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Tumour stem cells in meningioma: A review
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
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Review article
Tumour stem cells in meningioma: A review Ganeshwaran Shivapathasundram a,b, Agadha C. Wickremesekera a,b, Swee T. Tan a,c,⇑,1, Tinte Itinteang a,1 a
Gillies McIndoe Research Institute, Newtown, Wellington, New Zealand Department of Neurosurgery, Wellington Regional Hospital, Wellington, New Zealand c Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand b
a r t i c l e
i n f o
Article history: Received 7 August 2017 Accepted 22 October 2017 Available online xxxx Keywords: Meningioma Embryonic Stem cells Hierarchy Primitive population
a b s t r a c t Meningioma is a common intracranial and intraspinal neoplasm accounting for 25–30% of all primary neurological tumours. It is associated with high rates of recurrence especially in higher-grade tumours and lesions located at the skull base. Cancer stem cells are increasingly recognised as the origin of cancer and are attributed to loco-regional recurrence, metastasis and treatment resistance. This review presents the accumulating evidence of the presence of tumour stem cells within meningioma and the stem cell markers being used to characterise this putative primitive population within this common tumour. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Meningioma (MG) is a common intracranial and intraspinal neoplasm accounting for 25–30% of all primary neurological tumours [1,2]. MGs are presumed to arise from the arachnoid cap cells of the brain and spinal cord, based on histological and ultrastructural similarities between arachnoid cap cells and MG cells [3]. MGs are typically attached to the dura mater [4] but may also enter the ventricular spaces via folds of arachnoid mater known as tela choroidea [5]. Arachnoid cells are thought to be of neural crest neuroectodermal origin, differentiated from pluripotent stem cells [6]. The incidence of MG is 6/100,000 with a female preponderance (8/100,000) [7]. Most MGs are asymptomatic with autopsy studies demonstrating a 2.8% incidental MG rate [7]. The majority of MGs are benign WHO grade I lesions with approximately 8% considered atypical (grade II) and 2% anaplastic/malignant (grade III) [8]. A genetic predilection for MG is seen in patients with neurofibromatosis type 2 (NF2) [7], and other risk factors include ionising radiation exposure [7]. MGs typically present with headaches, seizures and focal neurological symptoms, determined by their intracranial location. Radiological features of MG include slight hyper-attenuation on CT (Fig. 1A and B), sometimes associated with calcification and ⇑ Corresponding author at: Gillies McIndoe Research Institute, PO Box 7184, Newtown 6242, Wellington, New Zealand. E-mail address: [email protected] (S.T. Tan). 1 Equal senior authors.
surrounding cerebral oedema with homogeneous enhancement [9,10]. MG typically appears hyper-intense on T2-weighted MRI (Fig. 2A) and iso-intense on T1-weighted sequence with homogeneous Gadolinium enhancement (Fig. 2B and C) [9,10]. Most MGs have a convexity dural base to which they are attached (Fig. 3) and derive their blood supply from meningeal arteries [11,12], with a minority being entirely intraventricular [5]. Current management of MG involves neurosurgical resection as the first-line treatment [13–15]. Up to 30% of MGs are located at the skull base, often adherent to cranial nerves, arteries of the Circle of Willis, dural venous sinuses and the brainstem [16], making complete surgical excision impossible due to the risk of neurological sequalae and vascular injury [17]. The residual disease from these MGs cause significant morbidity and requires multiple interventions [17,18]. Atypical and anaplastic MGs have reported recurrence rates of 40% and 80%, respectively [19,20]. In cases of recurrent and residual MG, further surgery is often attempted and/or radiotherapy is used, although radiotherapy resistance is not uncommon [19,21]. Unlike glioblastoma (GB) there has been limited investigation into the presence of stem cells within MG, with the first report by Hu et al. [22], who described a 62-year-old male with GB who subsequently developed an aggressive grade III MG following radiotherapy. The authors demonstrate cells within both the GB and MG that stained positively for the stem cell marker CD133. In this report, we review the literature on tumour stem cells in MG, highlighting the putative role of tumour stem cells in the patho-aetiogenesis of MG. We also review the stem cell markers currently used to identify this primitive population.
https://doi.org/10.1016/j.jocn.2017.10.059 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shivapathasundram G et al. Tumour stem cells in meningioma: A review. J Clin Neurosci (2017), https://doi.org/10.1016/ j.jocn.2017.10.059
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Fig. 1. Axial (A) and coronal (B) non-contrast CT scans demonstrating a right frontal meningioma with calcification and mass effect.
