Primary Human Brain Tumors Research Articles

Effect of luteolin on glioblastoma's immune microenvironment and tumor growth suppression

BackgroundGlioblastoma is the most malignant and prevalent primary human brain tumor, and the immunological microenvironment controlled by glioma stem cells is one of the essential elements contributing to its malignancy. The use of medications to ameliorate the tumor microenvironment may give a new approach for glioma treatment. MethodsGlioma stem cells were separated from clinical patient-derived glioma samples for molecular research. Other studies, including CCK8, EdU, Transwell, and others, supported luteolin's ability to treat glioma progenitor cells. Network pharmacology and molecular docking models were used to study the drug target, and qRT-PCR, WB, and IF were used to evaluate the molecular mechanism. Intracranial xenografts were examined using HE and IHC, while macrophage polarization was examined using FC. ResultsWe originally discovered that luteolin inhibits glioma stem cells. IL6 released by glioma stem cells is blocked during medication action and inhibits glioma stem cell proliferation and invasion via the IL6/STAT3 signaling pathway. Additionally, luteolin inhibits the secretion of TGFβ1, affects the polarization function of macrophages in the microenvironment, inhibits the polarization of M2 macrophages in TAM, and further inhibits various functions of glioma stem cells by affecting the IL6/STAT3 signaling pathway, luteolin crosstalk TGFβ1/SMAD3 signaling pathway, and so on. ConclusionsThrough the suppression of the immunological microenvironment and inhibition of the IL6/STAT3 signaling pathway, our study determined the inhibitory effect of luteolin on glioma stem cells. This medication's dual inhibitory action, which has a significant negative impact on the glioma stem cells' malignant process, makes it both a viable anti-glioma medication and a candidate for targeted glioma microenvironment therapy.

Upregulation of HAS2 promotes glioma cell proliferation and chemoresistance via c-myc

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant human brain tumor. Although comprehensive therapies, including chemotherapy and radiotherapy following surgery, have shown promise in prolonging survival, the prognosis for GBM patients remains poor, with an overall survival rate of only 14.6 months. Chemoresistance is a major obstacle to successful treatment and contributes to relapse and poor survival rates in glioma patients. Therefore, there is an urgent need for novel strategies to overcome chemoresistance and improve treatment outcomes for human glioma patients. Recent studies have shown that the tumor microenvironment plays a key role in chemoresistance. Our study demonstrates that upregulation of HAS2 and subsequent hyaluronan secretion promotes glioma cell proliferation, invasion, and chemoresistance in vitro and in vivo through the c-myc pathway. Targeting HAS2 sensitizes glioma cells to chemotherapeutic agents. Additionally, we found that hypoxia-inducible factor HIF1α regulates HAS2 expression. Together, our findings provide insights into the dysregulation of HAS2 and its role in chemoresistance and suggest potential therapeutic strategies for GBM.

Neuropathological Applications of Microscopy with Ultraviolet Surface Excitation (MUSE): A Concordance Study of Human Primary and Metastatic Brain Tumors.

Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.

CLEC19A overexpression inhibits tumor cell proliferation/migration and promotes apoptosis concomitant suppression of PI3K/AKT/NF-κB signaling pathway in glioblastoma multiforme.

