Highlights
- •Evidence of the presence of tumour stem cells (TSCs) in benign tumours is increasing.
- •Schwannoma expresses embryonic stem cell markers OCT4, SOX2, NANOG and c-MYC.
- •Progenitor cell markers CD133 and CD44 have also been demonstrated in schwannoma.
- •Characterisation of TSCs in schwannoma may improve understanding of its biology.
Abstract
Schwannoma is a peripheral nerve tumour, accounting for 5% of benign soft tissue tumours,
with vestibular schwannoma comprising 6% of all intracranial tumours. The tumour stem
cell concept is rapidly gaining traction underscoring the understanding of tumourigenesis.
It proposes a small subpopulation of primitive cells as the origin of the tumour and
these cells account for treatment resistance, local recurrence and distant metastasis
in malignant tumours. This review outlines the stem cell markers used to identify
and characterise stem cells and progenitor cells in tumours and examines current evidence
of the presence of tumour stem cells in schwannoma.
Keywords
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References
- Benign soft-tissue tumors in a large referral population: distribution of specific diagnoses by age, sex, and location.Am J Roentgenol. 1995; 164: 395-402https://doi.org/10.2214/ajr.164.2.7839977
- Peripheral nerve tumors: management strategies and molecular insights.J Neurooncol. 2004; 69: 335-349
- Malignant peripheral nerve sheath tumours in the head and neck region: retrospective analysis of clinicopathological features and treatment outcomes.Int J Oral Maxillofac Surg. 2014; 43: 924-932https://doi.org/10.1016/j.ijom.2014.03.006
- Schwannomas and their pathogenesis.Brain Pathol. 2014; 24: 205-220https://doi.org/10.1111/bpa.12125
- Cross-sectional imaging of peripheral nerve sheath tumors: characteristic signs on CT, MR imaging, and sonography.Am J Roentgenol. 2001; 176: 75-82https://doi.org/10.2214/ajr.176.1.1760075
- Pathologic classification of peripheral nerve tumors.Neurosurg Clin N Am. 2004; 15: 157-166https://doi.org/10.1016/j.nec.2004.02.005
- The Schwann cell precursor and its fate: a study of cell death and differentiation during gliogenesis in rat embryonic nerves.Neuron. 1994; 12: 509-527
- The origin and development of glial cells in peripheral nerves.Nat Rev Neurosci. 2005; 6: 671-682https://doi.org/10.1038/nrn1746
- Neuregulin-1 type III determines the ensheathment fate of axons.Neuron. 2005; 47: 681-694https://doi.org/10.1016/j.neuron.2005.08.017
- From the archives of the AFIP. Imaging of musculoskeletal neurogenic tumors: radiologic-pathologic correlation.Radiographics. 1999; 19: 1253-1280https://doi.org/10.1148/radiographics.19.5.g99se101253
- Descriptive epidemiology of vestibular schwannomas.Neuro Oncol. 2006; 8: 1-11https://doi.org/10.1215/S1522851704001097
- Management of 1000 vestibular schwannomas (acoustic neuromas): clinical presentation.Neurosurgery. 1997; 40 (discussion -10): 1-9
- Management of vestibular schwannomas (acoustic neuromas): radiological features in 202 cases–their value for diagnosis and their predictive importance.Neurosurgery. 1997; 40 (discussion 81–2): 469-481
- Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them.Neurosurgery. 1997; 40 (discussion -3): 11-21
- Radiotherapy for vestibular schwannomas: a critical review.Int J Radiat Oncol Biol Phys. 2011; 79: 985-997https://doi.org/10.1016/j.ijrobp.2010.10.010
- Conservative management of 386 cases of unilateral vestibular schwannoma: tumor growth and consequences for treatment.J Neurosurg. 2009; 110: 662-669https://doi.org/10.3171/2007.5.16836
- Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma.Nature. 1986; 322: 644-647https://doi.org/10.1038/322644a0
- A clinical study of type 2 neurofibromatosis.Q J Med. 1992; 84: 603-618
- Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.Nature. 1993; 363: 515-521https://doi.org/10.1038/363515a0
- Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac.Cancer Res. 2007; 67: 520-527https://doi.org/10.1158/0008-5472.CAN-06-1608
- Germline mutation of INI1/SMARCB1 in familial schwannomatosis.Am J Hum Genet. 2007; 80: 805-810https://doi.org/10.1086/513207
- Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis.Neurogenetics. 2012; 13: 141-145https://doi.org/10.1007/s10048-012-0319-8
- Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis.J Med Genet. 2008; 45: 332-339https://doi.org/10.1136/jmg.2007.056499
- Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.Nat Genet. 2014; 46: 182-187https://doi.org/10.1038/ng.2855
- Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease!.FEBS Lett. 2003; 546: 59-64
- Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization.J Biol Chem. 2004; 279: 18559-18566https://doi.org/10.1074/jbc.M313916200
- Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton.Oncogene. 2008; 27: 3233-3243https://doi.org/10.1038/sj.onc.1210988
- Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin.Oncogene. 2007; 26: 836-850https://doi.org/10.1038/sj.onc.1209849
- Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4DCAF1 to suppress oncogenic gene expression.Sci Signal. 2011; 4: pt6https://doi.org/10.1126/scisignal.2002314
- Merlin-deficient human tumors show loss of contact inhibition and activation of Wnt/beta-catenin signaling linked to the PDGFR/Src and Rac/PAK pathways.Neoplasia. 2011; 13: 1101-1112
- Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types.Mol Cancer Res. 2012; 10: 649-659https://doi.org/10.1158/1541-7786.MCR-11-0425-T
- Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L.Proc Natl Acad Sci USA. 2004; 101: 18200-18205https://doi.org/10.1073/pnas.0405971102
- Is tumor growth sustained by rare cancer stem cells or dominant clones?.Cancer Res. 2008; 68: 4018-4021https://doi.org/10.1158/0008-5472.CAN-07-6334
- Characterization of acute lymphoblastic leukemia progenitor cells.Blood. 2004; 104: 2919-2925https://doi.org/10.1182/blood-2004-03-0901
- Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci USA. 2003; 100: 3983-3988https://doi.org/10.1073/pnas.0530291100
- A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.Nature. 2007; 445: 106-110https://doi.org/10.1038/nature05372
- Prostate cancer stem cells: a new target for therapy.J Clin Oncol. 2008; 26: 2862-2870https://doi.org/10.1200/JCO.2007.15.1472
- Cancer stem cell hierarchy in glioblastoma multiforme.Front Surg. 2016; 3: 21https://doi.org/10.3389/fsurg.2016.00021
- Tumour stem cells in meningioma: a review.J Clin Neurosci. 2018; 47: 66-71https://doi.org/10.1016/j.jocn.2017.10.059
- The cancer stem cell hypothesis: in search of definitions, markers, and relevance.Lab Invest. 2008; 88: 459-463https://doi.org/10.1038/labinvest.2008.14
- Therapeutic implications of the cancer stem cell hypothesis.Semin Radiat Oncol. 2009; 19: 78-86https://doi.org/10.1016/j.semradonc.2008.11.002
- Cancer stem cells.N Engl J Med. 2006; 355: 1253-1261https://doi.org/10.1056/NEJMra061808
- Therapeutic implications of cancer stem cells.Curr Opin Genet Dev. 2004; 14: 43-47https://doi.org/10.1016/j.gde.2003.11.007
- Activation of PDGFR and EGFR promotes the acquisition of a stem cell-like phenotype in schwannomas.Otol Neurotol. 2012; 33: 1640-1647https://doi.org/10.1097/MAO.0b013e31826a540d
- Clinical and biological behaviour of vestibular schwannomas: signalling cascades involved in vestibular schwannoma resemble molecular and cellular mechanisms of injury-induced Schwann cell dedifferentiation.Head Neck Oncol. 2013; 16: 20
- Cancer stem cell-like cells derived from malignant peripheral nerve sheath tumors.PLoS One. 2011; 6e21099https://doi.org/10.1371/journal.pone.0021099
- Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells.Cell Res. 2008; 18: 1177-1189https://doi.org/10.1038/cr.2008.309
- Core transcriptional regulatory circuitry in human embryonic stem cells.Cell. 2005; 122: 947-956https://doi.org/10.1016/j.cell.2005.08.020
- Transcriptional regulation and transformation by Myc proteins.Nat Rev Mol Cell Biol. 2005; 6: 635-645https://doi.org/10.1038/nrm1703
- The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene.Nat Cell Biol. 2005; 7: 1074-1082https://doi.org/10.1038/ncb1314
- p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression.Nat Cell Biol. 2005; 7: 165-171https://doi.org/10.1038/ncb1211
- Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage.Nature. 2002; 419: 729-734https://doi.org/10.1038/nature01119
- Structure, expression and chromosomal location of the Oct-4 gene.Mech Dev. 1991; 35: 171-179
- The Oct4 protein: more than a magic stemness marker.Am J Stem Cells. 2014; 3: 74-82
- Epigenetic control of embryonic stem cell fate.J Exp Med. 2010; 207: 2287-2295https://doi.org/10.1084/jem.20101438
Rahimy E, Kiang A, Ongkeko WM. NF2 Regulation of schwannoma stem cell phenotype via microRNAs.
