Search Results (764)

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by invasive growth, intrinsic drug resistance, and the presence of the blood–brain barrier. All of these features make treatment extremely challenging and underscore the need for developing effective combination strategies and advanced drug delivery systems. This study aimed to develop a bovine serum albumin (BSA) nanoparticle (NP)-based delivery system to overcome the poor bioavailability and pharmacokinetic limitations of two potent anti-tumor agents, all-trans retinoic acid (ATRA) and curcumin (CURC), and to evaluate their antitumor activity in U87-MG GBM cells. Drug-free and ATRA/CURC-loaded BSA-NPs were synthesized using an optimized desolvation method and characterized in terms of particle size, polydispersity index, morphology, drug encapsulation efficiency, and release behavior. The cytotoxic, anti-migratory, and pro-apoptotic effects of the NPs on U87-MG GBM cells were assessed using real-time proliferation and migration assays and Annexin V/PI staining followed by flow cytometry. Collectively, the findings indicated that the co-delivery of ATRA and CURC using BSA-NPs showed enhanced antiproliferative, antimigratory, and pro-apoptotic effects. With its controlled release profile, high loading capacity, and favorable nanoscale dimensions, the ATRA-CURC-BSA–NP system represents a promising nanoplatform for GBM therapy that warrants further in vivo investigation. To the best of our knowledge, this is the first study demonstrating the inhibition of glioblastoma cell growth through the co-delivery of all-trans retinoic acid and curcumin using a bovine serum albumin-based nanoparticle system. Full article

Glioblastoma (GBM), the most common, invasive, and chemoresistant form of adult primary brain cancer, is characterized by rapid cell proliferation, local invasiveness, and resistance to chemotherapy (e.g., temozolomide (TMZ)) and radiation therapy. Curcumin, a bioactive polyphenol derived from Curcuma longa, has exhibited exceptional anti-cancer properties, including anti-proliferative, pro-apoptotic, anti-inflammatory, and anti-angiogenic activities in a wide range of cancer models, including GBM. However, the clinical application of curcumin has been seriously limited by several challenges, including low water solubility, low bioavailability, rapid systemic clearance, and poor blood–brain barrier (BBB) penetration. To overcome these challenges, several nanocarrier systems to produce nanocurcumin have been developed, including liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, and micelles. These nanoformulations improve the solubility, stability, systemic circulation, and target-directed delivery of curcumin to glioma cells, thereby resulting in a high level of accumulation in the glioma microenvironment. On the other hand, this work is devoted to the potential of curcumin and nanocurcumin for the treatment of GBM. The article provides a detailed review of the major molecular targets of curcumin, such as NF-κB, STAT3, PI3K/AKT/mTOR, and p53 signaling pathways, as well as recent advancements in nanotechnology-based delivery platforms that improve drug delivery across the BBB and their possible clinical translation. We also include a thorough examination of the issues, limitations, and potential opportunities associated with the clinical advancement of curcumin-based therapeutics for GBM. Full article

Brain tumors, particularly glioblastoma, remain among the most lethal cancers, with limited survival benefits from current genetic and molecular-targeted approaches. Emerging evidence reveals that beyond oncogenes and mutations, neuronal plasticity, long-term potentiation, synaptic remodeling, and neurotransmitter-driven signaling play a pivotal role in shaping tumor progression and therapeutic response. This convergence of neuroscience and oncology has given rise to the field of cancer neuroscience, which explores the bidirectional interactions between neurons and malignant cells. In this review, we summarize fundamental principles of neuronal plasticity, contrasting physiological roles with pathological reprogramming in brain tumors. We highlight how tumor cells exploit synaptic input, particularly glutamatergic signaling, to enhance proliferation, invasion, and integration into neural circuits. We further discuss how neuronal-driven feedback loops contribute to therapy resistance, including chemoresistance, radioresistance, and immune evasion, mediated through pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and calcium influx. The tumor microenvironment, including astrocytes, microglia, and oligodendrocyte-lineage cells, emerges as an active participant in reinforcing this neuron-tumor ecosystem. Finally, this review explores therapeutic opportunities targeting neuronal plasticity, spanning pharmacological interventions, neuromodulation approaches (transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), optogenetics), and computational/artificial intelligence frameworks that model neuron tumor networks to predict personalized therapy. Also, we propose future directions integrating connect omics, neuroinformatics, and brain organoid models to refine translational strategies. Full article

