Abstract
Aim: The presence of cells within meningioma (MG) that express embryonic stem cell (ESC) markers has been previously reported. However, the precise location of these cells has yet to be determined.Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 11 WHO grade I MG tissue samples for the expression of the ESC markers OCT4, NANOG, SOX2, KLF4 and c-MYC. Immunofluorescence (IF) IHC staining was performed to investigate the localization of each of these ESC markers. NanoString and colorimetric in situ hybridization (CISH) mRNA expression analyses were performed on six snap-frozen MG tissue samples to confirm transcriptional activation of these proteins, respectively.Results: DAB IHC staining demonstrated expression of OCT4, NANOG, SOX2, KLF4, and c-MYC within all 11 MG tissue samples. IF IHC staining demonstrated the expression of the ESC markers OCT4, NANOG, SOX2, KLF4, and c-MYC on both the endothelial and pericyte layers of the microvessels. NanoString and CISH mRNA analyses confirmed transcription activation of these ESC markers.Conclusion: This novel finding of the expression of all aforementioned ESC markers in WHO grade I MG infers the presence of a putative stem cells population which may give rise to MG.
Highlights
We investigated the expression of the ESCassociated markers OCT4, SOX2, NANOG, KLF4 and c-MYC in WHO grade I MG using immunohistochemical (IHC) staining, FIGURE 1 | Representative 3,3-diaminobenzidine immunohistochemical stained images of WHO grade I meningioma for OCT4 (A, brown), NANOG (B, purple), SOX2 (C, brown), KLF4 (D, purple) and c-MYC (E, brown) expressed on the endothelial and pericyte layers
colorimetric in situ hybridization (CISH) confirmed the expression of OCT4 (Figure 2A, brown), NANOG (Figure 2B, brown), SOX2 (Figure 2C, brown), KLF4 (Figure 2D, brown) and c-MYC (Figure 2E, brown) in both the endothelial (Figures 2A–E, arrowheads) and pericyte (Figures 2A–E, arrows) layers
NanoString mRNA analysis demonstrated transcriptional activation for all five embryonic stem cell (ESC) genes investigated (Figure 3), with significantly high expression of transcripts for KLF4 followed by c-MYC, NANOG, OCT4, and SOX2 (p < 0.05)
Summary
Meningioma (MG) accounts for 25–30% of primary intracranial and intraspinal tumors [1], and has been traditionally thought to be derived from arachnoid cap cells of the brain and spinal cord [2] based on the correlational histological and ultrastructural studies comparing arachnoid cap cells with MG cells [2].Tumor stem cells are proposed to be the cellular origin of cancer including glioblastoma (GB) [3] and leukemia [4], are increasingly thought to be the origin of benign entities such as Dupuytren’s disease [5], infantile hemangioma [6] and MG [1, 7,8,9]. Cultured MG cells form tumor spheres [8], demonstrate self-renewal, and express embryonic stem cell (ESC) associated markers including SOX2, nestin [1] and KLF4 [10]. Stem cells are characterized by their expression of certain ESC-associated markers including OCT4, SOX2, NANOG, KLF4 and c-MYC. OCT4, is a transcription factor that, plays a critical role in conjunction with SOX2 and NANOG in embyrogenesis [12] It is a gatekeeper for ESC pluripotency [12] and is important in tumor locoregional recurrence and metastasis [13]. KLF4, a transcription factor involved in cell proliferation, differentiation and apoptosis [17] It is one of the most frequently mutated genes in secretory MG but it contributes to the self-renewal and pluripotency of ESCs [10, 18]. The c-MYC oncoprotein is of critical importance in proliferation and growth of normal and neoplastic cells [19]. c-MYC is expressed by recurrent high-grade lesions, while low-grade lesions do not express c-MYC [20]
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