Search Results (260)

Background/Objectives: Colorectal cancer (CRC) is among the most prevalent malignant neoplasms globally. Chemotherapeutic treatment strategies have demonstrated minimal improvement over the past decade. Combination therapies, including those with nutraceuticals, are currently being investigated as promising alternatives to enhance therapeutic efficacy. The organosulfur garlic extract diallyl disulfide (DADS) has demonstrated anti-tumoral activity in several types of cancer. This study aimed to investigate the effects of DADS and 5-fluorouracil (5-FU), both individually and in combination, on the human CRC cell lines Caco-2 and HT-29. Methods: Caco-2, HT-29, and non-tumoral human umbilical vein endothelial cells (HUVEC) were exposed to DADS (25–600 µM) and 5-FU (5–100 µM), either individually or in simultaneous combination (DADS 100 µM + 5-FU 100 µM), for 24 h. Cytotoxicity was evaluated in all three cell lines. In addition, the effects of these treatments on oxidative stress, cell migration, genotoxicity, cell death, global DNA methylation, and gene–nutraceutical interactions were assessed in both tumor cell lines. Results: DADS demonstrated cytotoxic effects at high concentrations in Caco-2, HT-29, and HUVECs and induced DNA damage in both colorectal cancer cell lines. The combination of DADS and 5-FU significantly promoted apoptotic cell death, increased genotoxicity, elevated global DNA methylation, and inhibited cell migration, with these effects being particularly pronounced in HT-29 cells. Conclusions: We provide evidence that DADS combined with 5-FU is potentially useful in the therapy of CRC. However the combination of nutraceuticals and chemotherapy must consider the distinct molecular and phenotypic characteristics of each tumor cell line. Full article

Understanding the interactions between specific cell types within tissue environments is essential for elucidating key biological processes, such as immune responses, cancer progression, inflammation, and development, in both physiological and pathological studies. The predominant methods for analyzing cell–cell interactions (CCI) rely primarily on statistical inference using mapping or network-based techniques. However, these approaches often struggle to prioritize meaningful interactions owing to the high sparsity and heterogeneity inherent in single-cell RNA sequencing (scRNA-seq) data, where small but biologically important differences can be easily overlooked. To overcome these limitations, we developed PriorCCI, a deep-learning framework that leverages a convolutional neural network (CNN) alongside Grad-CAM++, an explainable artificial intelligence algorithm. This study aims to provide a scalable, interpretable, and biologically meaningful framework for systematically identifying and prioritizing key ligand–receptor interactions between defined cell-type pairs from single-cell RNA-seq data, particularly in complex environments such as tumors. PriorCCI effectively prioritizes interactions between cancer and other cell types within the tumor microenvironment and accurately identifies biologically significant interactions related to angiogenesis. By providing a visual interpretation of gene-pair contributions, our approach enables robust inference of gene–gene interactions across distinct cell types from scRNA-seq data. Full article

Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is expressed in various cell types during oncogenesis, yet its role in MB progression remains unclear. This study aimed to evaluate the expression and localization of NRP1 and glial fibrillary acidic protein (GFAP) in MB tissue. Methods: We analyzed MB tissue samples using immunohistochemistry, immunofluorescence, and quantitative PCR. Samples were stratified by molecular subgroup (WNT, SHH, non-WNT/non-SHH). We assessed NRP1 expression in tumor-associated microglia/macrophages (TAMs) and endothelial cells, as well as GFAP expression in astrocytes and tumor cells. Histopathological correlations and survival analyses were also conducted. Results: NRP1 was consistently expressed by TAMs across all MB molecular subgroups. Tumor vasculature showed strong endothelial NRP1 expression, while perivascular astrocytic coverage was frequently absent. Astrocytic processes exhibited spatial differences according to tumor histology. In SHH-MBs, a subset of tumor cells showed aberrant GFAP expression, which correlated with tumor recurrence or progression. Conclusions: NRP1 and GFAP display distinct expression patterns within the MB microenvironment, reflecting subgroup-specific biological behavior. Endothelial NRP1 positivity combined with limited vascular-astrocytic interaction and aberrant GFAP expression in SHH-MB may contribute to dysregulated angiogenesis and tumor progression. These findings warrant further investigation to explore their prognostic and therapeutic implications. Full article

Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl₂-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance. Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to the MDR1 and VEGF promoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function. Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes. Full article

