Search Results (22)

Background/Objectives: Glioblastoma (GBM) is a highly aggressive primary central nervous system tumor with a median survival of 14 months. MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation status is a key biomarker as a prognostic indicator and a predictor of chemotherapy response in GBM. Patients with MGMT methylated disease progress later and survive longer (median survival rate 22 vs. 15 months, respectively) as compared to patients with MGMT unmethylated disease. Patients with GBM undergo an MRI of the brain prior to diagnosis and following surgical resection for radiation therapy planning and ongoing follow-up. There is currently no imaging biomarker for GBM. Studies have attempted to connect MGMT methylation status to MRI imaging appearance to determine if brain MRI can be leveraged to provide MGMT status information non-invasively and more expeditiously. Methods: Artificial intelligence (AI) can identify MRI features that are not distinguishable to the human eye and can be linked to MGMT status. We employed the UPenn-GBM dataset patients for whom methylation status was available (n = 146), employing a novel radiomic method grounded in hybrid feature selection and weighting to predict MGMT methylation status. Results: The best MGMT classification and feature selection result obtained resulted in a mean accuracy rate value of 81.6% utilizing 101 selected features and five-fold cross-validation. Conclusions: This compared favorably with similar studies in the literature. Validation with external datasets remains critical to enhance generalizability and propagate robust results while reducing bias. Future directions include multi-channel data integration with radiomic features and deep and ensemble learning methods to improve predictive performance. Full article

Background: This short review and pictorial essay presents a morphological insight into cancer neuroscience, which is a complex and dynamic area of the pathobiology of tumors. Methods: We discuss the different methods and issues connected with structural research on tumor innervation, interactions between neoplastic cells and the nervous system, and dysregulated neural influence on cancer phenotypes. Results: Perineural invasion (PNI), the most-visible cancer–nerve relation, is briefly presented, focusing on its pathophysiology and structural diversity as well as its clinical significance. The morphological approach to cancer neurobiology further includes the analysis of neural density/axonogenesis, neural network topographic distribution, and composition of fiber types and size. Next, the diverse range of neurotransmitters and neuropeptides and the neuroendocrine differentiation of cancer cells are reviewed. Another morphological area of cancer neuroscience is spatial or quantitative neural-related marker expression analysis through different detection, description, and visualization methods, also on experimental animal or cellular models. Conclusions: Morphological studies with systematic methodologies provide a necessary insight into the structure and function of the multifaceted tumor neural microenvironment and in context of possible new therapeutic neural-based oncological solutions. Full article

The link between neurodegenerative diseases (NDs) and cancer has generated greater interest in biomedical research, with decades of global studies investigating neurodegenerative biomarkers in cancer to better understand possible connections. Tau, amyloid-β, α-synuclein, SOD1, TDP-43, and other proteins associated with nervous system diseases have also been identified in various types of solid and malignant tumors, suggesting a potential overlap in pathological processes. In this review, we aim to provide an overview of current evidence on the role of these proteins in cancer, specifically examining their effects on cell proliferation, apoptosis, chemoresistance, and tumor progression. Additionally, we discuss the diagnostic and therapeutic implications of this interconnection, emphasizing the importance of further research to completely comprehend the clinical implications of these proteins in tumors. Finally, we explore the challenges and opportunities in targeting these proteins for the development of new targeted anticancer therapies, providing insight into how to integrate knowledge of NDs in oncology research. Full article

