromal interactions, and tumour cell behaviour. This narrative review analyses collagen families and collagen-associated proteins implicated in BC, integrating evidence on their expression patterns, biological functions, clinical significance, and translational potential. We examine fibrillar and non-fibrillar collagens, including fibril-associated collagens with interrupted triple helices (FACITs), membrane-associated collagens with interrupted triple helices (MACITs), basement membrane (BM) collagens, and multiplexins, together with their interactions with cancer-associated fibroblasts (CAFs), immune cells, and signalling pathways involved in tumour progression. Alterations in collagen composition, organization, crosslinking, and degradation regulate ECM stiffness, epithelial–mesenchymal transition (EMT), invasion, metastatic dissemination, and therapy resistance. Several collagen types and collagen-derived fragments also show promise as prognostic biomarkers and therapeutic targets, particularly in aggressive BC subtypes such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC). Overall, this review highlights the collagenome as a dynamic component of the breast tumour microenvironment (TME) and supports collagen-informed strategies for improved patient stratification and targeted therapies. Full article