Search Results (97)

Background/Objectives: Cancer pain affects 55–95% of patients with advanced malignancy, representing a complex syndrome involving nociceptive, neuropathic and nociplastic mechanisms. Despite therapeutic advances, two-thirds of patients with metastatic cancer experience inadequate pain control. This scoping review synthesizes recent advances in cancer pain pathophysiology and management, focusing on molecular and cellular mechanisms, emerging pharmacological, interventional and technological therapies and key evidence gaps to inform future precision-based pain management strategies. Methods: Following PRISMA-ScR methodology, we searched PubMed, Embase, Scopus, and Web of Science for studies published between January 2022 and September 2025. After screening 3412 records, 278 studies were included and analyzed across different domains: biological mechanisms, pharmacological management, interventional and neuromodulatory approaches, radiotherapy developments, and digital health innovations. Results: Recent mechanistic research reveals cancer pain arises from tumor–neuron–immune crosstalk, with malignant cells secreting neurotrophic factors that promote axonal sprouting and nociceptor sensitization. Genetic polymorphisms and epigenetic modifications contribute to inter-individual pain variability. Management strategies are evolving toward multimodal precision medicine: NSAIDs and opioids remain foundational, complemented by adjuvant agents and interventional procedures including nerve blocks, intrathecal delivery, and neuromodulation (spinal cord and dorsal root ganglion stimulation). Stereotactic body radiotherapy demonstrates superior analgesic durability versus conventional approaches. Digital health innovations, such as mobile applications, remote monitoring, wearables, and AI-enabled predictive models, enable continuous assessment and personalized treatment optimization. Conclusions: Cancer pain management is transitioning toward mechanism-based precision medicine integrating biological insights, advanced interventional techniques, and digital technologies. However, implementation challenges persist, including limited randomized trials for interventional approaches, the incomplete external validation of AI tools, and digital health equity concerns. Future research must prioritize prospective controlled studies and equitable integration into routine care. 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

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

The cellular prion protein (PrP^C) displays a functional repertoire that extends well beyond its classical link to transmissible spongiform encephalopathies. Abundant in the nervous system and localized within lipid raft microdomains, PrP^C has emerged as a multifunctional signaling platform that regulates cell differentiation, neurogenesis, neuroprotection, and synaptic plasticity. Recent evidence highlights its dynamic expression in stem cell populations, where it participates in multimolecular complexes that control lineage commitment, particularly during neuronal differentiation. PrP^C expression tightly correlates with stem cell status, making it a promising biomarker of stemness and developmental progression. Through interactions with growth factors, extracellular matrix components, and synaptic proteins, PrP^C functions as a molecular integrator of signals essential for tissue repair and regeneration. Preclinical studies demonstrate that recombinant PrP^C can stimulate neurogenesis and tissue repair, while monoclonal antibodies modulate its physiological and pathological functions. Likewise, cell-based therapies leveraging PrP^C-enriched stem cells or PrP^C-dependent signaling profiles have shown promise in models of neurodegeneration and ischemia. Conversely, dysregulated PrP^C expression has also been observed in solid tumors, where it contributes to cancer cell survival, proliferation, metastasis, and therapy resistance, reinforcing its role as a regulator of cell fate and an oncological target. This review integrates stem cell biology, tissue regeneration, and oncology into a unified framework, offering a novel perspective in which PrP^C emerges as a shared molecular hub governing both physiological repair and pathological tumor behavior, opening previously unrecognized conceptual and translational opportunities. Full article

The expression of polysialic acid (polySia) on the neuronal cell adhesion molecule (NCAM) is called NCAM-polysialylation, which is strongly related to the migration and invasion of tumor cells and aggressive clinical status. During the NCAM polysialylation process, polysialyltransferases (polySTs), such as polysialyltransferase IV (ST8SIA4) or polysialyltransferase II (ST8SIA2), can catalyze the addition of CMP-sialic acid (CMP-Sia) to the NCAM to form polysialic acid (polySia). In this study, the docking models of polysialyltransferase IV (ST8Sia4) protein and different ligands were predicted using Alphafold 3 and DiffDock servers, and the prediction accuracy was further verified using the NMR experimental spectra of the interactions between polysialyltransferase domain (PSTD), a crucial peptide domain in ST8Sia4, and a different ligand. This combination strategy provides new insights into a quick and effective screening for inhibitors of tumor cell migration. Full article

