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APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade

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APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade pharmaceuticals Article APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade Debolina Ganguly 1, Chun Cai 1, Michelle M. Sims 1, Chuan He Yang 1, Matthew Thomas 1, Jinjun Cheng 1, Ali G. Saad 1 and Lawrence M. Pfeffer 2,* 1 Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; [email protected] (D.G.); [email protected] (C.C.); [email protected] (M.M.S.); [email protected] (C.H.Y.); [email protected] (M.T.); [email protected] (J.C.); [email protected] (A.G.S.) 2 Department of Pathology and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA * Correspondence: [email protected]; Tel.: +1-901-448-7855 Received: 18 February 2019; Accepted: 19 March 2019; Published: 26 March 2019 Abstract: Glioblastoma (GBM) is the most common and deadliest primary adult brain tumor. Invasion, resistance to therapy, and tumor recurrence in GBM can be attributed in part to brain tumor-initiating cells (BTICs). BTICs isolated from various patient-derived xenografts showed high expression of the poorly characterized Apelin early ligand A (APELA) gene. Although originally considered to be a non-coding gene, the APELA gene encodes a protein that binds to the Apelin receptor and promotes the growth of human embryonic stem cells and the formation of the embryonic vasculature. We found that both APELA mRNA and protein are expressed at high levels in a subset of brain tumor patients, and that APELA is also expressed in putative stem cell niche in GBM tumor tissue. Analysis of APELA and the Apelin receptor gene expression in brain tumor datasets showed that high APELA expression was associated with poor patient survival in both glioma and glioblastoma, and APELA expression correlated with glioma grade. In contrast, gene expression of the Apelin receptor or Apelin was not found to be associated with patient survival, or glioma grade. Consequently, APELA may play an important role in glioblastoma tumorigenesis and may be a future therapeutic target. Keywords: APELA; RNA-ISH; glioma; glioblastoma; cancer stem cells 1. Introduction Glioblastoma (GBM) is the most lethal intracranial neoplasm in adults and has a median survival of only 14–18 months [1]. Surgical resection combined with adjuvant chemotherapy and radiation therapy is the primary treatment of GBM, but has only provided slight improvement in the disease course and outcome for decades [2]. The cellular heterogeneity of GBM has been attributed to a subpopulation of brain tumor-initiating cells (BTICs), which express stem cell markers, can self-renew and undergo differentiation into multiple cell types [3–5]. BTICs have high tumor-initiating capacity and therapeutic resistance that can drive tumorigenesis and tumor recurrence after therapy [6]. We previously demonstrated that BTICs derived from patient-derived xenolines (PDXs) have markedly enhanced tumor-initiating activity when compared with BTICs induced to differentiate and form tumors that display identical histological features to the original PDX [7]. Apelin early ligand A (APELA), also called Elabela and Toddler, is an evolutionarily conserved peptide hormone that is essential for cardiovascular development in zebrafish through its binding to the G-protein coupled Apelin receptor (APLNR) [8]. APELA functions both as an endogenous ligand necessary for the growth of human embryonic stem cells [9] and in the formation of the embryonic vasculature [10]. Both Apelin and APELA bind to the Apelin receptor to transduce their distinct Pharmaceuticals 2019, 12, 45; doi:10.3390/ph12010045 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2019, 12, x FOR PEER REVIEW 2 of 12 vasculature [10]. Both Apelin and APELA bind to the Apelin receptor to transduce their distinct biological functions [9]. While the Apelin/APLNR pathway is associated with fluid homeostasis, the neuroendocrine response to stress, and cardiovascular function [11], the biological function of the APELA/APLNR pathway is poorly understood. In the present study, we found that Apelin early ligand A (APELA) gene expression was markedly upregulated in BTICs isolated from a number of PDXs when compared with BTICs induced to differentiate. BTICs with high expression of the stem cell markers, Nestin and CD133, are localized near Pharmaceuticalscapillaries in2019 brain, 12, 45tumors, and this vascular niche is apparently critical for stem cell renewal2 [12]. of 11 Since APELA [10] and the Apelin receptor [13] have been shown to play important roles in vascular development and stem cell proliferation, we examined whether APELA and APLNR were expressed biological functions [9]. While the Apelin/APLNR pathway is associated with fluid