Pancreatic ductal adenocarcinoma is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. Progress in the management of metastatic disease has been modest. A robust connection between nervous system and tumor progression exists, with prominent neural alterations having been observed during pancreatic cancer’s progression, including neural hypertrophy, neural density, and neural remodeling. The pancreatic tumor microenvironment includes s set of cells and structures that constantly dialogue with cancer cells, influencing its growth and behavior. The microglia is key cellular components of the tumor microenvironment, and Schwann cells are the principal glial cells in the peripheral neural system. Schwann cells can regulate changes in the tumor microenvironment and immune responses by secreting a variety of factors and can support a tumor’s invasion of nerves and distant metastasis, with further pain exacerbation. Schwann cells secrete various pain-related molecules, such as the neural growth factor, to mediate the activation of primary sensory neurons, leading to pain induction. The binding of the neural growth factor to tropomyosin receptor kinase A is an important signaling mechanism for pain perception in humans. Consequently, directing efforts towards targeting neural invasion may provide an alternative strategy to improve the prognosis of and alleviate pain in patients with pancreatic cancer. Full article

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, including the CNS. Among them, a flavonoid compound, sophoraflavanone G (SG), found in Sophora flavescens has been found to possess several medicinal properties, including anti-bacterial and anti-inflammatory effects. In this study, mouse brain microvascular endothelial cells (bMECs) were used to explore TNF-α-induced MMP-9 signaling. The effects of SG on TNF-α-induced MMP-9 expression and its mechanisms were further evaluated. Our study revealed that the expression of MMP-9 in bMECs was stimulated by TNF-α through the activation of ERK1/2, p38 MAPK, and JNK1/2 via the TNF receptor (TNFR) with a connection to the NF-κB signaling pathway. Moreover, we found that SG can interact with the TNFR. The upregulation of MMP-9 by TNF-α may lead to the disruption of zonula occludens-1 (ZO-1), which can be mitigated by SG administration. These findings provide evidence that SG may possess neuroprotective properties by inhibiting the signaling pathways associated with TNFR-mediated MMP-9 expression and the subsequent disruption of tight junctions in brain microvascular endothelial cells. Full article

This paper delves into the intricate structure and functionality of the brain’s glymphatic system, bringing forth new dimensions in its neuroscientific understanding. This paper commences by exploring the cerebrospinal fluid (CSF)—its localization, production, and pivotal role within the central nervous system, acting as a cushion and vehicle for nutrient distribution and waste elimination. We then transition into an in-depth study of the morphophysiological aspects of the glymphatic system, a recent discovery revolutionizing the perception of waste clearance from the brain, highlighting its lymphatic-like characteristics and remarkable operations. This paper subsequently emphasizes the glymphatic system’s potential implications in Alzheimer’s disease (AD), discussing the connection between inefficient glymphatic clearance and AD pathogenesis. This review also elucidates the intriguing interplay between the glymphatic system and the circadian rhythm, illustrating the optimal functioning of glymphatic clearance during sleep. Lastly, we underscore the hitherto underappreciated involvement of the glymphatic system in the tumoral microenvironment, potentially impacting tumor growth and progression. This comprehensive paper accentuates the glymphatic system’s pivotal role in multiple domains, fostering an understanding of the brain’s waste clearance mechanisms and offering avenues for further research into neuropathological conditions. Full article

Gliomas are common tumors of the central nervous system. The PLINs family is widely involved in the regulation of lipid metabolism and has been associated with the development and invasive metastasis of various malignancies. However, the biological role of the PLINs family in gliomas is still unclear. TIMER and UALCAN were used to assess PLINs mRNA expression in gliomas. “Survminer” and “Survival” were used to evaluate the connection between PLINs expression and glioma patients’ survival. cBioPortal was applied to assess PLINs’ genetic alterations in glioblastoma multiforme (GBM) and low-grade glioma (LGG). The correlation of PLINs expression with tumor immune cells was analyzed by TIMER. The expressions of PLIN1, PLIN4, and PLIN5 were decreased in GBM compared to normal tissues. However, PLIN2 and PLIN3 were significantly increased in GBM. Prognostic analysis showed that LGG patients with high PLIN1 expression had better overall survival (OS), and high expression of PLIN2/3/4/5 was associated with unfavorable OS. We further determined that the expression of PLINs members in gliomas was strongly related to tumor immune cells and immune checkpoint-associated genes. PLINS may be potential biomarkers for regulating the tumor microenvironment and predicting the efficacy of immunotherapy. In addition, we determined that PLIN1 may affect glioma patients’ therapeutic sensitivity to temozolomide. Our results demonstrated the biological significance and clinical values of PLINs in gliomas and provide a basis for future in-depth exploration of the specific mechanisms of each member of PLINs in gliomas. Full article

