The high-mobility group-box transcription factor sex-determining region Y-box 2 (Sox2) is essential for the maintenance of stem cells from early development to adult tissues. Sox2 can reprogram differentiated cells into pluripotent cells in concert with other factors and is overexpressed in various cancers. In glioblastoma (GBM), Sox2 is a marker of cancer stemlike cells (CSCs) in neurosphere cultures and is associated with the proneural molecular subtype. Here, we report that Sox2 expression pattern in GBM tumors and patient-derived mouse xenografts is not restricted to a small percentage of cells and is coexpressed with various lineage markers, suggesting that its expression extends beyond CSCs to encompass more differentiated neoplastic cells across molecular subtypes. Employing a CSC derived from a patient with GBM and isogenic differentiated cell model, we show that Sox2 knockdown in the differentiated state abolished dedifferentiation and acquisition of CSC phenotype. Furthermore, Sox2 deficiency specifically impaired the astrocytic component of a biphasic gliosarcoma xenograft model while allowing the formation of tumors with sarcomatous phenotype. The expression of genes associated with stem cells and malignancy were commonly downregulated in both CSCs and serum-differentiated cells on Sox2 knockdown. Genes previously shown to be associated with pluripontency and CSCs were only affected in the CSC state, whereas embryonic stem cell self-renewal genes and cytokine signaling were downregulated, and the Wnt pathway activated in differentiated Sox2-deficient cells. Our results indicate that Sox2 regulates the expression of key genes and pathways involved in GBM malignancy, in both cancer stemlike and differentiated cells, and maintains plasticity for bidirectional conversion between the two states, with significant clinical implications.
Glioblastomas, the most common and aggressive form of astrocytoma, are refractory to therapy, and molecularly heterogeneous. The ability to establish cell cultures that preserve the genomic profile of the parental tumors, for use in patient specific in vitro and in vivo models, has the potential to revolutionize the preclinical development of new treatments for glioblastoma tailored to the molecular characteristics of each tumor.Starting with fresh high grade astrocytoma tumors dissociated into single cells, we use the neurosphere assay as an enrichment method for cells presenting cancer stem cell phenotype, including expression of neural stem cell markers, long term self-renewal in vitro, and the ability to form orthotopic xenograft tumors. This method has been previously proposed, and is now in use by several investigators. Based on our experience of dissociating and culturing 125 glioblastoma specimens, we arrived at the detailed protocol we present here, suitable for routine neurosphere culturing of high grade astrocytomas and large scale expansion of tumorigenic cells for preclinical studies. We report on the efficiency of successful long term cultures using this protocol and suggest affordable alternatives for culturing dissociated glioblastoma cells that fail to grow as neurospheres. We also describe in detail a protocol for preserving the neurospheres 3D architecture for immunohistochemistry. Cell cultures enriched in CSCs, capable of generating orthotopic xenograft models that preserve the molecular signatures and heterogeneity of GBMs, are becoming increasingly popular for the study of the biology of GBMs and for the improved design of preclinical testing of potential therapies.