GBM is the most frequent malignant primary brain tumor in humans. The CLEC19A is a member of the C-type lectin family, which has a high expression in brain tissue. Herein, we sought to carry out an in-depth analysis to pinpoint the role of CLEC19A expression in GBM. To determine the localization of CLEC19A, this protein was detected using Western blot, Immunocytochemistry/Immunofluorescence, and confocal microscopy imaging. CLEC19A expression in glioma cells and tissues was evaluated by qRT-PCR. Cell viability, proliferation, migration, and apoptosis were examined through MTT assay, CFSE assay, colony formation, wound healing assay, transwell test, and flow cytometry respectively after CLEC19A overexpression. The effect of CLEC19A overexpression on the PI3K/AKT/NF-κB signaling pathway was investigated using Western blot. An in vivo experiment substantiated the in vitro results using the glioblastoma rat models. Our in-silico analysis using TCGA data and measuring CLEC19A expression level by qRT-PCR determined significantly lower expression of CLEC19A in human glioma tissues compared to healthy brain tissues. By employment of ICC/IF, confocal microscopy imaging, and Western blot we could show that CLEC19A is plausibly a secreted protein. Results obtained from several in vitro readouts showed that CLEC19A overexpression in U87 and C6 glioma cell lines is associated with the inhibition of cell proliferation, viability, and migration. Further, qRT-PCR and Western blot analysis showed CLEC19A overexpression could reduce the expression levels of PI3K, VEGFα, MMP2, and NF-κB and increase PTEN, TIMP3, RECK, and PDCD4 expression levels in glioma cell lines. Furthermore, flow cytometry results revealed that CLEC19A overexpression was associated with significant cell cycle arrest and promotion of apoptosis in glioma cell lines. Interestingly, using a glioma rat model we could substantiate that CLEC19A overexpression suppresses glioma tumor growth. To our knowledge, this is the first report providing in-silico, molecular, cellular, and in vivo evidences on the role of CLEC19A as a putative tumor suppressor gene in GBM. These results enhance our understanding of the role of CLEC19A in glioma and warrant further exploration of CLEC19A as a potential therapeutic target for GBM.

Proteomic Analysis on Sequential Samples of Cystic Fluid Obtained from Human Brain Tumors.

Cystic formation in human primary brain tumors is a relatively rare event whose incidence varies widely according to the histotype of the tumor. Composition of the cystic fluid has mostly been characterized in samples collected at the time of tumor resection and no indications of the evolution of cystic content are available. We characterized the evolution of the proteome of cystic fluid using a bottom-up proteomic approach on sequential samples obtained from secretory meningioma (SM), cystic schwannoma (CS) and cystic high-grade glioma (CG). We identified 1008 different proteins; 74 of these proteins were found at least once in the cystic fluid of all tumors. The most abundant proteins common to all tumors studied derived from plasma, with the exception of prostaglandin D2 synthase, which is a marker of cerebrospinal fluid origin. Overall, the protein composition of cystic fluid obtained at different times from the same tumor remained stable. After the identification of differentially expressed proteins (DEPs) and the protein-protein interaction network analysis, we identified the presence of tumor-specific pathways that may help to characterize tumor-host interactions. Our results suggest that plasma proteins leaking from local blood-brain barrier disruption are important contributors to cyst fluid formation, but cerebrospinal fluid (CSF) and the tumor itself also contribute to the cystic fluid proteome and, in some cases, as with immunoglobulin G, shows tumor-specific variations that cannot be simply explained by differences in vessel permeability or blood contamination.

Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation

The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13-expressing CD39+ potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.

Urolithin B loaded in cerium oxide nanoparticles enhances the anti-glioblastoma effects of free urolithin B in vitro

Glioblastoma multiforme (GBM) is the most aggressive kind of malignant primary brain tumor in humans. Given the limitation of Conventional therapeutic strategy, the development of nanotechnology and natural product therapy seems to be an effective method enhancing the prognosis of GBM patients. In this research, cell viability, mRNA expressions of various apoptosis-related genes apoptosis, and generation of reactive oxygen species (ROS) in human U-87 malignant GBM cell line (U87) treated with Urolithin B (UB) and CeO2-UB. Unlike CeO2-NPs, both UB and CeO2-UB caused a dose-dependent decrease in the viability of U87 cells. The half-maximal inhibitory concentration values of UB and CeO2-UB were 315 and 250 μM after 24 h, respectively. Moreover, CeO2-UB exerted significantly higher effects on U87 viability, P53 expression, and ROS generation. Furthermore, UB and CeO2-UB increased the accumulation of U87 cells in the SUB-G1 population, decreased the expression of cyclin D1, and increased the Bax/Bcl2 ratio expression. Collectively, these data indicate that CeO2-UB exhibited more substantial anti-GBM effects than UB. Although further in vivo investigations are needed, these results proposed that CeO2-NPs could be utilized as a potential novel anti-GBM agent after further studies.