Background/Purpose: Conventional three-dimensional in vitro tumor models often fail to fully capture the complexity of the tumor microenvironment, particularly the diverse populations of cancer-associated fibroblasts that contribute to poor prognosis and treatment resistance. The purpose of this study is to develop a patient-specific gastric cancer assembloid model that integrates tumor epithelial cells with matched stromal cell subtypes, each derived using tailored growth media to enhance cancer preclinical research and advance personalized therapeutic strategies. Methods: Tumor tissue was dissociated, and cells expanded in media for organoids, mesenchymal stem cells, fibroblasts, or endothelial cells. The resulting tumor-derived subpopulations were co-cultured in an optimized assembloid medium supporting each cell type’s growth. Biomarker expression was assessed by immunofluorescence staining, and transcriptomic profiles were analyzed by RNA sequencing. Drug responsiveness was evaluated using cell viability assays following treatment with various therapeutic agents. Results: The optimized co-culture conditions yielded assembloids that closely mimicked the cellular heterogeneity of primary tumors, confirmed by the expression of epithelial and stromal markers. Compared to monocultures, the assembloids showed higher expression of inflammatory cytokines, extracellular matrix remodeling factors, and tumor progression-related genes across different organoids and stromal ratios. Drug screening revealed patient- and drug-specific variability. While some drugs were effective in both organoid and assembloid models, others lost efficacy in the assembloids, highlighting the critical role of stromal components in modulating drug responses. Conclusions: This assembloid system offers a robust platform to study tumor–stroma interactions, identify resistance mechanisms, and accelerate drug discovery and personalized therapeutic strategies for gastric cancer. Full article

Pituitary neuroendocrine tumors (PitNETs) represent a complex pathology based on numerous incompletely elucidated molecular mechanisms. Beyond tumor cells, analyzing the tumor microenvironment may help identify novel prognostic markers and therapies. A key component of this environment is the folliculo-stellate (FS) cell. We examined FS cells in 77 PitNETs obtained by transsphenoidal surgery, using glial fibrillary acidic protein (GFAP) as an immunohistochemical marker. Immunohistochemistry for anterior pituitary hormones and transcription factors was performed to accurately classify the tumors. Our study included 19 somatotroph, 16 mammosomatotroph, 5 plurihormonal PIT-1 positive, 7 corticotroph, 14 gonadotroph, 11 unusual plurihormonal, and 5 null cell PitNETs. FS cells were observed in 55 of the cases, distributed isolated, in small groups or diffuse networks. A considerable number of tumors immunopositive for more than one hormone (including associations between GH/PRL, but also unusual combinations like GH/ACTH) also contained FS cells (p < 0.01), suggesting their involvement in tumor lineages differentiation. In 27 tumors, GFAP-positive cells clustered in highly vascularized areas. Additionally, in 11 of these cases a direct interaction between endothelial cells and FS cells was noted, sustaining their potential role in tumor angiogenesis. Given their complexity, FS cells may be crucial for understanding tumorigenesis mechanisms. Full article

The tumor microenvironment (TME) is crucial for the onset, development, and resistance to treatment of lung cancer. The tumor microenvironment consisting of a complex array of immune cells, fibroblasts, endothelial cells, extracellular matrix elements, and signaling molecules, facilitates tumor growth and spread while inhibiting the body’s antitumor immune response. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to create an immunosuppressive and proangiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial–mesenchymal transition, immune evasion, and metastasis. Moreover, miRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential therapeutic targets. Targeting dynamic interactions within the TME, particularly through the modulation of immune responses, angiogenesis, and stromal remodeling, offers promising avenues for precision pharmacological approaches. This review covers the current understanding of the lung TME, highlighting its impact on cancer pathophysiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions for lung cancer treatment. Full article

The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood–brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus–immune–brain axis in long COVID and inform effective clinical management. Full article

