Deema Hussein

Microarray Expression Data Identify DCC as a Candidate Gene for Early Meningioma Progression.

Meningiomas are the most common primary brain tumors bearing in a minority of cases an aggressive phenotype. Although meningiomas are stratified according to their histology and clinical behavior, the underlying molecular genetics predicting aggressiveness are not thoroughly understood. We performed whole transcript expression profiling in 10 grade I and four grade II meningiomas, three of which invaded the brain. Microarray expression analysis identified deleted in colorectal cancer (DCC) as a differentially expressed gene (DEG) enabling us to cluster meningiomas into DCC low expression (3 grade I and 3 grade II tumors), DCC medium expression (2 grade I and 1 grade II tumors), and DCC high expression (5 grade I tumors) groups. Comparison between the DCC low expression and DCC high expression groups resulted in 416 DEGs (p-value < 0.05; fold change > 2). The most significantly downregulated genes in the DCC low expression group comprised DCC, phosphodiesterase 1C (PDE1C), calmodulin-dependent 70kDa olfactomedin 2 (OLFM2), glutathione S-transferase mu 5 (GSTM5), phosphotyrosine interaction domain containing 1 (PID1), sema domain, transmembrane domain (TM) and cytoplasmic domain, (semaphorin) 6D (SEMA6D), and indolethylamine N-methyltransferase (INMT). The most significantly upregulated genes comprised chromosome 5 open reading frame 63 (C5orf63), homeodomain interacting protein kinase 2 (HIPK2), and basic helix-loop-helix family, member e40 (BHLHE40). Biofunctional analysis identified as predicted top upstream regulators beta-estradiol, TGFB1, Tgf beta complex, LY294002, and dexamethasone and as predicted top regulator effectors NFkB, PIK3R1, and CREBBP. The microarray expression data served also for a comparison between meningiomas from female and male patients and for a comparison between brain invasive and non-invasive meningiomas resulting in a number of significant DEGs and related biofunctions. In conclusion, based on its expression levels, DCC may constitute a valid biomarker to identify those benign meningiomas at risk for progression.

Current and emerging biomarkers in tumors of the central nervous system: Possible diagnostic, prognostic and therapeutic applications

Recent investments in research associated with the discovery of specific tumor biomarkers important for efficient diagnosis and prognosis are beginning to bear fruit. Key biomarkers could potentially outweigh traditional radiological or pathological methods by enabling specificity of early detection, when coupled with tumor molecular profiling and clinical associations. Only few biomarkers are approved by regulatory authorities for Central Nervous System Tumors (CNSTs), despite the evaluation of a large number of CNST related markers during clinical trials. Traditional CNSTs biomarkers include 1p/19q co-deletion, O6-Methylguanine-DNA Methyltransferase Methylation, and mutations in IDH1/IDH2. Recently tested CNSTs biomarkers include VEGFR-2, EGFRvIII, IL2, PDGFR, MMPs, BRAF, STAT3, PTEN, TERT, AKT, NF2, and BCL2. Additional studies have highlighted new and novel MicroRNAs, circular RNAs and long non-coding RNAs as promising biomarkers. Studies on microvesicles pinpoint exosomes as promising, less invasive biomarkers that could be isolated from the serum of cancer patients. Furthermore, Cancer Stem Cells (CSCs) related molecules, such as CD133, SOX2 and Nestin, utilized as CNST biomarkers, might enable efficient monitoring of cancer progression, and/or surveillance of emerging drug resistant cells. Approved protocols that implement novel molecular markers in diagnostics, prognostics and drug development will herald a new era of precision and personalized neuro-oncology. This review summarizes and discusses putative CNST biomarkers that are under clinical development, and are ready to move into diagnostic, prognostic and therapeutic applications. Data presented here is predicted to aid in streamlining the process of biomarkers research and development.