Comprehensive analysis: Necroptosis-related lncRNAs can effectively predict the prognosis of glioma patients.

Glioma is the most common and fatal primary brain tumor in humans. A significant role for long non-coding RNA (lncRNA) in glioma is the regulation of gene expression and chromatin recombination, and immunotherapy is a promising cancer treatment. Therefore, it is necessary to identify necroptosis-related lncRNAs in glioma. In this study, we collected and evaluated the RNA-sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA, https://www.ncbi.nlm.nih.gov/, Data Release 32.0, March 29, 2022) glioma patients, and necroptosis-related lncRNAs were screened. Cox regression and least absolute shrinkage and selection operator (LASSO) analysis were performed to construct a risk score formula to explore the different overall survival between high- and low-risk groups in TCGA. Gene Ontology (GO) and pathway enrichment analysis (Kyoto Encyclopedia of Genes and Genomes (KEGG)) were performed to identify the function of screened genes. The immune correlation analysis showed that various immune cells and pathways positively associated with a patient’s risk score. Furthermore, the analysis of the tumor microenvironment indicated many immune cells and stromal cells in the tumor microenvironment of glioma patients. Six necroptosis-related lncRNAs were concerned to be involved in survival and adopted to construct the risk score formula. The results showed that patients with high-risk scores held poor survival in TCGA. Compared with current clinical data, the area under the curve (AUC) of different years suggested that the formula had better predictive power. We verified that necroptosis-related lncRNAs play a significant role in the occurrence and development of glioma, and the constructed risk model can reasonably predict the prognosis of glioma. The results of these studies added some valuable guidance to understanding glioma pathogenesis and treatment, and these necroptosis-related lncRNAs may be used as biomarkers and therapeutic targets for glioma prevention.

Association Between Human Herpesvirus-6 and Primary Brain Tumors: A Systematic Review and Meta-Analysis

Aim: The present study aimed to find out the prevalence and any possible association between human herpesvirus (HHV-6) and primary brain tumors. Materials & methods: The systematic literature search was performed by finding related articles from major databases. Analysis was performed by comprehensive meta-analysis software. Results: A total of 13 (25 datasets) articles were included in the study, seven (15 datasets) of which were case/control and the rest (10 datasets) were cross-sectional studies. The pooled prevalence of HHV-6 among primary brain cancer patients was 29% (95% CI: 24–33%; I2 = 97.89%). An association was found between HHV-6 and primary brain cancer (summary odds ratio: 3.77% [95% CI: 2.59–5.49%; I2 = 19.0%]). Conclusion: Our analysis demonstrated that HHV-6 is associated with primary brain cancer. Reactivation of the virus could be triggered by the tumor, therefore, we cannot be certain that the virus appeared before the cancer development.

Inhibition of TRPM7 with carvacrol suppresses glioblastoma functions in vivo.

Glioblastoma (GBM) is the most prevalent and aggressive type of primary human brain tumours originating in the central nervous system. Despite the fact that current treatments involve surgery, chemotherapy (Temozolomide), and radiation therapy, the prognosis for patients diagnosed with GBM remains extremely poor. The standard treatment is not only unable to completely eradicate the tumour cells, but also tumour recurrence after surgical resection presents a major challenge. Furthermore, adjuvant therapies including radiation and chemotherapy have high cytotoxicity which causes extensive damage to surrounding healthy tissues and treatment is usually halted before GBM is fully eradicated. Finally, most GBM cases demonstrate temozolomide resistance, a common reason for GBM treatment failure. Therefore, there is an urgent need to develop a suitable alternative therapy that targets GBM specifically and has low cytotoxicity for healthy cells. We previously reported that transient receptor potential melastatin 7 (TRPM7) channels are aberrantly upregulated in GBM, and inhibition of TRPM7 reduced GBM cellular functions including proliferation, migration, and invasion. This suggests TRPM7 is a potential therapeutic target for GBM treatment. In this study, we investigated the effects of the TRPM7 inhibitor, carvacrol, on human GBM cell lines U87 and U251 in vivo. With the use of a flank xenograft GBM mouse model, we demonstrated that carvacrol significantly reduced the tumour size in both mice injected with U87 and U251 cells, decreased p-Akt protein level and increased p-GSK3β protein levels. Therefore, these results suggest that carvacrol may have therapeutic potential for GBM treatment.