Background/Objectives: Glioblastoma (GBM) exhibits heterogeneous, nonlinear invasion patterns that challenge conventional modeling and radiomic prediction. Most deep learning approaches describe the morphology but rarely capture the dynamical stability of tumor evolution. We propose an AI framework that approximates a latent attractor landscape of GBM morphodynamics—stable basins in a continuous manifold that are consistent with reproducible morphologic regimes. Methods: Multimodal MRI scans from BraTS 2020 (n = 494) were standardized and embedded with a 3D autoencoder to obtain 128-D latent representations. Unsupervised clustering identified latent basins (“attractors”). A neural ordinary differential equation (neural-ODE) approximated latent dynamics. All dynamics were inferred from cross-sectional population variability rather than longitudinal follow-up, serving as a proof-of-concept approximation of morphologic continuity. Voxel-level perturbation quantified local morphodynamic sensitivity, and proof-of-concept control was explored by adding small inputs to the neural-ODE using both a deterministic controller and a reinforcement learning agent based on soft actor–critic (SAC). Survival analyses (Kaplan–Meier, log-rank, ridge-regularized Cox) assessed associations with outcomes. Results: The learned latent manifold was smooth and clinically organized. Three dominant attractor basins were identified with significant survival stratification (χ² = 31.8, p = 1.3 × 10⁻⁷) in the static model. Dynamic attractor basins derived from neural-ODE endpoints showed modest and non-significant survival differences, confirming that these dynamic labels primarily encode the morphodynamic structure rather than fixed prognostic strata. Dynamic basins inferred from neural-ODE flows were not independently prognostic, indicating that the inferred morphodynamic field captures geometric organization rather than additional clinical risk information. The latent stability index showed a weak but borderline significant negative association with survival (ρ = −0.13 [−0.26, −0.01]; p = 0.0499). In multivariable Cox models, age remained the dominant covariate (HR = 1.30 [1.16–1.45]; p = 5 × 10⁻⁶), with overall C-indices of 0.61–0.64. Voxel-level sensitivity maps highlighted enhancing rims and peri-necrotic interfaces as influential regions. In simulation, deterministic control redirected trajectories toward lower-risk basins (≈57% success; ≈96% terminal distance reduction), while a soft actor–critic (SAC) agent produced smoother trajectories and modest additional reductions in terminal distance, albeit without matching the deterministic controller’s success rate. The learned attractor classes were internally consistent and clinically distinct. Conclusions: Learning a latent attractor landscape links generative AI, dynamical systems theory, and clinical outcomes in GBM. Although limited by the cross-sectional nature of BraTS and modest prognostic gains beyond age, these results provide a mechanistic, controllable framework for tumor morphology in which inferred dynamic attractor-like flows describe latent organization rather than a clinically predictive temporal model, motivating prospective radiogenomic validation and adaptive therapy studies. Full article

The glioblastoma multiforme (GBM) microenvironment, characterized by hypoxia and inflammation, is a principal driver of therapeutic resistance. Although natural compounds such as Caffeic Acid Phenethyl Ester (CAPE) are investigated for their anti-neoplastic properties, their bioactivity within the distinct metabolic landscape of the tumor core remains to be fully elucidated. Taking advantage of the recognized immunomodulatory properties of CAPE and its ability to cross the blood–brain barrier, we hypothesized that hypoxia is a key factor determining its effect on glioma-associated inflammation. To test this hypothesis, we investigated the immunomodulatory effects of CAPE on the human astrocytoma cell line CCF-STTG1. Cells were cultured under normoxic and hypoxic conditions, stimulated with lipopolysaccharide (LPS) and interferon-alpha (IFN-α) to induce an inflammatory phenotype, and subsequently treated with CAPE. The secretion profiles of key cytokines (IL-8, IL-10, IL-26) and matrix metalloproteinases (MMPs) as well as pentraxin-3 (PTX-3) were then quantified using a multiplex immunoassay. Our results revealed a striking functional dichotomy. Under normoxic conditions, CAPE suppressed the secretion of key pro-inflammatory mediators. Conversely, under hypoxic conditions, CAPE significantly amplified the release of pro-tumorigenic factors, including the mediator facilitating tumor cell migration, invasion, and angiogenesis such as IL-8 and the invasion-associated metalloproteinase MMP-2. These findings suggesting that hypoxia may fundamentally reprograms the immunomodulatory potential of CAPE. However, due to limitations of study requires further validation in a broader panel of glioblastoma models. Full article