Glioma is the most prevalent and aggressive primary nervous system tumor with an unfavorable prognosis. Microtubule plus-end-related genes (MPERGs) play critical biological roles in the cell cycle, cell movement, ciliogenesis, and neuronal development by coordinating microtubule assembly and dynamics. This research seeks to systematically explore the oncological characteristics of these genes in microtubule-enriched glioma, focusing on developing a novel MPERG-based prognostic signature to improve the prognosis and provide more treatment options for glioma patients. First, we thoroughly analyzed and identified 45 differentially expressed MPERGs in glioma. Based on these genes, glioma patients were well distinguished into two subgroups with survival and tumor microenvironment infiltration differences. Next, we further screened the independent prognostic genes (CTTNBP2, KIF18A, NAV1, SLAIN2, SRCIN1, TRIO, and TTBK2) using 36 prognostic-related differentially expressed MPERGs to construct a signature with risk stratification and prognostic prediction ability. An increased risk score was related to the malignant progression of glioma. Therefore, we also designed a nomogram model containing clinical factors to facilitate the clinical use of the risk signature. The prediction accuracy of the signature and nomogram model was verified using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. Finally, we examined the connection between the signature and tumor microenvironment. The signature positively correlated with tumor microenvironment infiltration, especially immunoinhibitors and the tumor mutation load, and negatively correlated with microsatellite instability and cancer stemness. More importantly, immune checkpoint blockade treatment and drug sensitivity analyses confirmed that this prognostic signature was helpful in anticipating the effect of immunotherapy and chemotherapy. In conclusion, this research is the first study to define and validate an MPERG-based signature closely associated with the tumor microenvironment as a reliable and independent prognostic biomarker to guide personalized choices of immunotherapy and chemotherapy for glioma patients. Full article

Gliomas are the most frequent central nervous system (CNS) primary tumors. The prognosis and clinical outcomes of these malignancies strongly diverge according to their molecular alterations and range from a few months to decades. The tumor-associated microenvironment involves all cells and connective tissues surrounding tumor cells. The composition of the microenvironment as well as the interactions with associated neoplastic mass, are both variables assuming an increasing interest in these last years. This is mainly because the microenvironment can mediate progression, invasion, dedifferentiation, resistance to treatment, and relapse of primary gliomas. In particular, the tumor microenvironment strongly diverges from isocitrate dehydrogenase (IDH) mutated and wild-type (wt) tumors. Indeed, IDH mutated gliomas often show a lower infiltration of immune cells with reduced angiogenesis as compared to IDH wt gliomas. On the other hand, IDH wt tumors exhibit a strong immune infiltration mediated by several cytokines and chemokines, including CCL2, CCL7, GDNF, CSF-1, GM-CSF, etc. The presence of several factors, including Sox2, Oct4, PD-L1, FAS-L, and TGF β2, also mediate an immune switch toward a regulatory inhibited immune system. Other important interactions are described between IDH wt glioblastoma cells and astrocytes, neurons, and stem cells, while these interactions are less elucidated in IDH-mutated tumors. The possibility of targeting the microenvironment is an intriguing perspective in terms of therapeutic drug development. In this review, we summarized available evidence related to the glioma microenvironment, focusing on differences within different glioma subtypes and on possible therapeutic development. Full article