The brain and the immune system communicate in many ways and interact directly at neuroimmune interfaces at brain borders, such as hippocampus, choroid plexus, and gateway reflexes. The first part of this review described intercellular communication (synapses, extracellular vesicles, and tunneling nanotubes) during homeostasis and neuroimmunomodulation upon dysfunction. This second part compares spatial orientation, learning, and memory function in both systems. The hippocampus, deep in the medial temporal lobes of the brain, is reported to play a central role in all three functions. Its medial entorhinal cortex contains neuronal spatial cells (place cells, head direction cells, boundary vector cells, and grid cells) that facilitate spatial navigation and allow the construction of cognitive maps. Sensory input (about 100 megabytes per second) via engram neurons and top down and bottom up information processing between the temporal lobes and other lobes of the brain are described to facilitate learning and memory function. Output impulses leave the brain via approximately 1.5 million fibers, which connect to effector organs such as muscles and glands. Spatial orientation in the immune system is described to involve gradients of chemokines, chemokine receptors, and cell adhesion molecules. These facilitate immune cell interactions with other cells and the extracellular matrix, recirculation via lymphatic organs (lymph nodes, thymus, spleen, and bone marrow), and via lymphatic fluid, blood, cerebrospinal fluid, and tissues. Learning in the immune system is summarized to include recognition of exogenous antigens from the outside world as well as endogenous blood-borne antigens, including tumor antigens. This learning process involves cognate interactions through immune synapses and the distinction between self and non-self antigens. Immune education via vaccination helps the process of development of protective immunity. Examples are presented concerning the therapeutic potential of memory T cells, in particular those derived from bone marrow. Like in the brain, memory function in the immune system is described to be facilitated by priming (imprinting), training, clonal cooperation, and an integrated perception of objects. The discussion part highlights evolutionary aspects. Full article

The FAM171A2 gene encodes a transmembrane protein that is not well characterized but is implicated in signaling, vesicle trafficking, and interactions with the extracellular matrix. Its specific role in gynecologic malignancies has yet to be defined. To our knowledge, this is the first systematic study to comprehensively assess FAM171A2 expression, clinical relevance, and molecular network interactions in gynecologic malignancies. We employed an integrative approach utilizing multi-platform transcriptomic and proteomic resources—GEPIA2, TNMplot, TIMER2, UALCAN, KM-plotter, Human Protein Atlas (HPA), Gene Expression Omnibus (GEO), STRING, TargetScan, and ENCORI—to comprehensively profile FAM171A2 expression, its clinicopathologic correlations, survival associations, predicted interaction networks, and post-transcriptional regulation in ovarian cancer (OV) and uterine corpus endometrial carcinoma (UCEC). Immunohistochemical analysis from the HPA indicated low or undetectable levels of the FAM171A2 protein in OV and UCEC. In contrast, RNA sequencing analyses demonstrated upregulated mRNA expression in OV and a modest, non-significant increase in UCEC compared to normal tissues. Pan-cancer screening using TNMplot and TIMER2 revealed elevated expression in gynecologic tumors relative to most other cancer types. In OV, UALCAN analysis identified associations with demographic and molecular characteristics, such as increased expression in TP53-mutant tumors, while trends related to stage and grade were minimal. Similarly, stratifications in UCEC suggested modulation by race, body mass index (BMI), and menopausal status rather than stage. Survival analyses using KM-plotter showed no significant association with overall survival in either type of cancer. TargetScan predicted 211 microRNAs potentially targeting FAM171A2, and ENCORI correlations supported tumor-type-specific post-transcriptional regulation: in OV, negative correlations were observed with miR-15b-5p, miR-16-5p, and miR-497-5p, along with long non-coding RNA (lncRNA) effects, including positive correlations with BACE1-AS and negative correlations with PVT1 and UCA1. In UCEC, significant negative correlations were found with LINC00582, LINC-ROR, MEG3, NEAT1, and SNHG12. STRING network analysis suggested two modules associated with FAM171A2: a neuronal/synaptic cluster, exemplified by NPTX1, and an immune/transcriptional cluster, exemplified by ZNF696. Validation using the GEO showed mixed results: two UCEC datasets were non-significant, whereas one OV cohort (GSE36368) exhibited higher tumor expression. FAM171A2 demonstrates context-dependent expressions that are modulated post-transcriptionally in gynecologic cancers. While it is not independently prognostic, it may serve as a molecular hub at the intersection of neuronal and immune pathways, warranting further mechanistic investigations and exploration as a panel-based biomarker. Full article