Background/Objectives: The ineffectiveness of current treatments for glioblastoma underscores the urgent need for effective alternatives. This study aimed to investigate the effectiveness of sodium dichloroacetate (NaDCA) and a sodium valproate NaDCA combination (NaVPA–NaDCA) on formed patients’ primary cell tumors on the chick embryo chorioallantoic membrane (CAM). Methods: Glioblastoma tissue samples were obtained from three patients during tumor surgery. WHO grade IV, IDH wild-type, and a strong positive cytoplasmic GFAP reaction in tumor cells characterized the investigated glioblastoma cases. The tumor cells GBM2-2F, GBM2-3F, and GBM-4M from the patients were examined. Histological examination of tumor invasion into CAM, angiogenesis, and immunohistochemical expression of GFAP-, PCNA-, p53-, EZH2- and vimentin-positive cells were examined. Results: No difference in GFAP expression was observed between the patient’s GBM tumor tissue and the tumor formed on CAM from the same patient’s tumor cells. There were no significant differences in invasion or in the frequency of GFAP- and p53-positive cells among the study control groups. The expression of PCNA-, EZH2-, and vimentin-positive cells in control tumors varied significantly. Treatment significantly reduced the incidence of tumor invasion in GBM2-2F and GBM2-4M and did not affect GBM2-3F tumors; treatment also significantly reduced GFAP expression in GBM2-3F and GBM2-4M and did not affect GBM2-2F tumors. The treatment with NaVPA–NaDCA significantly reduced the expression of PCNA, p53, EZH2 and vimentin in the tested tumors. Conclusions: Data demonstrated an antitumor effect of NaVPA–NaDCA in an in vivo model of a patient’s primary glioblastoma cells. Full article

Introduction: Glioblastomas have poor prognosis despite aggressive treatment. Patterns of recurrence and overall survival (OS) can be very different. The population with complete resection having a so-called good prognosis can nevertheless present poor OS. Our purpose was to assess the OS and patterns of recurrence thanks to multimodal statistical maps in glioblastoma with large extent of resection (residue < 10 mL). Methods: adult patients presenting IDH wild-type glioblastoma between 2013 and 2019 were selected. Clinical data and MRI characteristics were collected. Preoperative, postoperative, and recurrence volumes were segmented and normalized in the MNI space to compute statistical maps. Log-rank test and Cox model were used to assess OS and prognosis factors. Results: 60 patients were included. Mean residual volume was 0.89 ± 2 mL. Median OS was 22.3 months (95% CI: (20–35)). Initial location in the corpus callosum was associated with low OS (317 vs. 783 days, HR = 0.46, p = 0.003). At recurrence, KPS > 90 and tumor volume < 10 mL were associated with higher OS (p =0.006 and p = 0.05). Tumor contact with the SVZ as well as multifocal recurrence did not show any impact on the OS. Conclusions: High OS can be obtained thanks to surgery with residual volume < 10 mL. Invasion of the corpus callosum at diagnosis is associated with a poor prognosis despite a large extent of resection. Results suggest that large resection near the SVZ might decrease its putative influence on OS. Full article

Glioblastoma (GBM) represents a highly invasive primary malignant tumor within the central nervous system (CNS). Temozolomide (TMZ), a first-line chemotherapy agent for GBM treatment, has significant limitations, including drug resistance, poor water solubility, a short half-life, and notable toxic side effects. The innovation of the TMZ dosage form is pivotal for enhancing its therapeutic efficacy. In this study, solid lipid nanoparticles (SLN) loaded with Angiopep-2 (A2) and TMZ (TMZ-A2SLN), a nanopolymer featuring a solid spherical morphology and a particle size of approximately 100 nm, were constructed. The combined effect of TMZ-A2SLN and small-interfering RNA (siRNA) that can knock down the expression of the HOXB9 gene (siHOXB9) augmented the sensitivity of the glioma cell line U251 to TMZ. Under the combined effect, the viability of U251 cells was reduced by 77%. Meanwhile, the mortality rate increased by approximately 45%, and the cell apoptosis rate rose by around 36%. The number of cells arrested in the G2/M and S phases rose. Proteomic analysis indicates that TMZ-A2SLN might be implicated in the pro-inflammatory signaling cascade, tumor migration, invasion, and angiogenesis during the treatment of glioma cells. Moreover, HOXB9 may play a crucial regulatory role in the PPAR signaling pathway, the neural signaling pathway, the phospholipase D signaling pathway, the IL-17 signaling pathway, mineral absorption, and other pathways during glioma cell treatment. Full article