Fig. 2. Left temporal meningioma showing hyper-intensity on T2-weighted axial MRI (Fig. 2A) with homogeneous Gadolinium enhancement on axial (B) and coronal (C) T1 sequences.
2. Genetics The most common genetic changes reported in MG relate to the loss of chromosome 22, deletion of the short arm of chromosome 1, and the loss of chromosome 14 [23,24]. A number of tumour suppressor genes have been implicated in the formation of MG including NF2, DAL-1, various tissue inhibitors of matrix metalloproteinases (TIMPs) and genes associated with the short arm of chromosome 9 including CDKN2A, CDKN2B and p14ARF [25,26]. The NF2 gene on the long arm of chromosome 22 is commonly involved in the development of MG with approximately 60% of patients with sporadic MG possessing a loss of the NF2 gene [25,27]. Bi-allelic inactivation of the NF2 gene results in loss of the merlin protein and may be associated with NF2, which is associated with multiple MGs and schwannomas [25,28,29]. DAL-1 which is found at chromosome 18p11.3 has been reported in 60% of sporadic MGs [30,31], and has been reported to play a role in the progression rather than initiation of MG [25,32]. TIMP and the chromosome 9 tumour suppressor genes CDKN2A, CDKN2B and p14ARF are proposed to play a crucial role due to their association with the higher grade MGs [25,33]. The chromosome 9 tumour suppressor genes have been identified in 46% of anaplastic MGs and 3% of atypical MGs [34]. Oncogenes c-Myc and STAT3
have also been implicated in the pathogenesis of MG, especially in higher-grade lesions [25,35,36]. Lastly, the Wnt signalling pathway, implicated in the development of a number of types of cancer, has also been implicated in the progression of MG especially in clinically aggressive lesions [25,37,38]. 2.1. Tumour stem cells in meningioma MGs displaying one of the following morphological characteristics: meningothelial, fibrous, microcystic, psammomatous, transitional, secretory, angiomatous, metaplastic or lymphoplasmacytic-rich, are considered grade I lesions (Fig. 4A) [39,40]. Importantly these lesions do not demonstrate any features of higher grade lesions (Fig. 4B), being more than 4 mitotic figures per 10 high-powered field, brain invasion, or three out of the five following histological features: spontaneous necrosis, prominent nucleoli, high nucleus to cytoplasm ratios, increased cellularity or patternless sheet-like growth [39,41,42]. Cancer stem cells (CSCs) have been proposed to be the origin of many types of cancer, including GB [43], oral cavity squamous cell carcinoma (OCSCC) affecting different subsites [44–46] and leukaemia [47]. The CSC concept proposes that cancer originates from a small population of CSCs, which possess the capacity for
Please cite this article in press as: Shivapathasundram G et al. Tumour stem cells in meningioma: A review. J Clin Neurosci (2017), https://doi.org/10.1016/ j.jocn.2017.10.059
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Fig. 3. A meningioma (A) resected en bloc with dural attachment (B and C), further demonstrated on sectioning (D).
Fig. 4. H&E image of a grade I meningothelial meningioma with distinctive whorls (A) and a grade II meningioma displaying cells with mitotic figures and necrosis (B). Original magnification: 200.
self-renewal and differentiate to form cancer cells in an unregulated manner resulting in carcinogenesis [48]. Increased expression of markers of CSCs has also been associated with worsening prognosis of glial tumours, treatment resistance and higher risk of loco-regional recurrence and distant metastasis following chemotherapy and radiotherapy [49]. Identification and characterisation of tumour stem cells within MG may offer an insight into their involvement in the pathoaetiogenesis of this tumour. This may result in novel treatment, especially for the more aggressive anaplastic, recurrent and skull base lesions.