Suicide gene therapy by canine mesenchymal stem cell transduced with thymidine kinase in a u-87 glioblastoma murine model: Secretory profile and antitumor activity.

The role played by certain domestic species such as dogs as a translational model in comparative oncology shows great interest to develop new therapeutic strategies in brain tumors. Gliomas are a therapeutic challenge that represents the most common form of malignant primary brain tumors in humans and the second most common form in dogs. Gene-directed enzyme/prodrug therapy using adipose mesenchymal stem cells (Ad-MSCs) expressing the herpes simplex virus thymidine kinase (TK) has proven to be a promising alternative in glioblastoma therapy, through its capacity to migrate and home to the tumor and delivering local cytotoxicity avoiding other systemic administration. In this study, we demonstrate the possibility for canine Ad-MSCs (cAd-MSCs) to be genetically engineered efficiently with a lentiviral vector to express TK (TK-cAd-MSCs) and in combination with ganciclovir (GCV) prodrug demonstrated its potential antitumor efficacy in vitro and in vivo in a mice model with the human glioblastoma cell line U87. TK-cAd-MSCs maintained cell proliferation, karyotype stability, and MSCs phenotype. Genetic modification significantly affects its secretory profile, both the analyzed soluble factors and exosomes. TK-cAd-MSCs showed a high secretory profile of some active antitumor immune response cytokines and a threefold increase in the amount of secreted exosomes, with changes in their protein cargo. We also found that the prodrug protein is not released directly into the culture medium by TK-cAd-MSCs. We believe that our work provides new perspectives for glioblastoma gene therapy in dogs and a better understanding of this therapy in view of its possible implantation in humans.

High myosin binding protein H expression predicts poor prognosis in glioma patients

Glioma is the most common and fatal primary brain tumor in humans. Myosin binding protein H (MYBPH), which was first identified as an important myofibrillar constituent of vertebrate skeletal and cardiac muscles, reduces cell motility and metastasis. However, its role in gliomas remains unclear. We evaluated the expression of MYBPH in glioma using Gene Expression Profiling Interactive Analysis (http://gepia.cancer-pku.cn/) and Chinese Glioma Genome Atlas (https://www.cgga.org.cn/). The results showed that MYBPH was highly expressed in glioma tissues. Moreover, MYBPH expression was significantly associated with high tumor aggressiveness and poor outcomes in glioma patients. Mechanistically, the results suggested that MYBPH might promote tumor progression by improving tumor invasion and migration. Our results establish MYBPH as an important prognostic biomarker that could be considered a potential epigenetic and immunotherapeutic target for treatment. We showed that MYBPH is a novel biomarker that is variably expressed in glioblastoma (GBM). The association of high MYBPH expression with poor prognosis in newly diagnosed GBM patients and increased expression in recurrent GBM is indicative of its role in tumor aggressiveness.

Genome-scale CRISPR Cas9a knockout screen reveals genes that control glioblastoma susceptibility to the alkylating agent temozolomide

ABSTRACT Glioblastoma is the most fatal of all primary human brain tumors, with a 14-month median survival. The mainstay therapy for this tumor involves temozolomide, surgery, radiotherapy, and tumor-treating electric field. Cancer resistance to commonly available chemotherapeutics remains a major challenge in glioblastoma patients receiving treatment and unfavorably impacts their overall survival and outcome. However, the lack of progress in this area could be attributed to the lack of tools to probe unbiasedly at the genome-wide level the coding and non-coding elements’ contribution on a large scale for factors that control resistance to chemotherapeutics. Understanding the mechanisms of resistance to chemotherapeutics will enable precision medicine in the treatment of cancer patients. CRISPR Cas9a has emerged as a functional genomics tool to study at the genome level the factors that control cancer resistance to drugs. Recently, we used genome-wide CRISPR-Cas9a screen to identify genes responsible for glioblastoma susceptibility to etoposide. We extended our inquiry to understanding genes that control glioblastoma response to temozolomide using the genome-scale CRISPR. This study shows that the unbiased genome-wide loss of function approach can be applied to discover genes that influence tumor resistance to chemotherapeutics and contribute to chemoresistance in glioblastoma.

