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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0441-7) contains supplementary material, which is available to authorized users.

Integration and Comparison of Transcriptomic and Proteomic Data for Meningioma

“…Overexpression of AGR2 has been linked to the proliferation, migration and invasion of several cancers [32,33]. Indeed, AGR2 has previously been implicated as a novel stem cell biomarker overexpressed in a subset of aggressive primary meningioma cell lines [34]. Hence, combined, these data suggest AGR2 may be a contributor to an aggressive meningioma phenotype and should be considered as a possible molecular marker or therapeutic target on the transcript or protein level.…”

In situ characterization of stem cells-like biomarkers in meningiomas

“…In CNSTs, high CD133 expression has been associated with poor survival [ 18 – 21 ]. In meningioma cell lines, higher CD133 expression correlates positively with cell proliferation and drug resistance [ 9 , 13 , 22 , 23 ].…”

“…Previously, we published gene expression profiles for most of the meningioma patients’ tissues collected for our cohort [ 64 , 65 ], as well as for their corresponding cell lines [ 22 ]. For this work, we aimed to determine the hetero-dynamic characteristics of MCSCs in situ and identify differential patterns associated with grades II/III tumors.…”

Array expression meta-analysis of cancer stem cell genes identifies upregulation of PODXL especially in DCC low expression meningiomas

“…Furthermore, in non-muscle-invasive bladder cancer, lower expression of BRINP1 is associated with unfavorable prognosis [69]. PROM1 is a pentaspan transmembrane glycoprotein that has been described by different research groups as a CSC factor in meningiomas [9, 10, 12, 13]. In our survey, PROM1 was markedly downregulated in DCC low expression meningiomas in five array expression studies.…”

“…An immunohistochemical study detected higher expression of nestin (NES), SOX2, and prominin 1 (PROM1), also known as CD133, in more progressive meningiomas [9]. In meningioma cultures, cells with pleomorphic characteristics show markedly increased numbers of CSCs scoring positive for PROM1 and SOX2, or AGR2 and BMI1 [12]. Similarly, meningioma cells expressing PROM1 revealed a higher proliferation rate and the formation of tumorspheres [13].…”