Stem cell markers that have been demonstrated in GB and OCSCC include OCT4, SOX2, SALL4, pSTAT3, NANOG, CD133 and nestin [44,46,50,51]. Hueng et al. [19] isolated cells from nine MGs that were able to form MG spheres, a characteristic of embryonic stem cells (ESCs), and were capable of self-renewal. These cells also stained positively for stem cell marker CD133. Interestingly they did not express nestin, a neuronal progenitor marker; and epithelial membrane antigen (EMA), a differentiated meningioma marker. Bradshaw et al. [43] postulate the presence of a hierarchy of CSCs in GB. The presence of a stem cell hierarchy is supported by the observation of Hueng
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et al. [19] who demonstrated that MG tumour spheres xenoplanted to the brains of non-obese diabetic/severe combined immunodeficient mice, developed into MG 60 days following implantation. These tumours express vimentin, EMA and CD133, and are chemotherapy and radiotherapy resistant. Rath et al. [2] cultured cells harvested from an atypical MG that expressed SOX2 and nestin and they developed an orthoptic model of this tumour. In an in vivo arm of their study they injected these cells into the flank of 6–7 week-old athymic female nude mice and showed that the cultured cells expressed SOX2 and nestin in contrast to the findings of Hueng et al. [19]. The cultured MG stem cells also expressed CD133 as seen in the other studies [19,22]. Furthermore, instead of forming tight spheres as described by Hueng et al. [19] the cultured cells formed small clusters, although they were capable of self-renewal. The in vivo arm of their study demonstrated growth of MG in the flank of athymic mice, which displayed diffuse areas of staining for vimentin and EMA, similar to the primary tumour [2]. These three studies demonstrate the presence of stem cells within MG that express CD133, SOX2 and possibly nestin. Tang et al. [52] recently demonstrated that spheroid stem cells derived from anaplastic MG specimens were capable of selfrenewal. Consistent with the work of Rath et al. [2] they determined that the cultured stem cells expressed CD133 which when inoculated to the flanks of nude mice, developed into anaplastic MG after 7 weeks. Using mRNA analysis on three grades of MGs, Tang et al. [52] demonstrated that KLF4 expression was high in benign tumours, and lower in atypical and anaplastic lesions. They postulated that KLF4 possesses antitumoral properties, and demonstrated in their mice model that there was suppression of tumour with inoculation of KLF4 overexpressing cells [52]. 3. Stem cell markers 3.1. OCT4 OCT 4 is a transcription factor protein belonging to the Pit, Oct and Unc (POU) family of DNA binding proteins [53]. It plays a critical role in embryogenesis, and in conjunction with SOX2 and NANOG, it is a gatekeeper for ESC pluripotency [53]. It plays a key role in tumorigenicity, tumour metastasis and locoregional recurrence [54]. OCT4 has been associated with a number of cancers including prostate [53], OCSCC [54] and GB [50]. OCT4 has also been demonstrated in benign conditions such as infantile haemangioma [55] and Dupuytren’s disease [56]. OCT4 is a crucial gene in the formation of induced pluripotent stem cells (iPSC) with an important role in high-grade glial tumours, although there is limited data on the expression and the role of this transcription factor in the biology of MG [49,57]. It is intriguing that the expression of OCT4, a marker putatively expressed by the most primitive CSCs [43], has been demonstrated both diffusely within the tumour bulk [50], as in GB, and in a separate subpopulation of cells as reported in OCSCC [44,45,51]. Freitag et al. [58] have recently demonstrated OCT4 expression in MG.
SOX2 has been demonstrated in atypical MG and in stem cells cultured from atypical MG [2] with Freitag et al. [58] reporting expression of SOX2 in 3% in low-grade and 9% in high-grade lesions. 3.3. NANOG NANOG is a homeobox binding protein found in ESCs and plays a role in transcriptional regulation of self-renewal and pluripotency [53,58]. It is a stem cell marker that coordinates selfrenewal and differentiation of ESCs [53]. NANOG plays a role in metastasis, and carcinogenesis [58]. Freitag et al. [58] demonstrated the presence of NANOG in MG tissue with increased expression in the tumour compared with ‘normal’ dura. Interestingly NANOG is co-expressed with SOX2 and OCT4 in both lowand high-grade MG lesions [58]. 3.4. c-Myc The c-Myc oncoprotein plays a vital role in proliferation and growth of normal and neoplastic cells [64,65]. Deregulated c-Myc has been associated with aggressive malignancy and poorer prognosis [64]. c-Myc has been found to be a key component of iPSC formation and self-renewal of stem cells [66,67]. Expression of cMyc by MG has been studied although this yields mixed results with low-grade lesions being c-Myc negative, while recurrent high-grade lesions express c-Myc [65,68,69]. 3.5. KLF4 Kruppel-like factor 4 (KLF4) is a transcription factor involved in cell proliferation, differentiation and apoptosis [70]. It also plays a role in maintenance of stemness and is required for self-renewal of ESCs, and maintenance of pluripotency [52,71]. KLF4 is expressed by MG, and is one of the most frequently mutated genes in benign secretory MGs [38,52]. 3.6. CD133 CD133 is a pentaspan transmembrane protein that is also one of the cluster of differentiation antigens [72]. CD133 plays a key role in tumorigenesis, metastasis, chemotherapy and radiotherapy resistance and anti-apoptosis [72]. CD133 has been expressed by stem cells in MG [2,19,22]. Stem cells expressing CD133 have been identified in different cancers including GB [2] and colon [2,73], liver [72], and prostate [74] cancers. 3.7. Nestin Nestin is a class VI intermediate filament protein first detected in neural stem cells during development [75]. It is expressed in a number of cancers including epithelial, mesenchymal and neuroectodermal neuroepithelial cancers [75]. It is commonly coexpressed with CD133 and SOX2 in prostate cancer [75]. MG stem cells have been demonstrated to express nestin [2].