Expression of pluripotency-related genes in human glioblastoma.

BackgroundCancer is a group of heterogeneous diseases characterized by several disruptions of the genetic and epigenetic components of cell biology. Some types of cancer have been shown to be constituted by a mosaic of cells with variable differentiation states, with more aggressive tumors being more undifferentiated. In most cases, undifferentiated tumor cells express associated embryonic markers such as the OCT4, NANOG, SOX2, and CARM1 genes. The ectopic or reminiscent expression of some master regulator genes of pluripotency has been indicated as the cause of the poorly differentiated state of tumors, and based on the evidence of some reports, can be used as a possible therapeutic target. Considering this information, a more detailed investigation of the expression of pluripotency-associated genes is necessary to evaluate the roles of these genes in the etiology of some tumors and their use targets of therapy.MethodsThe expression of four pluripotency-related genes was investigated (OCT4, NANOG, SOX2, and CARM1) in the most malignant primary human brain tumor, glioblastoma (GBM).Results and ConclusionThe results demonstrated a signature of OCT4/SOX2/CARM1 genes and a significant increase of CARM1 expression in GBM cases.

P04.20 The role of YAP in Glioblastoma cell lines

Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.

Therapeutic potential of marine peptides in glioblastoma: Mechanistic insights

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in humans. It is characterized by excessive cell growth and accelerated intrusion of normal brain tissue along with a poor prognosis. The current standard of treatment, including surgical removal, radiation therapy, and chemotherapy, is largely ineffective, with high mortality and recurrence rates. As a result, traditional approaches have evolved to include new alternative remedies, such as natural compounds. Aquatic species provide a rich supply of possible drugs. The physiological effects of marine peptides in glioblastoma are mediated by a range of pathways, including apoptosis, microtubule balance disturbances, suppression of angiogenesis, cell migration/invasion, and cell viability; autophagy and metabolic enzymes downregulation. Herein, we address the efficacy of marine peptides as putative safe therapeutic agents for glioblastoma coupled with detail molecular mechanisms.

Glioblastoma cells express crucial enzymes involved in androgen synthesis: 3β-hydroxysteroid dehydrogenase, 17-20α-hydroxylase, 17β-hydroxysteroid dehydrogenase and 5α-reductase.

Glioblastoma (GB) is the most common and aggressive primary brain tumour in adult humans. Therapeutic resistance and tumour recurrence after surgical removal contribute to poor prognosis for glioblastoma patients. Men are known to be more likely than women to develop an aggressive form of GB, and differences in sex steroids have emerged as a leading explanation for this finding. Studies indicate that the metabolism and proliferation of GB‐derived cells are increased by sex steroids, the expression of androgen receptors (ARs) and the synthesis of androgens and oestrogens, suggesting that these hormones have a role in the tumour pathogenesis. The expression of aromatase, the enzyme that converts androgens to oestrogens, has been reported in glial cells and GB cell lines. Thus, it was necessary to test whether the steroidogenic enzymes involved in androgen synthesis are expressed in GB cells. Therefore, here, we investigated the expression of four key enzymes involved in androgen synthesis in human‐derived GB cells. U87 cells were cultured in Dulbecco's modified Eagle medium plus foetal bovine serum and antibiotics on slides for immunocytochemistry or immunofluorescence. U87, LN229 and C6 cells were also cultured in multi‐well chambers to obtain proteins for Western blotting. We used primary antibodies against 3β‐hydroxysteroid dehydrogenase (3β‐HSD), 17α‐hydroxilase/17,20‐lyase (P450c17), 17β‐hydroxysteroid dehydrogenase (17β‐HSD) and 5α‐reductase. Immunocytochemistry, and immunofluorescence results revealed that glioblastoma cells express 3β‐HSD, P450c17, 17β‐HSD and 5α‐reductase proteins in their cytoplasm. Moreover, Western blot analyses revealed bands corresponding to the molecular weight of these four enzymes in the three GB cell lines. Thus, glioblastoma cells have the key enzymatic machinery necessary to synthesize androgens, and these enzymes might be useful targets for new therapeutic approaches.