The low effectiveness of various brain cancer treatment methods is due to a number of significant challenges. Most of them are unable to penetrate the blood–brain barrier (BBB) when drugs are administered systemically through the bloodstream. Nanoscale particles play a special role among materials capable of binding drug molecules and successfully crossing the BBB. Biopolymeric nanoparticles (NPs) demonstrate excellent biocompatibility and have the remarkable ability to modify the environment surrounding tumor cells, thereby potentially improving cellular uptake of delivery agents. In our research, nanoscale polyelectrolyte complexes (PECs) ranging in size from 56 to 209 nm were synthesized by ionic interaction of the oppositely charged polysaccharides pectin and chitosan. The structural characteristics of these complexes were carefully characterized by infrared (FTIR) and Raman spectroscopy. The immobilization efficiency of antitumor drugs was comprehensively evaluated using UV spectrophotometry. The cytotoxicity of the NPs was evaluated in the U87-MG cell line. The preliminary data indicate a significant decrease in the metabolic activity of these tumor cells. Important details on the interaction of the NPs with an endothelial layer structurally similar to the BBB were obtained by simulating the BBB using a model based on human blood vessels. Our studies allowed us to establish a significant correlation between the kinetic parameters of drug immobilization and the ratio of biopolymer concentrations in the initial compositions, which provides valuable information for future optimization of drug delivery system design. Full article

Arterial stiffness indicates early atherosclerotic changes prevalent in children and adolescents with type 1 diabetes (T1D), even in those with a well–controlled disease and without additional cardiovascular risk factors. This study aimed to determine whether low–density lipoprotein (LDL) cholesterol and cytokine levels can indicate vascular stiffness in pediatric patients without conventional microangiopathic complications who are not undergoing lipid–lowering therapy. The total study group consisted of 59 pediatric patients divided into two subgroups based on their LDL cholesterol levels and matched for age, age at onset, and duration of diabetes. The investigation involved the precise measurement of several biomarkers including tumor necrosis factor (TNF–α), interleukin 35 (IL-35), interleukin 4 (IL-4), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 18 (IL-18), vascular endothelial growth factor (VEGF), Soluble Vascular Cell Adhesion Molecule–1 (sVCAM–1), Intercellular Adhesion Molecule–1 (ICAM-1), Soluble Platelet Selectin (sP–Selectin), Advanced Glycation End Products (AGEs), and Receptors for Advanced Glycation End Products (sRAGE). Arterial stiffness was assessed by calculating pulsatility indices in the common carotid artery and the peripheral arteries in the upper and lower limbs. The comparative analysis indicated that, in the subgroup with LDL cholesterol levels below 100 mg/dL, in comparison to the subgroup with LDL above 100 mg/dL, there was a significant increase in pulsatility indices in elastic and large muscle arteries and notably higher levels of IL-35, IL-10, sVCAM–1, and ICAM-1. This study is the first to recommend the pulsatility index of elastic and large muscular arteries as an effective diagnostic tool for evaluating early atherosclerotic lesions in children and adolescents diagnosed with type 1 diabetes. Elevated LDL cholesterol levels may contribute to vascular stiffness through mechanisms related to a weakened inflammatory response, highlighting the complex interaction between lipid levels, inflammation, and vascular health in patients with type 1 diabetes. Full article

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components—such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines—contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes. Full article

Aggressive cancer cells can form new, functional blood vessel-like structures independently of endothelial cells, known as vasculogenic mimicry (VM), instead of the usual tumor blood vessel formation process. However, the symbiotic relationship between microbial communities and human cells ensures the upkeep of cellular metabolism and the functionality of the immune system and metastatic cancers. This interaction typically happens through the generation and management of hormonal intermediates, metabolites, secondary metabolites, proteins, and toxins. A disturbance in the balance between the host and microbiota can alter the dynamics of their relationship, creating a conducive environment for the development of diseases, such as cancers. This review aims to synthesize the initial evidence on the molecular processes governing the interactions between GM and cancer development and emphasize microbial metabolites’ effects on vasculogenic mimicry. Some microbial metabolites could also contribute to developing interactions between microbes and the tumor microenvironment. While numerous obstacles persist, GM’s immense significance and complete capability in shaping tailored anticancer plans cannot be exaggerated, highlighting the need to investigate a holistic method that includes microbial modulation therapy in cancer management. Full article