3.2. SOX2 3.8. Vimentin SOX2 protein is a high-mobility SRY-related HMG box transcription factor [59,60] involved in multiple signal transduction pathways. It is implicated in both physiological and pathological cell proliferation, migration, invasion, tumorigenesis and antiapoptosis [59]. SOX2 has been demonstrated to be an ESC marker that promotes differentiation of neural progenitor cells into neurons, astrocytes and oligodendrocytes [61]. SOX2 plays a role in maintaining pluripotency of CSCs in cancer and is critical for stem cell maintenance [62,63]. The presence of stem cells expressing
Vimentin is a class III member of the intermediate filament protein family [76]. Its expression in adults is largely limited to connective tissue mesenchymal cells in the central nervous system and muscle [76]. Vimentin is expressed by ependymal cells, choroid plexus, meningeal cells and some sub-pial cells, while there is weak expression in endothelial cells [77]. Vimentin is expressed by MG [78] and specific phosphorylated forms of vimentin have been shown to be expressed by non-infiltrative tumours [79].
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4. Discussion While there is growing evidence supporting the CSC concept of cancer, the role of tumour stem cells in the pathogenesis of benign tumours remains largely unexplored. In this review we underscore the increasing evidence in the literature of the presence of tumour stem cells in MG and outline a number of key stem cell markers used for the identification of this primitive population. Some markers such as vimentin, nestin and CD133 have been described in some depth [2,19,22] and are expressed by stem cells cultured from MG [2,19]. These stem cell markers are considered downstream stem cell markers that are expressed by more differentiated, progenitor cells [43]. More primitive markers including the ESC markers SALL4, OCT4, NANOG, c-Myc, pSTAT3 and KLF4 have been studied in cancers including GB [50] and OCSCC [44]. There has been limited investigation into the presence of upstream stem cell markers such as NANOG, c-Myc, KLF4 and SOX2 in MG [19,35,52,58,65,68,69]. ESC markers NANOG and c-Myc have been associated with higher grade MG [35,58,65,68,69]. Interestingly, KLF4 has been shown to be overexpressed in grade I MG compared with grade II and III lesions, and it possesses apoptotic, anti cell proliferation and invasion characteristics [52]. The concept of a CSC hierarchy has been proposed recently [43]. The paucity of data on tumour stem cells in MG calls for further investigation into the unique expression patterns of the primitive population in this common tumour. Despite reports supporting the existence of tumour stem cells in MG that possess the ability to form MG-like tumours both in vitro and in vivo, there remains significant gaps in our understanding of this primitive phenotype within MG. The presence of phenotypic heterogeneity of these tumour stem cells within MG, that exists within malignant tumours [80], and their precise roles in the biology of this tumour remains to be elucidated. Funding None. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. TI and STT are inventors of the PCT patent applications Cancer Diagnosis and Therapy (No. PCT/NZ2015/050108) and Cancer Therapeutic (US62/452479). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.jocn.2017.10.059. References [1] El-Saka AM, Zamzam YA. Stem cell markers CD133, MMP-9, and Ki-67 expressions in different grades of meningiomas and their prognostic significance. Egypt J Pathol 2013;33:6. https://doi.org/10.1097/01. XEJ.0000436656.60903.0b. [2] Rath P, Miller DC, Litofsky NS, Anthony DC, Feng Q, Franklin C, Pei L, Free A, Liu J, Ren M, Kirk MD, Shi H. Isolation and characterization of a population of stemlike progenitor cells from an atypical meningioma. Exp Mol Pathol 2011;90 (2):179–88. https://doi.org/10.1016/j.yexmp.2010.12.003. [3] Albayrak SB, Black PML. The origin of meningiomas. In: Pamir MN, Black PML, Fahlbusch R, editors. Meningiomas: A Comprehensive Text. Philadelphia, Pennsylvania: Saunders/Elsevier; 2010. [4] Frosch MP, Anthony DC, De Girolami U. The central nervous system. In: Kumar V, Abbas AK, editors. Robbins and Cotran Pathologic Basis of Disease. Philadelphia, Pennsylvania: Elsevier Saunders; 2009.