Pleomorphism and drug resistant cancer stem cells are characteristic of aggressive primary meningioma cell lines

BackgroundMeningioma tumors arise in arachnoid membranes, and are the most reported central nervous system (CNS) tumors worldwide. Up to 20% of grade I meningioma tumors reoccur and currently predictive cancer stem cells (CSCs) markers for aggressive and drug resistant meningiomas are scarce.MethodsMeningioma tissues and primary cell lines were investigated using whole transcriptome microarray analysis, immunofluorescence staining of CSCs markers (including CD133, Sox2, Nestin, and Frizzled 9), and drug treatment with cisplatin or etoposide.ResultsUnsupervised hierarchical clustering of six meningioma samples separated tissues into two groups. Analysis identified stem cells related pathways to be differential between the two groups and indicated the de-regulation of the stem cell associated genes Reelin (RELN), Calbindin 1 (CALB1) and Anterior Gradient 2 Homolog (AGR2). Immunofluorescence staining for four tissues confirmed stemness variation in situ. Biological characterization of fifteen meningioma primary cell lines concordantly separated cells into two functionally distinct sub-groups. Pleomorphic cell lines (NG type) grew significantly faster than monomorphic cell lines (G type), had a higher number of cells that express Ki67, and were able to migrate aggressively in vitro. In addition, NG type cell lines had a lower expression of nuclear Caspase-3, and had a significantly higher number of CSCs co-positive for CD133+ Sox2+ or AGR2+ BMI1+. Importantly, these cells were more tolerant to cisplatin and etoposide treatment, showed a lower level of nuclear Caspase-3 in treated cells and harbored drug resistant CSCs.ConclusionCollectively, analyses of tissues and primary cell lines revealed stem cell associated genes as potential targets for aggressive and drug resistant meningiomas.

Updates on Therapeutics in Clinical Trials for Spinal Cord Injuries: Key Translational Applications of Human Embryonic Stem Cells-Derived Neural Progenitors

Injuries to the spinal cord often have devastating physiological impacts due to the organs vital role in neuro-impulse communications between muscles and the brain. Spinal Cord Injuries (SCIs) have recently been estimated to affect up to 80,000 individuals per year worldwide, with most occurring following a traumatic event. Unfortunately, effective treatments standardised globally for patients with SCIs have not yet been established. For many years, inadequate understanding of the complexities of the Central and Peripheral Nervous Systems and Neurogenesis has limited progression towards effective cures. However, in the last century, scientific advancements have generated new paradigms for medical treatments of SCIs. Basic as well as translational studies have progressed to such an extent that many kinds of protective and regenerative therapeutics are available in clinical trials. In particular, uncovering the mechanisms responsible for controlling the pluripotent state of Human Embryonic Stem Cells (hESCs) was proved vital for recognizing the prospective role in regenerative medicine for SCIs. Elucidating knowledge of neurogenesis alongside hESCs in relation to SCIs has been crucial for critical assessments of the existing translational therapeutic strategies for SCIs.

Initial characterization of drug resistant cancer stem cells isolated from primary brain tumors (astrocytoma) cell lines generated from Saudi patients

Background The Cancer Stem Cells (CSCs) hypothesis proposes that malignant brain tumours are organized into aberrant cell hierarchies where a subset of parent CSCs replicate asymmetrically and unlimitedly to produce differentiated daughter cell [1,2]. These parent CSCs are highly adaptive and resistant to the chemotherapeutic drugs [3]. Developing new drugs that target CSCs requires a comprehensive understanding of the pharmacogenomics behavior of these cells [4,5]. Such understanding requires reliable in vitro and in vivo models that represent the beneficial patients. This project is set out to: i) Establish a collection of astrocytoma cell lines generated from Saudi patients, ii) Select drug resistant brain tumour CSCs, iii) Characterize drug resistant brain tumour CSCs individually, and iv) Deduce common features for drug resistant brain tumour CSCs.