Cancer neuroscience is an emerging field revealing how malignancies interact with the nervous system to shape disease progression and symptom burden. In colorectal cancer (CRC), increasing evidence suggests a direct interplay between tumor cells and peripheral sensory neurons, contributing not only to cancer progression but also to chemotherapy-induced side effects such as peripheral neuropathy. Chemokines, particularly CCL3, appear to be key players in this bidirectional communication. This literature review aims to critically examine the role of CCL3 in CRC and chemotherapy-induced peripheral neuropathy (CIPN), with a focus on identifying potential mechanistic overlaps. Specifically, we evaluate whether CCL3 may serve as a molecular link between cancer progression and the development of neuropathic pain. In CRC, CCL3 is frequently upregulated, promoting tumor proliferation, invasion, and immune remodeling through CCR5- and MAPK-dependent pathways. Elevated CCL3 expression correlates with advanced stage, nerve infiltration, and worse prognosis, while select studies suggest it may also enhance antitumor immunity via dendritic cell recruitment. In parallel, CCL3 is also upregulated in the nervous system during CIPN, where it contributes to chronic pain through activation of glial cells, sensitization of nociceptive pathways (e.g., TRPV1, P2X7), and desensitization of opioid receptors. Notably, MAPK signaling is a shared downstream pathway in both contexts, suggesting a potential mechanistic bridge between tumor biology and neurotoxicity. In conclusion, CCL3 emerges as a central molecule at the intersection of CRC and CIPN. Understanding its context-dependent roles may offer new opportunities for risk prediction, biomarker development, and therapeutic intervention—contributing to the broader goals of cancer neuroscience in improving both oncologic and neurologic outcomes. Full article

Background and objectives: Melanocytic nevi are among the most common skin lesions, yet their relationship with the peripheral nervous system has remained understudied. Given the neural crest origin of melanocytes and Schwann cells, and the neurotrophic signaling capabilities of pigment cells, this study aimed to investigate the density of nerve fibers within nevi and assess how it varies with respect to histological subtype and anatomical location. Materials and Methods: A total of 90 nevi were analyzed, including junctional, compound, and intradermal types, distributed across the head, trunk, and limbs. Immunofluorescence staining for the pan-neuronal marker PGP 9.5 and for CGRP were performed and nerve fiber density was quantified. Statistical evaluation using two-way ANOVA revealed that both nevus type and anatomical site significantly influenced the degree of total innervation. Results: Junctional nevi demonstrated the highest total nerve fiber density, significantly exceeding that of compound and intradermal nevi. Likewise, nevi located on the head exhibited a significantly greater density of PGP 9.5-positive nerve fibers compared to those on the trunk and limbs. No significant correlation was observed between nevus type and location, suggesting that both factors contribute independently to the differences in innervation. CGRP-positive innervation was uniform regardless of the histological type of nevus and anatomical location. Conclusions: These findings likely reflect the facts that junctional nevi reside at the dermo-epidermal junction, where nerve fibers are most abundant, while the skin of the head and neck is well known to be more richly innervated than other regions. In contrast, analysis of CGRP-positive fibers suggests that the heterogeneity detected with PGP 9.5 is primarily driven by other neuronal populations. The results support the hypothesis of a dynamic relationship between nevi and the peripheral nervous system, potentially mediated by neurotrophic factors. Understanding this interaction may provide insight into nevus biology, sensory symptoms reported in some lesions, and the evolving role of nerves in the tumor microenvironment. Full article

Innervation is ubiquitous in diseased tissues, including cancer. Increasing evidence suggests that innervation not only plays a direct role in cancer pain, but is also closely related to disease progression, including cancer growth, metastasis, and drug resistance. At the molecular level, tumor-associated nerves can interact with cancer cells and the tumor microenvironment through neurotrophic factors, thereby promoting tumor occurrence and development, and represent a potential intervention for solid tumors with nerve enrichment. By dissecting the transcriptome dynamics of cancer-associated neurons with single cell resolution, numbers of novel therapeutic targets for tumor denervation have been uncovered, including a novel phenomenon—Macrophage to Neuron-like cell Transition (MNT). This review systematically summarizes the latest research findings of tumor denervation, from molecular mechanisms to the innovative denervation strategies, paving the way for novel, safe, and effective cancer treatments in the clinic. Full article

Background: The vast majority of GBMs recur within 2 years following standard treatment, including radiotherapy. Seizures and epilepsy are common in GBM patients, suggesting tumor-cell-induced neuron toxicity. Additionally, the tumor cells and neurons interact during tumor development; however, the effects of tumor cells on the neurons remain unclear. Methods: Orthotopic xenografts initiated from GSCs expressing GFP implanted into the right striatum of nude mice were irradiated (10 Gy) 35 days after implantation, followed by immunohistochemistry (IHC) to investigate the tumor cell–neuron interactions. Moreover, we established a direct coculture of human GSCs and neurons differentiated from human iPSC-derived neural progenitor cells (NPCs) to investigate the impact of the tumor cells on the neurons. Neuronal cell counts were monitored to assess neurotoxicity. Culture CM were analyzed through cytokine profiling. Results: In untreated mice, tumors invaded across the right hemisphere (RH), with increased cell contact with the mouse neurons. In irradiated mice, the tumor regrowth was less invasive and had fewer neurons. In vitro, the GSCs induced neuronal death in the direct coculture. Similarly, the CM from the direct cocultures caused significant neuronal death. The cytokine analysis revealed that the cocultures uniquely secreted IL-8 into the CM. Furthermore, treatment with recombinant (r) human IL-8 caused significant neuron death, while IL-8 blocking antibodies prevented this neurotoxicity in the coculture. Conclusions: This study demonstrates that GBM tumors regrown after radiation lack neurons, and direct interaction between GSCs and the neurons is necessary for GSC-mediated neurotoxicity, likely involving IL-8 in neuronal death. Full article