Central nervous system disorders, especially neurodegenerative diseases, are a public health priority and demand a strong scientific response. Various therapy procedures have been used in the past, but their therapeutic value has been insufficient. The blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier is two of the barriers that protect the central nervous system (CNS), but are the main barriers to medicine delivery into the CNS for treating CNS disorders, such as brain tumors, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Nanotechnology-based medicinal approaches deliver valuable cargos targeting molecular and cellular processes with greater safety, efficacy, and specificity than traditional approaches. CNS diseases include a wide range of brain ailments connected to short- and long-term disability. They affect millions of people worldwide and are anticipated to become more common in the coming years. Nanotechnology-based brain therapy could solve the BBB problem. This review analyzes nanomedicine’s role in medication delivery; immunotherapy, chemotherapy, and gene therapy are combined with nanomedicines to treat CNS disorders. We also evaluated nanotechnology-based approaches for CNS disease amelioration, with the intention of stimulating the immune system by delivering medications across the BBB. Full article

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections. Full article

We propose an overview of the molecular cues and their intracellular signaling involved in the crosstalk between cancer and the nervous system. While “cancer neuroscience” as a field is still in its infancy, the relation between cancer and the nervous system has been known for a long time, and a huge body of experimental data provides evidence that tumor–nervous system connections are widespread. They encompass different mechanisms at different tumor progression steps, are multifaceted, and display some intriguing analogies with the nervous system’s physiological processes. Overall, we can say that many of the paradigmatic “hallmarks of cancer” depicted by Weinberg and Hanahan are affected by the nervous system in a variety of manners. Full article

Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy. Full article

Fatty acids (FAs) are essential components of the central nervous system (CNS), where they exert multiple roles in health and disease. Among the FAs, docosahexaenoic acid (DHA) has been widely recognized as a key molecule for neuronal function and cell signaling. Despite its relevance, the molecular pathways underlying the beneficial effects of DHA on the cells of the CNS are still unclear. Here, we summarize and discuss the molecular mechanisms underlying the actions of DHA in neural cells with a special focus on processes of survival, morphological development, and synaptic maturation. In addition, we examine the evidence supporting a potential therapeutic role of DHA against CNS tumor diseases and tumorigenesis. The current results suggest that DHA exerts its actions on neural cells mainly through the modulation of signaling cascades involving the activation of diverse types of receptors. In addition, we found evidence connecting brain DHA and ω-3 PUFA levels with CNS diseases, such as depression, autism spectrum disorders, obesity, and neurodegenerative diseases. In the context of cancer, the existing data have shown that DHA exerts positive actions as a coadjuvant in antitumoral therapy. Although many questions in the field remain only partially resolved, we hope that future research may soon define specific pathways and receptor systems involved in the beneficial effects of DHA in cells of the CNS, opening new avenues for innovative therapeutic strategies for CNS diseases. Full article

Many nervous proteins are expressed in cancer cells. In this report, we asked whether the synaptic protein neuroligin 1 (NLGN1) was expressed by prostatic and pancreatic carcinomas; in addition, given the tendency of these tumors to interact with nerves, we asked whether NLGN1 played a role in this process. Through immunohistochemistry on human tissue microarrays, we showed that NLGN1 is expressed by prostatic and pancreatic cancer tissues in discrete stages and tumor districts. Next, we performed in vitro and in vivo assays, demonstrating that NLGN1 promotes cancer cell invasion and migration along nerves. Because of the established role of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) in tumor–nerve interactions, we assessed a potential NLGN1–GDNF cooperation. We found that blocking GDNF activity with a specific antibody completely inhibited NLGN1-induced in vitro cancer cell invasion of nerves. Finally, we demonstrated that, in the presence of NLGN1, GDNF markedly activates cofilin, a cytoskeletal regulatory protein, altering filopodia dynamics. In conclusion, our data further prove the existence of a molecular and functional cross-talk between the nervous system and cancer cells. NLGN1 was shown here to function along one of the most represented neurotrophic factors in the nerve microenvironment, possibly opening new therapeutic avenues. Full article