Malignant Transformation and Spine Metastasis of an Intracranial Grade I Meningioma: In Situ Immunofluorescence Analysis of Cancer Stem Cells Case Report and Literature Review

BACKGROUND Malignant meningiomas are rare neoplasms of the central nervous system that occur de novo or rarely as a result of transformation. They have a higher rate of recurrence and metastasis accompanied by a significantly shorter survivorship compared with benign variants. Meningioma cancer stem cells (CSCs) have been previously shown to be associated with resistance and aggressiveness. However, the role they play in meningioma progression is still being investigated. CASE DESCRIPTION We report a 29-year-old man who underwent a resection of a grade I meningioma in 2011. The patient had multiple local recurrences of the tumor that showed an aggressive change in behavior and transformation to grade III meningioma, and developed extracranial metastasis to the cervical spine. He underwent multiple operations and received radiotherapy. Analysis of the tissues indicated the presence of CSC markers before metastasis, and showed increased expressions of associated markers in the metastasized tissue. In addition, similar to the patients profile, the pharmacological testing of a primary cell line retrieved from the metastasized tissues showed a high level of drug tolerance and a diminished ability to initiate apoptosis. CONCLUSIONS Malignant progression of grade I meningioma can occur, and its eventuality may be anticipated by detecting CSCs. We performed a comprehensive literature review of relevant cases and discussed the clinical, diagnostic, and management characteristics of the reported cases.

In situ characterization of stem cells-like biomarkers in meningiomas

BackgroundMeningioma cancer stem cells (MCSCs) contribute to tumor aggressiveness and drug resistance. Successful therapies developed for inoperable, recurrent, or metastatic tumors must target these cells and restrict their contribution to tumor progression. Unfortunately, the identity of MCSCs remains elusive, and MSCSs’ in situ spatial distribution, heterogeneity, and relationship with tumor grade, remain unclear.MethodsSeven tumors classified as grade II or grade III, including one case of metastatic grade III, and eight grade I meningioma tumors, were analyzed for combinations of ten stem cell (SC)-related markers using immunofluorescence of consecutive sections. The correlation of expression for all markers were investigated. Three dimensional spatial distribution of markers were qualitatively analyzed using a grid, designed as a repository of information for positive staining. All statistical analyses were completed using Statistical Analysis Software Package.ResultsThe patterns of expression for SC-related markers were determined in the context of two dimensional distribution and cellular features. All markers could be detected in all tumors, however, Frizzled 9 and GFAP had differential expression in grade II/III compared with grade I meningioma tissues. Correlation analysis showed significant relationships between the expression of GFAP and CD133 as well as SSEA4 and Vimentin. Data from three dimensional analysis showed a complex distribution of SC markers, with increased gene hetero-expression being associated with grade II/III tumors. Sub regions that showed multiple co-staining of markers including CD133, Frizzled 9, GFAP, Vimentin, and SSEA4, but not necessarily the proliferation marker Ki67, were highly associated with grade II/III meningiomas.ConclusionThe distribution and level of expression of CSCs markers in meningiomas are variable and show hetero-expression patterns that have a complex spatial nature, particularly in grade II/III meningiomas. Thus, results strongly support the notion of heterogeneous populations of CSCs, even in grade I meningiomas, and call for the use of multiple markers for the accurate identification of individual CSC subgroups. Such identification will lead to practical clinical diagnostic protocols that can quantitate CSCs, predict tumor recurrence, assist in guiding treatment selection for inoperable tumors, and improve follow up of therapy.

Brain and bone metastasis from malignant thyroid carcinomas originating in western Saudi Arabia

Background We have previously investigated the frequency of gene mutations in RET and HRAS affecting medullary thyroid carcinomas (MTCs) and gene mutations in BRAF, HRAS, KRAS, and NRAS affecting non-medullary thyroid carcinomas (non-MTCs). Non-MTCs include follicular TCs (FTCs), anaplastic TCs (ATCs), and papillary TCs (PTCs) and its histological variants. In this study we surveyed the frequency of metastasis to the brain or bone in our case series of MTCs and non-MTCs.