Expression of Components of the Renin-Angiotensin System by the Putative Stem Cell Population Within WHO Grade I Meningioma.

Ganeshwaran Shivapathasundram,Swee T Tan,Agadha C Wickremesekera,Reginald W Marsh,Helen D Brasch,Tinte Itinteang,Bede Van Schaijik

doi:10.3389/fsurg.2019.00023

Abstract

Aim: We have recently demonstrated a putative stem cell population within WHO grade I meningioma (MG) that expressed embryonic stem cell (ESC) markers OCT4, NANOG, SOX2, KLF4 and c-MYC, localized to the endothelial and pericyte layers of the microvessels. There is increasing recognition that the renin-angiotensin system (RAS) plays a critical role in stem cell biology and tumorigenesis. This study investigated the expression of components of the RAS: pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), and angiotensin II receptor 2 (ATIIR2) on the putative stem cell population on the microvessels of WHO grade I MG.Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on WHO grade I MG tissue samples from 11 patients for PRR, ACE, ATIIR1, and ATIIR2. Two of the MG samples subjected to DAB IHC staining underwent immunofluorescence (IF) IHC staining to investigate co-expression of each of these components of the RAS in using combinations of CD34 and ESC marker SOX2 or OCT4. NanoString mRNA expression analysis and Western blotting (WB), were performed on six snap-frozen MG tissue samples to confirm mRNA and protein expression of these proteins, respectively.Results: DAB IHC staining demonstrated expression of PRR, ACE, ATIIR1, and ATIIR2 within all 11 MG tissue samples. WB and NanoString mRNA analyses, confirmed protein and mRNA expression of these proteins, respectively. IF IHC staining showed PRR, ATIIR1 and ATIIR2 were localized to the OCT4+ and SOX2+ endothelium and the pericyte layer of MG while ACE was localized to the OCT4+ endothelium of the microvesels.Conclusion: The novel finding of the expression of PRR, ACE, ATIIR1, and ATIIR2 on the putative stem cell population on the microvessels of WHO grade I MG, suggests that these stem cells may be a potential therapeutic target by manipulation of the RAS.

Highlights

Meningioma (MG) is a common primary central nervous system neoplasm accounting for 25–30% of primary intracranial and intraspinal tumors [1]
We have demonstrated that this primitive population within MG is localized to both the endothelial and pericyte layers of the microvessels within the tumor by its expression of the embryonic stem cell (ESC) markers including OCT4 and NANOG [12]
We have demonstrated the presence of components of the renin-angiotensin system (RAS) within the putative stem cell population in WHO grade I MG with PRR being the most abundantly expressed at both the protein and mRNA levels, by IHC staining, Western blotting (WB) and NanoString mRNA analyses

Summary

Introduction

Meningioma (MG) is a common primary central nervous system neoplasm accounting for 25–30% of primary intracranial and intraspinal tumors [1]. Arachnoid cap cells are thought to arise from neural crest neuroectoderm which differentiates from pluripotent stem cells [3]. Tumor stem cells are the suggested cellular origin of cancer including glioblastoma (GB) [4] and leukemia [5] and are increasingly thought to give rise to benign conditions such as Dupuytren’s disease [6], infantile hemangioma (IH) [7], and MG [1, 8,9,10]. Cultured MG cells demonstrate tumorsphere formation [9], self-renewal, and expression of embryonic stem cell (ESC) associated markers including SOX2, nestin [1], and KLF4 [11]. We have previously identified and characterized a putative stem cell population, localized to both the endothelial and the pericyte layers of the microvessels of WHO grade I MG [12]

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