The molecular biology and novel treatments of vestibular schwannomas

A review

Restricted access

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin. Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development. Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment. In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus with E3 ubiquitin ligase CRL4DCAF1. A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma. Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation. With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.

Abbreviations used in this paper: NF1 = neurofibromatosis Type 1; NF2 = NF Type 2.

Article Information

Address correspondence to: Isaac Yang, M.D., Department of Neurological Surgery, University of California, Los Angeles, 695 Charles E. Young Drive South, Gonda 3357, Los Angeles, California 90095-1761. email: iyang@mednet.ucla.edu.

Please include this information when citing this paper: published online July 29, 2011; DOI: 10.3171/2011.6.JNS11131.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Schematic of merlin domains. Merlin consists of a FERM component at the N-terminal domain, which is subdivided into subdomains A, B, and C, and a C-terminal end. The N-terminal domain is postulated to be responsible for merlin's role in cell-cell adhesion and signal transduction. Reproduced with permission from Shimizu et al.: J Biol Chem 277:10332–10336, 2002.

  • View in gallery

    Theoretical merlin signaling pathway. Merlin stabilizes cadherin interactions at the cell membrane and is inhibited from phosphorylation by cadherin binding (contact-inhibition). Accumulation of dephosphorylated merlin has an inhibitory function on the Rac pathway, further inhibiting mitogenic signaling. Once merlin is no longer bound to cadherin, PAK can phosphorylate merlin and remove the inhibition on the Rac pathway, which allows for mitogenic signaling. Reproduced with permission from Okada et al.: J Cell Biol 171:361–371, 2005.

References

1

Abe TIzumiyama HImaizumi YKobayashi SShimazu MSasaki K: Staged resection of large hypervascular vestibular schwannomas in young adults. Skull Base 11:1992062001

2

Agrawal YClark JHLimb CJNiparko JKFrancis HW: Predictors of vestibular schwannoma growth and clinical implications. Otol Neurotol 31:8078122010

3

Ahmad ZBrown CMPatel AKRyan AFOngkeko RDoherty JK: Merlin knockdown in human Schwann cells: clues to vestibular schwannoma tumorigenesis. Otol Neurotol 31:4604662010

4

Ammoun SCunliffe CHAllen JCChiriboga LGiancotti FGZagzag D: ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma. Neuro Oncol 12:8348432010

5

An MMZou ZShen HLiu PChen MLCao YB: Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated metaanalysis. Eur J Clin Pharmacol 66:8138212010

6

Baek SYKim SU: Proliferation of human Schwann cells induced by neu differentiation factor isoforms. Dev Neurosci 20:5125171998

7

Bai YLiu YJWang HXu YStamenkovic IYu Q: Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin. Oncogene 26:8368502007

8

Bari MEForster DMKemeny AAWalton LHardy DAnderson JR: Malignancy in a vestibular schwannoma. Report of a case with central neurofibromatosis, treated by both stereotactic radiosurgery and surgical excision, with a review of the literature. Br J Neurosurg 16:2842892002

9

Battaglia AMastrodimos BCueva R: Comparison of growth patterns of acoustic neuromas with and without radiosurgery. Otol Neurotol 27:7057122006

10

Bernards AGusella JF: The importance of genetic mosaicism in human disease. N Engl J Med 331:144714491994

11

Bianchi ABHara TRamesh VGao JKlein-Szanto AJMorin F: Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types. Nat Genet 6:1851921994

12

Bosco EENakai YHennigan RFRatner NZheng Y: NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation. Oncogene 29:254025492010

13

Bourn DCarter SAMason SGareth DEvans RStrachan T: Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. Hum Mol Genet 3:8138161994

14

Bretcher AEdwards KFehon R: ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3:5865992002

15

Carroll SLMiller MLFrohnert PWKim SSCorbett JA: Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci 17:164216591997

16

Cayé-Thomasen PBorup RStangerup SEThomsen JNielsen FC: Deregulated genes in sporadic vestibular schwannomas. Otol Neurotol 31:2562662010

17

Cayé-Thomasen PWerther KNalla ABøg-Hansen TCNielsen HJStangerup SE: VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate. Otol Neurotol 26:981012005

18

CBTRUS: Central Brain Tumor Registry of the United States 1997 Annual Report ChicagoCentral Brain Tumor Registry of the United States1998

19

CBTRUS: Primary Brain Tumors in the United States: Statistical Report 1995–1999 ChicagoCentral Brain Tumor Registry of the United States20022003

20

Clark JJProvenzano MDiggelmann HRXu NHansen SSHansen MR: The ErbB inhibitors trastuzumab and erlotinib inhibit growth of vestibular schwannoma xenografts in nude mice: a preliminary study. Otol Neurotol 29:8468532008

21

Cole BKCurto MChan AWMcClatchey AI: Localization to the cortical cytoskeleton is necessary for Nf2/merlin-dependent epidermal growth factor receptor silencing. Mol Cell Biol 28:127412842008

22

Curto MCole BKLallemand DLiu CHMcClatchey AI: Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J Cell Biol 177:8939032007

23

Deacon SWBeeser AFukui JARennefahrt UEMyers CChernoff J: An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem Biol 15:3223312008

24

Evans DGBirch JMRamsden RTSharif SBaser ME: Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet 43:2892942006