homeostasis, in a stem cell niche in GBM patient tumor tissue by testing both RNA in situ hybridization (ISH) and the neuroendocrine response to stress, and cardiovascular function [11], the biological function of the immunohistochemistry (IHC), and found that APELA/APLNR-expressing cells were localized in a APELA/APLNR pathway is poorly understood. In the present study, we found that Apelin early putative stem cell niche. Analysis of brain tumor expression datasets showed that high APELA ligand A (APELA) gene expression was markedly upregulated in BTICs isolated from a number of expression was associated with poor patient survival. Our data suggest that APELA may play an PDXs when compared with BTICs induced to differentiate. important role in glioblastoma initiation and/or development, and could be a therapeutic target. BTICs with high expression of the stem cell markers, Nestin and CD133, are localized near capillaries in brain tumors, and this vascular niche is apparently critical for stem cell renewal [12]. 2. Results Since APELA [10] and the Apelin receptor [13] have been shown to play important roles in vascular development2.1. Identification and of stem APELA cell as proliferation, a Gene Overexpressed we examined in GBM whether and BTICs APELA and APLNR were expressed in a stem cell niche in GBM patient tumor tissue by testing both RNA in situ hybridization (ISH) and immunohistochemistryAPELA was originally identified (IHC), and as founda signaling that APELA/APLNR-expressingprotein in zebrafish embryos cellsby database were localized mining infor a non-annotated putative stem celltranslated niche. Analysisopen reading of brain frames tumor [14]. expression Subsequently, datasets APELA showed was thatfound high to promote APELA expressionboth the growth was associated of human with embryonic poor patient stem cells survival. and the Our formation data suggest of the that embryonic APELA may vasculature play an important[9,10]. To characterize role in glioblastoma the potential initiation importance and/or development,of APELA in stem-like and could cells be a in therapeutic GBM, we target.examined APELA expression by qPCR in BTICs isolated from different GBM PDXs (GBM6, GBMX10, and 2.GBMX16) Results and BTICs induced to differentiate. High APELA expression was found in BTICs isolated from various GBM PDXs as compared to BTICs induced to differentiate in the presence of serum 2.1.(Figure Identification 1A). Asof previously APELA as ashown Gene Overexpressed [15], serum-induced in GBM and differentiation BTICs of BTICs increased the expressionAPELA of was the originallyastrocyte marker identified glial as fibrillary a signaling acidic protein protein in zebrafish (GFAP) and embryos decreased by database the expression mining forof neural non-annotated stem cells translated markers, open including reading Nestin frames and [14 Sox2]. Subsequently,. In addition, APELA significantly was found higher to promote APELA bothexpression the growth was offound human in embryonicBTICs isolated stem from cells andthe thecentral formation region of of the a GBM embryonic tumor vasculature (BT238Z) [when9,10]. Tocompared characterize with theBTICs potential isolated importance from the tumor of APELA periphery in stem-like (BT238XY) cells (Figure in GBM, 1B). we examined APELA expressionBecause by APELA qPCR in was BTICs overexpressed isolated from in differentBTICs, APELA GBM PDXs expression (GBM6, was GBMX10, then determined and GBMX16) by qPCR and BTICsin RNA induced isolated to from differentiate. formalin-fixed High paraffin-emb APELA expressionedded (FFPE) was found biopsy in BTICsspecimens isolated obtained from from various the GBMUniversity PDXs of as Tennessee compared Health to BTICs Science induced Center to (UTHSC) differentiate tissue in services the presence core from of serumprimary (Figure low-grade1A). Asglioma previously (LGG) (World shown [Health15], serum-induced Organization differentiationclassification I and of BTICs II), GBM increased (World the Health expression Organization of the astrocyteclassification marker IV), glialand histologically fibrillary acidic benign protein brai (GFAP)n samples. and decreasedAlthough APELA the expression was expressed of neural at stemvery cellslow levels markers, in normal including brain Nestin samples, and Sox2statistically. In addition, significant significantly higher APELA higher expression APELA expression was found was in foundGBM inspecimens BTICs isolated (Figure from 1C), the which central appeared region of to a GBMreflect tumor a discrete (BT238Z) subset when of compared GBM patients with BTICs with isolatedmarkedly from higher the tumorAPELA periphery expression. (BT238XY) (Figure1B). Figure 1. APELA gene expression in brain tumor-initiating cells (BTICs), and in normal brain
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