Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.

Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention.

Gliomas are the most common and aggressive of brain tumors in adults. Cancer stem cells (CSC) contribute to chemoresistance in many solid tumors including gliomas. The function of prostate apoptosis response-4 (Par-4) as a pro-apoptotic protein is well documented in many cancers; however, its role in CSC remains obscure. In this study, we aimed to explore the role of Par-4 in drug-induced cytotoxicity using human glioma stem cell line - HNGC-2 and primary culture (G1) derived from high grade glioma. We show that among the panel of drugs- lomustine, carmustine, UCN-01, oxaliplatin, temozolomide and tamoxifen (TAM) screened, only TAM induced cell death and up-regulated Par-4 levels significantly. TAM-induced apoptosis was confirmed by PARP cleavage, Annexin V and propidium iodide staining and caspase-3 activity. Knock down of Par-4 by siRNA inhibited cell death by TAM, suggesting the role of Par-4 in induction of apoptosis. We also demonstrate that the mechanism involves break down of mitochondrial membrane potential, down regulation of Bcl-2 and reduced activation of Akt and ERK 42/44. Secretory Par-4 and GRP-78 were significantly expressed in HNGC-2 cells on exposure to TAM and specific antibodies to these molecules inhibited cell death suggesting that extrinsic Par-4 is important in TAM-induced apoptosis. Interestingly, TAM decreased the expression of neural stem cell markers - Nestin, Bmi1, Vimentin, Sox2, and Musashi in HNGC-2 cell line and G1 cells implicating its potential as a stemness inhibiting drug. Based on these data and our findings that enhanced levels of Par-4 sensitize the resistant glioma stem cells to drug-induced apoptosis, we propose that Par-4 may be explored for evaluating anti-tumor agents in CSC.

Objectives:To study 1)the efficacy of transforaminal percutaneous endoscopic lumbar discectomy in lumbar disc herniations.2) limitations and advantages of the surgical procedure. 3)morbidity and complications associated with the procedure.Materials and Methods:This study was carried out on 120 patients who had single level herniated disc Pre-operative assessment of VAS and MSS scoring systems were documented one day prior to surgery. Post operative results were determined by MacNab criteria and by modified Suezawa and Schreiber clinical scoring system (MSS score).Results:Maximum patients were in the age group of 31 to 40 years and 83.43% of the patients were males. 80% patients had lumbar disc herniation at L4-L5 level, The mean operative time of endoscopic discectomy was 52.28 minutes and the mean hospital stay was 2.1days.8 cases of L5-S I were abandoned due to high iliac bone and hence their disc could not be accessed. Out of 112 patients who underwent operation, 2 patients developed discitis and 1 was found to have dysesthesia. Also recurrent prolapsed intervertebral disc was seen in 6 cases The mean preoperative and 6 months follow-up VAS score was 8.4 and 1.89 respectively. Mean preoperative and 6 months follow-up Modified Suezawa And Schreiber Clinical Scoring System(MSS Score) was 3.47 and 7.92 respectively. MSS score showed excellent and good outcome in 82.12% patients and Modified Macnab Criteria showed excellent and good outcome in 89.3% patients at 6months follow-up.Conclusion:TPELD can be a reasonable alternative to conventional microscopic discectomy for the treatment of patients with LDH. We also conclude that TPELD is not an effective procedure for L5-S 1 disc and an open procedure should be opted for better outcomes.

HighlightsMulticellular spheroids (MCS) express low levels of Par-4 and are resistant to TAM-induced cytotoxicity.Par-4 is secreted in TAM-treated monolayers but not MCS and is crucial for cell death.Secretory Par-4 (from TAM-treated cells) renders MCS sensitive to cell death.Inhibitors to AKT/PKCζ sensitized MCS to TAM-induced cytotoxicity.A combination of TAM with PI3K inhibitor resulted in secretory Par-4.