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Review article
Tumour stem cells in meningioma: A review Ganeshwaran Shivapathasundram a,b, Agadha C. Wickremesekera a,b, Swee T. Tan a,c,⇑,1, Tinte Itinteang a,1 a
Gillies McIndoe Research Institute, Newtown, Wellington, New Zealand Department of Neurosurgery, Wellington Regional Hospital, Wellington, New Zealand c Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand b
a r t i c l e
i n f o
Article history: Received 7 August 2017 Accepted 22 October 2017 Available online xxxx Keywords: Meningioma Embryonic Stem cells Hierarchy Primitive population
a b s t r a c t Meningioma is a common intracranial and intraspinal neoplasm accounting for 25–30% of all primary neurological tumours. It is associated with high rates of recurrence especially in higher-grade tumours and lesions located at the skull base. Cancer stem cells are increasingly recognised as the origin of cancer and are attributed to loco-regional recurrence, metastasis and treatment resistance. This review presents the accumulating evidence of the presence of tumour stem cells within meningioma and the stem cell markers being used to characterise this putative primitive population within this common tumour. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Meningioma (MG) is a common intracranial and intraspinal neoplasm accounting for 25–30% of all primary neurological tumours [1,2]. MGs are presumed to arise from the arachnoid cap cells of the brain and spinal cord, based on histological and ultrastructural similarities between arachnoid cap cells and MG cells [3]. MGs are typically attached to the dura mater [4] but may also enter the ventricular spaces via folds of arachnoid mater known as tela choroidea [5]. Arachnoid cells are thought to be of neural crest neuroectodermal origin, differentiated from pluripotent stem cells [6]. The incidence of MG is 6/100,000 with a female preponderance (8/100,000) [7]. Most MGs are asymptomatic with autopsy studies demonstrating a 2.8% incidental MG rate [7]. The majority of MGs are benign WHO grade I lesions with approximately 8% considered atypical (grade II) and 2% anaplastic/malignant (grade III) [8]. A genetic predilection for MG is seen in patients with neurofibromatosis type 2 (NF2) [7], and other risk factors include ionising radiation exposure [7]. MGs typically present with headaches, seizures and focal neurological symptoms, determined by their intracranial location. Radiological features of MG include slight hyper-attenuation on CT (Fig. 1A and B), sometimes associated with calcification and ⇑ Corresponding author at: Gillies McIndoe Research Institute, PO Box 7184, Newtown 6242, Wellington, New Zealand. E-mail address: [email protected] (S.T. Tan). 1 Equal senior authors.
surrounding cerebral oedema with homogeneous enhancement [9,10]. MG typically appears hyper-intense on T2-weighted MRI (Fig. 2A) and iso-intense on T1-weighted sequence with homogeneous Gadolinium enhancement (Fig. 2B and C) [9,10]. Most MGs have a convexity dural base to which they are attached (Fig. 3) and derive their blood supply from meningeal arteries [11,12], with a minority being entirely intraventricular [5]. Current management of MG involves neurosurgical resection as the first-line treatment [13–15]. Up to 30% of MGs are located at the skull base, often adherent to cranial nerves, arteries of the Circle of Willis, dural venous sinuses and the brainstem [16], making complete surgical excision impossible due to the risk of neurological sequalae and vascular injury [17]. The residual disease from these MGs cause significant morbidity and requires multiple interventions [17,18]. Atypical and anaplastic MGs have reported recurrence rates of 40% and 80%, respectively [19,20]. In cases of recurrent and residual MG, further surgery is often attempted and/or radiotherapy is used, although radiotherapy resistance is not uncommon [19,21]. Unlike glioblastoma (GB) there has been limited investigation into the presence of stem cells within MG, with the first report by Hu et al. [22], who described a 62-year-old male with GB who subsequently developed an aggressive grade III MG following radiotherapy. The authors demonstrate cells within both the GB and MG that stained positively for the stem cell marker CD133. In this report, we review the literature on tumour stem cells in MG, highlighting the putative role of tumour stem cells in the patho-aetiogenesis of MG. We also review the stem cell markers currently used to identify this primitive population.
https://doi.org/10.1016/j.jocn.2017.10.059 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
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Fig. 1. Axial (A) and coronal (B) non-contrast CT scans demonstrating a right frontal meningioma with calcification and mass effect.