PR/SET domain 2 (PRDM2)/RIZ is a member of the histone/protein methyltransferases (PRDMs) superfamily. Discovered to have the ability to bind retinoblastoma in the mid-1990s, PRDM2 was assumed to play a role in neuronal development. Like other family members characterized by a conserved N-terminal PR structural domain and a classical C2H2 zinc-finger array at the C-terminus, PRDM2 encodes two major protein types, the RIZ1 and RIZ2 isoforms. The two subtypes differ in the presence or absence of the PR domain: the RIZ1 subtype has the PR domain, whereas the RIZ2 subtype lacks it. The PR domain exhibits varying conservation levels across species and shares structural and functional similarities with the catalytic SET domain, defining histone methyltransferases. Functioning as an SET domain, the PR domain possesses protein-binding interfaces and acts as a lysine methyltransferase. The variable number of classic C2H2 zinc fingers at the C-terminus may mediate protein–protein, protein–RNA, or protein–DNA interactions. An imbalance in the RIZ1/RIZ2 mechanism may be an essential cause of malignant tumors, where PR-positive isoforms are usually lost or downregulated. Conversely, PR-negative isoforms are always present at higher levels in cancer cells. RIZ1 isoforms are also important targets for estradiol interaction with hormone receptors. PRDM2 can regulate gene transcription and expression combined with transcription factors and plays a role in the development of several systemic diseases through mRNA expression deletion, code-shift mutation, chromosomal deletion, and missense mutation occurrence. Thus, PRDM2 is a key indicator for disease diagnosis, but it lacks systematic summaries to serve as a reference for study. Therefore, this paper describes the structure and biological function of PRDM2 from the perspective of its role in various systemic diseases. It also organizes and categorizes its latest research progress to provide a systematic theoretical basis for a more in-depth investigation of the molecular mechanism of PRDM2’s involvement in disease progression and clinical practice. Full article

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, largely due to its profound intratumoral heterogeneity and immunosuppressive microenvironment. Various classifications of GBM subtypes were created based on transcriptional and methylation profiles. This effort, followed by the development of new technology such as single-nuclei sequencing (snRNAseq) and spatial transcriptomics, led to a better understanding of the glioma cells’ plasticity and their ability to transition between diverse cellular states. GBM cells can mimic neurodevelopmental programs to resemble oligodendrocyte or neural progenitor behavior and hitchhike the local neuronal network to support their growth. The tumor microenvironment, especially under hypoxic conditions, drives the tumor cell clonal selection, which then reshapes the immune cells’ functions. These adaptations contribute to immune evasion by progressively disabling T cell and myeloid cell functions, ultimately establishing a highly immunosuppressive tumor milieu. This complex and metabolically constrained environment poses a major barrier to effective antitumor immunity and limits the success of conventional therapies. Understanding the dynamic interactions between glioma cells and their microenvironment is essential for the development of more effective immunotherapies and rational combination strategies aimed at overcoming resistance and improving patient outcomes. Full article

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article

Background: Spinal cord injury (SCI) remains a profound medical challenge, with limited therapeutic options available. Studies focusing on individual molecular markers have limitations in addressing the complex disease process. Methods: This study utilizes RNA-sequencing (RNA-seq) to investigate the differentially expressed genes (DEGs) in spinal cord tissue from a rat SCI model at 1 and 21 days post-injury (dpi). After data processing and analysis, a series of biological pathway enrichment analyses were performed using online tools DAVID and GSEA. Interactions among the enriched genes were studied using Cytoscape software to visualize protein–protein interaction networks. Results: Our analysis identified 595 DEGs, with 399 genes significantly upregulated and 196 significantly downregulated at both time points. CD68 was the most upregulated gene at 21 dpi, with a significant fold change at 1 dpi. Conversely, MPZ was the most downregulated gene. Key immune response processes, including tumor necrosis factor (TNF) production, phagocytosis, and complement cascades, as well as systemic lupus erythematosus (SLE)-associated pathways, were enriched in the upregulated group. The enriched pathways in the downregulated group were related to the myelin sheath and neuronal synapse. Genes of interest from the most significantly downregulated DEGs were SCD, DHCR24, PRX, HHIP, and ZDHHC22. Upregulation of Fc-γ receptor genes, including FCGR2B and FCGR2A, points to potential autoimmune mechanisms. Conclusions: Our findings highlight complex immune and autoimmune responses that contribute to ongoing inflammation and tissue damage post-SCI, underscoring new avenues for therapeutic interventions targeting these molecular processes. Full article