11 The majority of Grade I meningiomas behave in an indolent manner and can be completely removed by resective surgery, or their growth can be controlled by radiation therapy. A small percentage of meningiomas are Grades II and III, which have variable growth patterns and are likely to recur after initial treatment. Grade III meningiomas are considered to be anaplastic (malignant) and warrant aggressive management. Unfortunately, there are limited treatment options beyond surgery and radiation for patients with Grades II and III meningiomas. In many patients the Grade II meningioma will gradually convert to Grade III. Initial treatment(s) will fail in most patients with Grade III meningiomas, and they will ultimately succumb to recurrent and progressive tumor. In this report, we present an encouraging case of a patient who-after 5 intracranial surgeries and 3 stereotactic radiation treatments for malignant meningioma-has had stable disease for 3.5 years following the initiation of octreotide therapy. We also review the current treatment options for recurrent malignant meningioma. case report History and ExaminationIn 1994, a 35-year-old woman presented with worsening seizures and was found to have a right frontal mass, which was embolized and subsequently resected. Histological examination demonstrated a proliferation of relatively uniform, bland meningothelial cells that were frequently arranged as the characteristic whorls ( Fig. 1). At most, we identified 2 mitoses per 10 hpf (magnification ×400). A thin rim of brain tissue was present and did not show invasion by the meningioma. Per the 2007 WHO Classification of Tumours of the Central Nervous System guidelines, 11 this tumor was consistent with the diagnosis of a Grade I meningioma. In 1998, the patient experienced a small recurrence that was treated by Gamma Knife radiosurgery with 16 Gy to the 90% isodose line. Subsequent progression at the treated site led to additional radiosurgery in 2002 (16 Gy to the 15% isodense line) and 2004 (15 Gy to the 40% isodense line).In 2008, the tumor continued to progress and was noted primarily on the right side of the falx and extending slightly across the midline, occluding the sagittal sinus ( Fig. 2A). The next intervention was embolization followed by resection leading to minimal residual tumor at the posterior aspect of the involved sagittal sinus (Fig. 2B). Histological examination revealed an atypical meningioma (WHO Grade II; Fig. 2C) with marked cytological atypia, up to 6 mitoses per 10 hpf, and a Ki 67 labeling index of approximately 30% in the most active areas. Repeat MRI 2 months postoperatively demonstrated an increased size of the residual tumor. Stereotactic radiation was recomabbreviatioNs PBS = phosphate-buffered saline; SST = somatostatin receptor. submitted October 1, 2014. accepted January 28, 2015. iNclude wheN citiNg Published online August 14, 2015; DOI: 10.3171/2015.1.JNS142260. disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the ...
Background Systemic (Sys) and tumor microenvironment (TME) immune milieus play a pivotal role in tumor development, outcome and immunotherapy response predictions across a variety of central nervous system tumors. Genome-wide methylation profiling can reliably discriminate and estimate immune cell proportions present in the blood and within the tumor and has not been reported across sellar tumor types (STT). Material and Methods We estimated cell composition in liquid biopsy (LB, serum/plasma) and tissue specimens from 42 STT collections (i.e., pituitary neuroendocrine tumors [PitNETs; n=37] and craniopharyngiomas [CP; n=5]), and 26 nontumor controls (LB: 11; Tissue: 15) using MethylCIBERSORT, a methylation-based deconvolution algorithm and established immune cell signatures as reference. LB methylation was profiled with EPIC array. Correlations between estimated cell proportions across sample sources were explored (Spearman). Immune cell proportion hierarchical k-means clustering was performed across tissue and LB specimens. Similarly, mean comparisons between and across sample types and subgroups of interest were performed [Non-parametric Kruskal-Wallis, Wilcoxon rank-sum tests; p<0.05]. Results We identified three immune-clusters across tissue specimens which distinguished controls (k3-cluster) from sellar tumor specimens (k1- and k2- clusters), primarily attributable to differential B-cell and monocyte proportions. Interestingly, a subset of PitNET and CP, belonging to the k2-cluster, presented a distinct immune profile compared to their K1-sellar tumor counterparts. Analysis of plasma-derived immune clusters revealed that PitNETs were distributed across four distinct immune patterns and CP clustered together with controls and a PitNET subset. One of the PitNET clusters was enriched with patients that died during follow-up and presented an enrichment of CD4-(including the regulatory subtype), CD8 and CD56-T and depletion of natural killer cells. Differences across serum- and tissue-derived clusters were present but less prominent than their plasma counterparts. No correlation between immune cell proportions across other clinicopathological features within each tumor type (sex, age, histotypes, invasion etc) was observed. Conclusion Our results suggest that PitNETs are characterized by differential TME and systemic immune subtypes which also distinguish these tumors from CP and controls. Additionally, distinct systemic immune composition between tissue and LB sources, more readily observed in plasma, suggest that the systemic response to the presence of the tumor is distinct from the immune response noted in the TME. Tumor immune subtyping may allow the stratification of STT according to immunotherapy response vulnerabilities.
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