- The multiple roles for Sox2 in stem cell maintenance and tumorigenesis.Cell Signal. 2013; 25: 1264-1271https://doi.org/10.1016/j.cellsig.2013.02.013
- Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.Proc Natl Acad Sci USA. 2005; 102: 2596-2601https://doi.org/10.1073/pnas.0407836102
- Expression of c-Jun and Sox-2 in human schwannomas and traumatic neuromas.Histopathology. 2013; 62: 651-656https://doi.org/10.1111/his.12062
- Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.Cell. 2003; 113: 643-655
- Transcriptional regulation of nanog by OCT4 and SOX2.J Biol Chem. 2005; 280: 24731-24737https://doi.org/10.1074/jbc.M502573200
- Concise review: NANOG in cancer stem cells and tumor development: an update and outstanding questions.Stem Cells. 2015; 33: 2381-2390https://doi.org/10.1002/stem.2007
- Nanog, a novel prognostic marker for lung cancer.Surg Oncol. 2013; 22: 224-229https://doi.org/10.1016/j.suronc.2013.08.001
- Induction of pluripotent stem cells from fibroblast cultures.Nat Protoc. 2007; 2: 3081-3089https://doi.org/10.1038/nprot.2007.418
- Wnt/beta-catenin signaling.Cytokine Growth Factor Rev. 2000; 11: 273-282
- Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence.Braz J Med Biol Res. 2016; 49e5125https://doi.org/10.1590/1414-431X20155125
- c-myc oncogene family expression in glioblastoma and survival.Surg Neurol. 1999; 51: 536-542
- Merlin inhibits Wnt/beta-catenin signaling by blocking LRP6 phosphorylation.Cell Death Differ. 2016; 23: 1638-1647https://doi.org/10.1038/cdd.2016.54
- The biology of the mammalian Kruppel-like family of transcription factors.Int J Biochem Cell Biol. 2000; 32: 1103-1121
- Embryonic stem cell markers.Molecules. 2012; 17: 6196-6236https://doi.org/10.3390/molecules17066196
- Roles of Krupel-like factor 4 in normal homeostasis, cancer and stem cells.Acta Biochim Biophys Sin (Shanghai). 2008; 40: 554-564
- The transcription regulator Kruppel-Like Factor 4 and its dual roles of oncogene in glioblastoma and tumor suppressor in neuroblastoma.Immunopathol Dis Ther. 2016; 7: 127-139https://doi.org/10.1615/ForumImmunDisTher. 2016017227
- Identification of a cancer stem cell in human brain tumors.Cancer Res. 2003; 63: 5821-5828
- AC133, a novel marker for human hematopoietic stem and progenitor cells.Blood. 1997; 90: 5002-5012
- CD133: a stem cell biomarker and beyond.Exp Hematol Oncol. 2013; 2: 17https://doi.org/10.1186/2162-3619-2-17
- Stem cell marker CD133 affects clinical outcome in glioma patients.Clin Cancer Res. 2008; 14: 123-129https://doi.org/10.1158/1078-0432.CCR-07-0932
- Variant cell lines selected for alterations in the function of the hyaluronan receptor CD44 show differences in glycosylation.J Exp Med. 1995; 182: 431-437
- CD44 in cancer.Crit Rev Clin Lab Sci. 2002; 39: 527-579https://doi.org/10.1080/10408360290795574
- Galectin-3 and CD44v6 isoforms in the preoperative evaluation of thyroid nodules.J Clin Oncol. 1999; 17: 3494-3502https://doi.org/10.1200/JCO.1999.17.11.3494
- CD44 expression in benign, premalignant, and malignant ovarian neoplasms: relation to tumour development and progression.J Pathol. 1999; 189: 326-337https://doi.org/10.1002/(SICI)1096-9896(199911)189:3<326::AID-PATH425>3.0.CO;2-6
- Reduced expression of CD44v3 variant isoform is associated with unfavorable outcome in non-small cell lung carcinoma.Hum Pathol. 2000; 31: 1088-1095https://doi.org/10.1053/hupa.2000.16277
- Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.Nat Med. 2004; 10: 175-181https://doi.org/10.1038/nm966
- Dynamic changes of CD44 expression from progenitors to subpopulations of astrocytes and neurons in developing cerebellum.PLoS One. 2013; 8e53109https://doi.org/10.1371/journal.pone.0053109
- Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting.J Biol Chem. 2001; 276: 45509-45512https://doi.org/10.1074/jbc.C100527200
- CXCR4 signaling in health and disease.Immunol Lett. 2016; 177: 6-15https://doi.org/10.1016/j.imlet.2016.06.006
- A review on CXCR4/CXCL12 axis in oncology: no place to hide.Eur J Cancer. 2013; 49: 219-230https://doi.org/10.1016/j.ejca.2012.05.005
- Homeostatic chemokine receptors and organ-specific metastasis.Nat Rev Immunol. 2011; 11: 597-606https://doi.org/10.1038/nri3049
- SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease.PLoS One. 2014; 9e92227https://doi.org/10.1371/journal.pone.0092227
- CXCR4: a new player in vestibular schwannoma pathogenesis.Oncotarget. 2018; 9: 9940-9950https://doi.org/10.18632/oncotarget.24119
- Roles of SDF-1/CXCR4 axis in cartilage endplate stem cells mediated promotion of nucleus pulposus cells proliferation.Biochem Biophys Res Commun. 2018; https://doi.org/10.1016/j.bbrc.2018.10.069
Article info
Publication history
Published online: January 06, 2019
Accepted:
December 22,
2018
Received:
November 28,
2018
Identification
Copyright
© 2018 Elsevier Ltd. All rights reserved.