Fig. 2. Left temporal meningioma showing hyper-intensity on T2-weighted axial MRI (Fig. 2A) with homogeneous Gadolinium enhancement on axial (B) and coronal (C) T1 sequences.
2. Genetics The most common genetic changes reported in MG relate to the loss of chromosome 22, deletion of the short arm of chromosome 1, and the loss of chromosome 14 [23,24]. A number of tumour suppressor genes have been implicated in the formation of MG including NF2, DAL-1, various tissue inhibitors of matrix metalloproteinases (TIMPs) and genes associated with the short arm of chromosome 9 including CDKN2A, CDKN2B and p14ARF [25,26]. The NF2 gene on the long arm of chromosome 22 is commonly involved in the development of MG with approximately 60% of patients with sporadic MG possessing a loss of the NF2 gene [25,27]. Bi-allelic inactivation of the NF2 gene results in loss of the merlin protein and may be associated with NF2, which is associated with multiple MGs and schwannomas [25,28,29]. DAL-1 which is found at chromosome 18p11.3 has been reported in 60% of sporadic MGs [30,31], and has been reported to play a role in the progression rather than initiation of MG [25,32]. TIMP and the chromosome 9 tumour suppressor genes CDKN2A, CDKN2B and p14ARF are proposed to play a crucial role due to their association with the higher grade MGs [25,33]. The chromosome 9 tumour suppressor genes have been identified in 46% of anaplastic MGs and 3% of atypical MGs [34]. Oncogenes c-Myc and STAT3
have also been implicated in the pathogenesis of MG, especially in higher-grade lesions [25,35,36]. Lastly, the Wnt signalling pathway, implicated in the development of a number of types of cancer, has also been implicated in the progression of MG especially in clinically aggressive lesions [25,37,38]. 2.1. Tumour stem cells in meningioma MGs displaying one of the following morphological characteristics: meningothelial, fibrous, microcystic, psammomatous, transitional, secretory, angiomatous, metaplastic or lymphoplasmacytic-rich, are considered grade I lesions (Fig. 4A) [39,40]. Importantly these lesions do not demonstrate any features of higher grade lesions (Fig. 4B), being more than 4 mitotic figures per 10 high-powered field, brain invasion, or three out of the five following histological features: spontaneous necrosis, prominent nucleoli, high nucleus to cytoplasm ratios, increased cellularity or patternless sheet-like growth [39,41,42]. Cancer stem cells (CSCs) have been proposed to be the origin of many types of cancer, including GB [43], oral cavity squamous cell carcinoma (OCSCC) affecting different subsites [44–46] and leukaemia [47]. The CSC concept proposes that cancer originates from a small population of CSCs, which possess the capacity for
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Fig. 3. A meningioma (A) resected en bloc with dural attachment (B and C), further demonstrated on sectioning (D).
Fig. 4. H&E image of a grade I meningothelial meningioma with distinctive whorls (A) and a grade II meningioma displaying cells with mitotic figures and necrosis (B). Original magnification: 200.
self-renewal and differentiate to form cancer cells in an unregulated manner resulting in carcinogenesis [48]. Increased expression of markers of CSCs has also been associated with worsening prognosis of glial tumours, treatment resistance and higher risk of loco-regional recurrence and distant metastasis following chemotherapy and radiotherapy [49]. Identification and characterisation of tumour stem cells within MG may offer an insight into their involvement in the pathoaetiogenesis of this tumour. This may result in novel treatment, especially for the more aggressive anaplastic, recurrent and skull base lesions.