Current Development of Glioblastoma Therapeutic Agents.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans. Over the past several decades, despite improvements in neurosurgical techniques, development of powerful chemotherapeutic agents, advances in radiotherapy, and comprehensive genomic profiling and molecular characterization, treatment of GBM has achieved very limited success in increasing overall survival. Thus, identifying and understanding the key molecules and barriers responsible for the malignant phenotypes and treatment resistance of GBM will yield new potential therapeutic targets. We review the most recent development of receptor tyrosine kinase targeted therapy for GBM and discuss the current status of several novel strategies with the emphasis on blood-brain barrier penetration as a major obstacle for small-molecule drugs to achieve their therapeutic goals. Likewise, a major opportunity for the treatment of GBM lies in the use of biomarkers for the discovery and development of new receptor tyrosine kinase targeted therapy.

Enhancing Anti-Tumoral Potential of CD-NHF by Modulating PI3K/Akt Axis in U87 Ex Vivo Glioma Model.

Background: In the latest years, there has been an increased interest in nanomaterials that may provide promising novel approaches to disease diagnostics and therapeutics. Our previous results demonstrated that Carbon-dots prepared from N-hydroxyphthalimide (CD-NHF) exhibited anti-tumoral activity on several cancer cell lines such as MDA-MB-231, A375, A549, and RPMI8226, while U87 glioma tumor cells were unaffected. Gliomas represent one of the most common types of human primary brain tumors and are responsible for the majority of deaths. In the present in vitro study, we expand our previous investigation on CD-NHF in the U87 cell line by adding different drug combinations. Methods: Cell viability, migration, invasion, and immunofluorescent staining of key molecular pathways have been assessed after various treatments with CD-NHF and/or K252A and AKTVIII inhibitors in the U87 cell line. Results: Association of an inhibitor strongly potentiates the anti-tumoral properties of CD-NHF identified by significant impairment of migration, invasion, and expression levels of phosphorylated Akt, p70S6Kinase, or by decreasing expression levels of Bcl-2, IL-6, STAT3, and Slug. Conclusions: Using simultaneously reduced doses of both CD-NHF and an inhibitor in order to reduce side effects, the viability and invasiveness of U87 glioma cells were significantly impaired.

Tumor-specific overexpression of histone gene, H3C14 in gastric cancer is mediated through EGFR-FOXC1 axis

Incorporation of different H3 histone isoforms/variants have been reported to differentially regulate gene expression via alteration in chromatin organization during diverse cellular processes. However, the differential expression of highly conserved histone H3.2 genes, H3C14 and H3C13 in human cancer has not been delineated. In this study, we investigated the expression of H3.2 genes in primary human gastric, brain, breast, colon, liver, and head and neck cancer tissues and tumor cell lines. The data showed overexpression of H3.2 transcripts in tumor samples and cell lines with respect to normal counterparts. Furthermore, TCGA data of individual and TCGA PANCAN cohort also showed significant up-regulation of H3.2 genes. Further, overexpressed H3C14 gene coding for H3.2 protein was regulated by FOXC1 transcription factor and G4-cassette in gastric cancer cell lines. Elevated expression of FOXC1 protein and transcripts were also observed in human gastric cancer samples and cell lines. Further, FOXC1 protein was predominantly localized in the nuclei of neoplastic gastric cells compared to normal counterpart. In continuation, studies with EGF induction, FOXC1 knockdown, and ChIP-qPCR for the first time identified a novel axis, EGFR-FOXC1-H3C14 for regulation of H3C14 gene overexpression in gastric cancer. Therefore, the changes the epigenomic landscape due to incorporation of differential expression H3 variant contributes to change in gene expression pattern and thereby contributing to pathogenesis of cancer.