Immune checkpoint blockade is one of the current treatments for glioblastoma (GBM), which is still a very aggressive and treatment-resistant tumor of the central nervous system. This study focused on the LYZ gene to find new therapeutic targets. We performed a thorough screening of differential gene expressions between GBM and normal samples using many databases (TCGA, GTEx, GEO, and CGGA). Because LYZ is significantly upregulated in GBM tissues and is associated with shorter patient survival periods, we identified it as a gene of interest. LYZ’s position on the exterior side of the plasma membrane and its participation in leukocyte-mediated immunity were identified by functional enrichment analysis, indicating a role in cell surface immune responses. Significant associations between LYZ expression and particular immune cell types were found using immune infiltration analysis, suggesting that LYZ may have an impact on the tumor microenvironment. Within GBM, single-cell research verified LYZ expression in macrophages and monocytes. LYZ was shown to express differently in GBM cell lines than in normal glial cells, according to cellular experimental verification. The LYZ gene’s functional importance in the pathophysiology of GBM was highlighted by the dramatic reduction in cell proliferation, motility, and invasion that resulted from its knockout. These results suggest that LYZ is a viable therapeutic target and possible GBM diagnostic biomarker, which calls for more research into its mechanisms of action and potential clinical use. Full article

Glioblastoma multiforme (GBM) remains a devastating brain tumor with poor prognosis, traditionally viewed as non-metastatic. The recent detection of circulating tumor cells (CTCs) in glioblastoma challenges this long-held view and opens new opportunities for liquid biopsy in neuro-oncology. This review summarizes current understanding of glioblastoma CTCs, emphasizing their unique properties, detection technologies, and differences compared to CTCs in extracranial cancers. Key challenges include their rarity, the absence of epithelial markers, and the presence of the blood–brain barrier. Despite the need for specialized enrichment approaches, CTC analysis in glioblastoma can offer helpful information regarding tumor heterogeneity, treatment response, and minimal residual disease. We discuss emerging clinical studies leveraging CTCs for early relapse detection and therapy monitoring. Integrating CTC phenotyping with molecular and functional characterization may enhance future personalized treatment strategies in glioblastoma. Refined CTC methodologies combined with other liquid biopsy modalities may transform glioblastoma management, improving patient outcomes through less invasive, dynamic tumor surveillance. Full article

Background: Nanomedicine has demonstrated great potential to improve drug delivery across various diseases. However, accurately monitoring the real-time trafficking of organic nanoparticles (NPs) within biological systems remains a significant challenge. Current detection methods rely heavily on fluorescence, while high-resolution, label-free imaging is often precluded by the limited optical contrast of organic materials, limiting a comprehensive understanding of NP fate. Metallic doping allows simultaneous detection of carriers using multiple imaging and analysis techniques. This study presents a novel approach to prepare gold-doped hybrid NPs compatible with multimodal imaging, thus facilitating multimodal tracking. Methods: Gold-doped NPs were successfully synthesized via nanoprecipitation, yielding stable, monodisperse carriers with optimal size, confirmed by Dynamic Light Scattering and Nanoparticle Tracking Analysis. UV/Vis spectroscopy confirmed effective gold-doping, with doping efficiency of approximately 50%. Transmission Electron Microscopy (TEM) showed gold NP accumulation throughout the polymer core and near the lipid shell. Results: Although gold doping resulted in a slight increase in NP size and zeta potential, no effects on cytocompatibility or cellular uptake by glioblastoma and microglia cells were observed. Furthermore, the optical properties (i.e., the refractive index and the UV spectrum) of the NPs were successfully modified to enable tracking across complementary imaging modalities. Real-time, label-free visualization of NP accumulation in the cytoplasm of U87 cells was achieved via holotomography by exploiting the enhanced refractive index after gold-doping. This observation was confirmed through correlation with fluorescence confocal microscopy, using fluorescently labelled gold-doped NPs. Furthermore, the high electron density of the gold tracer facilitated the precise localization of NPs within intracellular compartments via TEM, bypassing the inherently low contrast of organic NPs. Conclusions: These findings validated the gold-doped NPs as versatile nanoplatforms for multimodal imaging, showcasing their potential for non-invasive, high-resolution tracking and more accurate quantification of intracellular accumulation using diverse analytical techniques. Full article