Objectives: Tissue factor pathway inhibitor 2 (TFPI2) is a serine protease inhibitor that suppresses tumors by preventing extracellular matrix degradation and invasion. In many malignancies, the TFPI2 promoter hypermethylation silences its transcription, increasing tumor aggressiveness. However, TFPI2 paradoxically facilitates tumor progression in certain malignancies. Elevated circulating TFPI2 levels correlate with increased cancer aggressiveness and poor prognosis in ovarian, endometrial, and renal cell carcinoma, though the mechanisms underlying its tumor-promoting effects remain unclear. This review consolidates recent findings on TFPI2 regulation, its downstream targets in cellular homeostasis, and its prognostic significance. Additionally, we reassess TFPI2′s role in tumorigenesis, particularly in clear cell carcinoma, as well as in chronic inflammation. Methods: A comprehensive literature search was performed in PubMed and Google Scholar without time restriction. Results: TFPI2 expression is tightly regulated by transcription factors, signaling molecules, growth factors, cytokines, and epigenetic modification. TFPI2 regulates cell proliferation, inflammation, and extracellular matrix (ECM) remodeling, preserving tissue homeostasis. TFPI2 also regulates vascular endothelial and smooth muscle cell proliferation, key elements of the tumor microenvironment (TME). In the nucleus, it may modulate transcription factors to influence tumor-associated macrophage (TAM) polarization, facilitating cancer invasion. Its expression may be shaped by interactions between cancer cells and TAM activation. Beyond tumorigenesis, TFPI2 contributes to both inflammatory progression and resolution in diabetes, atherosclerosis, and preeclampsia. Conclusions: TFPI2 may interact with TAMs and inflammatory cells to regulate cell proliferation and inflammation, maintaining tissue homeostasis. Full article

Background/Objectives: The low permeability of the blood-brain barrier (BBB) represents a significant challenge to effective systemic chemotherapy for primary and metastatic brain cancers. Kinin receptors play a crucial role in modulating BBB permeability, and their agonist analogs have been explored in preclinical animal models to enhance drug delivery to the brain. In this study, we investigated whether des-Arg⁹-bradykinin (DBK), a physiological agonist of kinin B₁ receptor (B1R), acts as a brain drug delivery adjuvant by promoting the transient opening of the BBB. Methods: Human brain microvascular endothelial cells (HBMECs) were treated with DBK in the culture medium and in conditioned media from glioblastoma cell lines, namely T98G (CMT98G) and U87MG (CMU87). Immunofluorescence, RT-qPCR, in-cell Western assay, and proximity ligation assay (PLA) were performed to analyze BBB components, kinin receptors and TLR4, a receptor associated with the kinin pathway and inflammation. The effect of DBK on enhancing paracellular molecule transport was evaluated using Evans blue dye (EB) quantification in a cell culture insert assay and in an in vivo model, where mice with and without brain tumors were treated with DBK. To assess the functional impact of the transient BBB opening induced by DBK, the chemotherapeutic drug doxorubicin (DOX) was administered. Results: Treatment with DBK facilitates the presence of EB in the brain parenchyma by transiently disrupting the BBB, as further evidenced by the increased paracellular passage of the dye in an in vitro assay. B1R activation by DBK induces transient BBB opening lasting less than 48 h, enhancing the bioavailability of the DOX within the brain parenchyma and glioma tumor mass. The interaction between B1R and TLR4 is disrupted by the secreted factors released by glioblastoma cells, as conditioned media from T98G and U87 reduce TLR4 staining in endothelial cells without affecting B1R expression. Conclusions: These results further support the potential of B1R activation as a strategy to enhance targeted drug delivery to the brain. Full article

The natural, highly lipophilic bicyclic sesquiterpenes, Beta-Caryophyllene (BCP), was highlighted in several recent preclinical studies to enhance chemo-sensitization in chemo-resistant tumors and to efficiently inhibit angiogenesis and cancer cells’ ability to invade and metastasize. Previous studies have researched the reasons for the synergistic effect of Beta-Caryophyllene in combination therapy and its role as a chemosensitizer and an inhibitor of angiogenesis through investigating the involved mechanisms and signaling molecules. These include the lipophilic nature of BCP, the selective interaction of BCP with CB2, the binding affinity of BCP to the receptor binding sites at the angiogenic vascular endothelial growth factor, and the upstream effect on JAK1/STAT3 pathway and other signaling pathways. Herein, the BCP role in enhancing chemo-sensitization of chemo-resistant tumors and in inhibiting angiogenesis and cancer cells’ ability to invade and metastasize are highlighted. Beta-Caryophyllene appears to be a promising candidate in treating cancer when co-supplemented with drugs such as cisplatin, gemcitabine and sorafenib. Clinical trials are needed to validate the potential therapeutic effect of BCP as a co-supplementary drug in cancer therapy, helping to sensitize cancer response to drugs, modulating signaling pathways, and lowering the drugs’ doses besides working as anti-angiogenetic drug. Full article