Stem cell markers that have been demonstrated in GB and OCSCC include OCT4, SOX2, SALL4, pSTAT3, NANOG, CD133 and nestin [44,46,50,51]. Hueng et al. [19] isolated cells from nine MGs that were able to form MG spheres, a characteristic of embryonic stem cells (ESCs), and were capable of self-renewal. These cells also stained positively for stem cell marker CD133. Interestingly they did not express nestin, a neuronal progenitor marker; and epithelial membrane antigen (EMA), a differentiated meningioma marker. Bradshaw et al. [43] postulate the presence of a hierarchy of CSCs in GB. The presence of a stem cell hierarchy is supported by the observation of Hueng
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et al. [19] who demonstrated that MG tumour spheres xenoplanted to the brains of non-obese diabetic/severe combined immunodeficient mice, developed into MG 60 days following implantation. These tumours express vimentin, EMA and CD133, and are chemotherapy and radiotherapy resistant. Rath et al. [2] cultured cells harvested from an atypical MG that expressed SOX2 and nestin and they developed an orthoptic model of this tumour. In an in vivo arm of their study they injected these cells into the flank of 6–7 week-old athymic female nude mice and showed that the cultured cells expressed SOX2 and nestin in contrast to the findings of Hueng et al. [19]. The cultured MG stem cells also expressed CD133 as seen in the other studies [19,22]. Furthermore, instead of forming tight spheres as described by Hueng et al. [19] the cultured cells formed small clusters, although they were capable of self-renewal. The in vivo arm of their study demonstrated growth of MG in the flank of athymic mice, which displayed diffuse areas of staining for vimentin and EMA, similar to the primary tumour [2]. These three studies demonstrate the presence of stem cells within MG that express CD133, SOX2 and possibly nestin. Tang et al. [52] recently demonstrated that spheroid stem cells derived from anaplastic MG specimens were capable of selfrenewal. Consistent with the work of Rath et al. [2] they determined that the cultured stem cells expressed CD133 which when inoculated to the flanks of nude mice, developed into anaplastic MG after 7 weeks. Using mRNA analysis on three grades of MGs, Tang et al. [52] demonstrated that KLF4 expression was high in benign tumours, and lower in atypical and anaplastic lesions. They postulated that KLF4 possesses antitumoral properties, and demonstrated in their mice model that there was suppression of tumour with inoculation of KLF4 overexpressing cells [52]. 3. Stem cell markers 3.1. OCT4 OCT 4 is a transcription factor protein belonging to the Pit, Oct and Unc (POU) family of DNA binding proteins [53]. It plays a critical role in embryogenesis, and in conjunction with SOX2 and NANOG, it is a gatekeeper for ESC pluripotency [53]. It plays a key role in tumorigenicity, tumour metastasis and locoregional recurrence [54]. OCT4 has been associated with a number of cancers including prostate [53], OCSCC [54] and GB [50]. OCT4 has also been demonstrated in benign conditions such as infantile haemangioma [55] and Dupuytren’s disease [56]. OCT4 is a crucial gene in the formation of induced pluripotent stem cells (iPSC) with an important role in high-grade glial tumours, although there is limited data on the expression and the role of this transcription factor in the biology of MG [49,57]. It is intriguing that the expression of OCT4, a marker putatively expressed by the most primitive CSCs [43], has been demonstrated both diffusely within the tumour bulk [50], as in GB, and in a separate subpopulation of cells as reported in OCSCC [44,45,51]. Freitag et al. [58] have recently demonstrated OCT4 expression in MG.
SOX2 has been demonstrated in atypical MG and in stem cells cultured from atypical MG [2] with Freitag et al. [58] reporting expression of SOX2 in 3% in low-grade and 9% in high-grade lesions. 3.3. NANOG NANOG is a homeobox binding protein found in ESCs and plays a role in transcriptional regulation of self-renewal and pluripotency [53,58]. It is a stem cell marker that coordinates selfrenewal and differentiation of ESCs [53]. NANOG plays a role in metastasis, and carcinogenesis [58]. Freitag et al. [58] demonstrated the presence of NANOG in MG tissue with increased expression in the tumour compared with ‘normal’ dura. Interestingly NANOG is co-expressed with SOX2 and OCT4 in both lowand high-grade MG lesions [58]. 3.4. c-Myc The c-Myc oncoprotein plays a vital role in proliferation and growth of normal and neoplastic cells [64,65]. Deregulated c-Myc has been associated with aggressive malignancy and poorer prognosis [64]. c-Myc has been found to be a key component of iPSC formation and self-renewal of stem cells [66,67]. Expression of cMyc by MG has been studied although this yields mixed results with low-grade lesions being c-Myc negative, while recurrent high-grade lesions express c-Myc [65,68,69]. 3.5. KLF4 Kruppel-like factor 4 (KLF4) is a transcription factor involved in cell proliferation, differentiation and apoptosis [70]. It also plays a role in maintenance of stemness and is required for self-renewal of ESCs, and maintenance of pluripotency [52,71]. KLF4 is expressed by MG, and is one of the most frequently mutated genes in benign secretory MGs [38,52]. 3.6. CD133 CD133 is a pentaspan transmembrane protein that is also one of the cluster of differentiation antigens [72]. CD133 plays a key role in tumorigenesis, metastasis, chemotherapy and radiotherapy resistance and anti-apoptosis [72]. CD133 has been expressed by stem cells in MG [2,19,22]. Stem cells expressing CD133 have been identified in different cancers including GB [2] and colon [2,73], liver [72], and prostate [74] cancers. 3.7. Nestin Nestin is a class VI intermediate filament protein first detected in neural stem cells during development [75]. It is expressed in a number of cancers including epithelial, mesenchymal and neuroectodermal neuroepithelial cancers [75]. It is commonly coexpressed with CD133 and SOX2 in prostate cancer [75]. MG stem cells have been demonstrated to express nestin [2].