The high attrition rates in glioblastoma (GB) therapeutic development stem largely from preclinical models that fail to adequately recapitulate the dynamic tumor–host ecosystem. Unlike previous reviews that characterize glioma cell lines in isolation, this article integrates tumor biology with the distinct neuro-immune–endocrine landscapes of major laboratory rat strains. We critically evaluate standard rat malignant glioma cell lines (C6, F98, RG2, 9L) alongside transplantable tissue models (GB 101.8, GB 15/47), which offer enhanced translational relevance, demonstrating that the predictive value of any model is contingent upon the specific “glioma model and host strain” pairing and the individual physiological characteristics of the host. We provide evidence that strain-specific hypothalamic–pituitary–adrenal (HPA) axis reactivity (e.g., hyper-reactive Fischer 344 versus normo-reactive Wistar) acts as a decisive, yet often overlooked, modulator of the tumor microenvironment and therapeutic response. The review delineates the utility and limitations of these models, specifically addressing the MHC incompatibilities of the widely used C6 model in immunotherapy research, while contrasting it with the immune-evasive phenotypes of RG2 and the GB 101.8 tissue model. Furthermore, we highlight the superiority of tissue transplants in preserving cellular polyclonality and diffuse infiltration patterns compared to the circumscribed growth often observed in cell line-derived tumors. Consequently, we propose a strategic selection paradigm wherein immunogenic models serve as bioindicators of host immunocompetence, while invasive, non-immunogenic systems (F98, RG2, and GB 101.8) are utilized to investigate therapeutic resistance and systemic host-tumor interactions. Full article

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a median survival of 14–15 months despite aggressive treatment. Monitoring relies on MRI, but differentiating tumor progression from pseudo-progression or radiation necrosis remains difficult. Plasma extracellular vesicles (EVs) are emerging as promising non-invasive biomarkers due to their molecular cargos and accessibility. This review evaluates studies that specifically isolated plasma EVs for molecular profiling in GBM diagnosis and monitoring. Biomarkers (miRNA, RNA, DNA, proteins), EV characterization methods, and advancements in enriching tumor-derived EV subpopulations and assessing their diagnostic and prognostic potential are highlighted. Plasma EVs carry diverse cargos, including miRNAs (e.g., miR-21, miR-15b-3p), mRNAs (e.g., EGFRvIII), circRNAs, and proteins (e.g., CD44, GFAP). Composite molecular signatures have achieved sensitivities of 87–100% and specificities of 73–100% for GBM diagnosis. Tumor-derived EVs, enriched using techniques like SEC-CD44 immunoprecipitation, microfluidic platforms, or 5-ALA-induced PpIX fluorescence, enhance biomarker detection. Non-tumor-derived EVs may also reflect GBM’s systemic effects. Challenges include EV heterogeneity, non-EV contamination, and variable biomarker expression across studies. Plasma-EV-based liquid biopsies offer significant potential for GBM monitoring, with advanced enrichment methods improving tumor-specific biomarker detection. Standardizing isolation protocols and validating biomarkers in larger cohorts are critical for clinical translation. Full article

Background/Objectives: High-grade gliomas (HGGs), including glioblastomas, are among the most aggressive brain tumors due to their high intratumoral heterogeneity and extensive infiltration. Glioma stem-like cells (GSCs) frequently invade along white matter tracts such as the corpus callosum, but the molecular programs driving this region-specific invasion remain poorly defined. The aim of this study was to identify transcriptional signatures associated with GSC infiltration into the corpus callosum. Methods: We established an orthotopic xenograft model by implanting fluorescently labeled human GSCs into nude mouse brains. Tumor growth and invasion patterns were assessed using tissue clearing, light-sheet fluorescence microscopy, and histological analyses. To characterize region-specific molecular profiles, we performed microfluidic-based single-cell RNA expression analysis of 48 invasion- and stemness-related genes in cells isolated from the tumor bulk (TB) and corpus callosum (CC). Results: By six weeks post-implantation, GSCs displayed marked tropism for the corpus callosum, with distinct infiltration patterns captured by three-dimensional imaging. Single-cell gene expression profiling revealed significant differences in 7 of the 48 genes (14.6%) between TB- and CC-derived GSCs. These genes—NES, CCND1, GUSB, NOTCH1, E2F1, EGFR, and TGFB1—collectively defined a “corpus callosum invasion signature” (CC-Iv). CC-derived cells showed a unimodal, high-expression profile of CC-Iv genes, whereas TB cells exhibited bimodal distributions, suggesting heterogeneous transcriptional states. Importantly, higher CC-Iv expression correlated with worse survival in patients with low-grade gliomas. Conclusions: This multimodal approach identified a corpus callosum-specific invasion signature in glioma stem-like cells, revealing how local microenvironmental cues shape transcriptional reprogramming during infiltration. These findings provide new insights into the spatial heterogeneity of gliomas and highlight potential molecular targets for therapies designed to limit tumor spread through white matter tracts. Full article