3.2. SOX2 3.8. Vimentin SOX2 protein is a high-mobility SRY-related HMG box transcription factor [59,60] involved in multiple signal transduction pathways. It is implicated in both physiological and pathological cell proliferation, migration, invasion, tumorigenesis and antiapoptosis [59]. SOX2 has been demonstrated to be an ESC marker that promotes differentiation of neural progenitor cells into neurons, astrocytes and oligodendrocytes [61]. SOX2 plays a role in maintaining pluripotency of CSCs in cancer and is critical for stem cell maintenance [62,63]. The presence of stem cells expressing
Vimentin is a class III member of the intermediate filament protein family [76]. Its expression in adults is largely limited to connective tissue mesenchymal cells in the central nervous system and muscle [76]. Vimentin is expressed by ependymal cells, choroid plexus, meningeal cells and some sub-pial cells, while there is weak expression in endothelial cells [77]. Vimentin is expressed by MG [78] and specific phosphorylated forms of vimentin have been shown to be expressed by non-infiltrative tumours [79].
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4. Discussion While there is growing evidence supporting the CSC concept of cancer, the role of tumour stem cells in the pathogenesis of benign tumours remains largely unexplored. In this review we underscore the increasing evidence in the literature of the presence of tumour stem cells in MG and outline a number of key stem cell markers used for the identification of this primitive population. Some markers such as vimentin, nestin and CD133 have been described in some depth [2,19,22] and are expressed by stem cells cultured from MG [2,19]. These stem cell markers are considered downstream stem cell markers that are expressed by more differentiated, progenitor cells [43]. More primitive markers including the ESC markers SALL4, OCT4, NANOG, c-Myc, pSTAT3 and KLF4 have been studied in cancers including GB [50] and OCSCC [44]. There has been limited investigation into the presence of upstream stem cell markers such as NANOG, c-Myc, KLF4 and SOX2 in MG [19,35,52,58,65,68,69]. ESC markers NANOG and c-Myc have been associated with higher grade MG [35,58,65,68,69]. Interestingly, KLF4 has been shown to be overexpressed in grade I MG compared with grade II and III lesions, and it possesses apoptotic, anti cell proliferation and invasion characteristics [52]. The concept of a CSC hierarchy has been proposed recently [43]. The paucity of data on tumour stem cells in MG calls for further investigation into the unique expression patterns of the primitive population in this common tumour. Despite reports supporting the existence of tumour stem cells in MG that possess the ability to form MG-like tumours both in vitro and in vivo, there remains significant gaps in our understanding of this primitive phenotype within MG. The presence of phenotypic heterogeneity of these tumour stem cells within MG, that exists within malignant tumours [80], and their precise roles in the biology of this tumour remains to be elucidated. Funding None. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. TI and STT are inventors of the PCT patent applications Cancer Diagnosis and Therapy (No. PCT/NZ2015/050108) and Cancer Therapeutic (US62/452479). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.jocn.2017.10.059. References [1] El-Saka AM, Zamzam YA. Stem cell markers CD133, MMP-9, and Ki-67 expressions in different grades of meningiomas and their prognostic significance. Egypt J Pathol 2013;33:6. https://doi.org/10.1097/01. XEJ.0000436656.60903.0b. [2] Rath P, Miller DC, Litofsky NS, Anthony DC, Feng Q, Franklin C, Pei L, Free A, Liu J, Ren M, Kirk MD, Shi H. Isolation and characterization of a population of stemlike progenitor cells from an atypical meningioma. Exp Mol Pathol 2011;90 (2):179–88. https://doi.org/10.1016/j.yexmp.2010.12.003. [3] Albayrak SB, Black PML. The origin of meningiomas. In: Pamir MN, Black PML, Fahlbusch R, editors. Meningiomas: A Comprehensive Text. Philadelphia, Pennsylvania: Saunders/Elsevier; 2010. [4] Frosch MP, Anthony DC, De Girolami U. The central nervous system. In: Kumar V, Abbas AK, editors. Robbins and Cotran Pathologic Basis of Disease. Philadelphia, Pennsylvania: Elsevier Saunders; 2009.
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