25

Evans DGHuson SMDonnai DNeary WBlair VTeare D: A genetic study of type 2 neurofibromatosis in the United Kingdom. I Prevalance, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet 29:8418461992

26

Fernandez-Valle CGwynn LWood PMCarbonetto SBunge MB: Anti-beta 1 integrin antibody inhibits Schwann cell myelination. J Neurobiol 25:120712261994

27

Fernandez-Valle CTang YRicard JRodenas-Ruano ATaylor AHackler E: Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nat Genet 31:3543622002

28

Ferrara NGerber HPLeCouter J: The biology of VEGF and its receptors. Nat Med 9:6696762003

29

Flaiz CAmmoun SBiebl AHanemann CO: Altered adhesive structures and their relation to RhoGTPase activation in merlin-deficient Schwannoma. Brain Pathol 19:27382009

30

Flaiz CChernoff JAmmoun SPeterson JRHanemann CO: PAK kinase regulates Rac GTPase and is a potential target in human schwannomas. Exp Neurol 218:1371442009

31

Flaiz CUtermark TParkinson DBPoetsch AHanemann CO: Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells. Glia 56:5065152008

32

Fucci MJBuchman CABrackmann DEBerliner KI: Acoustic tumor growth: implications for treatment choices. Am J Otol 20:4954991999

33

Giovannini MRobanus-Maandag Evan der Valk MNiwa-Kawakita MAbramowski VGoutebroze L: Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev 14:161716302000

34

Gril BPalmieri DBronder JLHerring JMVega-Valle EFeigenbaum L: Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100:109211032008

35

Hadfield KDSmith MJUrquhart JEWallace AJBowers NLKing AT: Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas. Oncogene 29:621662212010

36

Halliday ALSobel RAMartuza RL: Benign spinal nerve sheath tumors: their occurrence sporadically and in neurofibromatosis types 1 and 2. J Neurosurg 74:2482531991

37

Hansen MRClark JJGantz BJGoswami PC: Effects of ErbB2 signaling on the response of vestibular schwannoma cells to gamma-irradiation. Laryngoscope 118:102310302008

38

Hansen MRRoehm PCChatterjee PGreen SH: Constitutive neuregulin-1/ErbB signaling contributes to human vestibular schwannoma proliferation. Glia 53:5936002006

39

Herbst RS: Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 59:2 Suppl21262004

40

Houshmandi SSEmnett RJGiovannini MGutmann DH: The neurofibromatosis 2 protein, merlin, regulates glial cell growth in an ErbB2- and Src-dependent manner. Mol Cell Biol 29:147214862009

41

Hrecka KGierszewska MSrivastava SKozaczkiewicz LSwanson SKFlorens L: Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci U S A 104:11778117832007

42

Hughes SCFehon RG: Understanding ERM proteins—the awesome power of genetics finally brought to bear. Curr Opin Cell Biol 19:51562007

43

Hung GColton JFisher LOppenheimer MFaudoa RSlattery W: Immunohistochemistry study of human vestibular nerve schwannoma differentiation. Glia 38:3633702002

44

Jääskeläinen JPaetau APyykkö IBlomstedt GPalva TTroupp H: Interface between the facial nerve and large acoustic neurinomas. Immunohistochemical study of the cleavage plane in NF2 and non-NF2 cases. J Neurosurg 80:5415471994

45

James MFManchanda NGonzalez-Agosti CHartwig JHRamesh V: The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association. Biochem J 356:3773862001

46

Johnson JRCohen MSridhara RChen YFWilliams GMDuan J: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 11:641464212005

47

Kaempchen KMielke KUtermark TLangmesser SHanemann CO: Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells. Hum Mol Genet 12:121112212003

48

Kissil JLBlakeley JOFerner REHuson SMKalamarides MMautner VF: What's new in neurofibromatosis? Proceedsings from the 2009 NF conference: new frontiers. Am J Med Genet Part A 152A:2692832009

49

Kissil JLJohnson KCEckman MSJacks T: Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem 277:10394103992002

50

Kissil JLWilker EWJohnson KCEckman MSYaffe MBJacks T: Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell 12:8418492003

51

Kluwe LMautner VF: Mosaicism in sporadic neurofibromatosis 2 patients. Hum Mol Genet 7:205120551998

52

LaJeunesse DRMcCartney BMFehon RG: Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization. J Cell Biol 141:158915991998

53

Lallemand DCurto MSaotome IGiovannini MMcClatchey AI: NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev 17:109011002003

54

Lanman THBrackmann DEHitselberger WESubin B: Report of 190 consecutive cases of large acoustic tumors (vestibular schwannoma) removed via the translabyrinthine approach. J Neurosurg 90:6176231999

55

Laulajainen MMuranen TCarpén OGrönholm M: Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton. Oncogene 27:323332432008

56

Lee DJWestra WHStaecker HLong DNiparko JKSlattery WH III: Clinical and histopathologic features of recurrent vestibular schwannoma (acoustic neuroma) after stereotactic radiosurgery. Otol Neurotol 24:6506602003

57

Li QNance MRKulikauskas RNyberg KFehon RKarplus P: Self-masking in an intact ERM-merlin protein: an active role for the central apical-helical domain. J Mol Biol 365:144614592007

58

Li WYou LCooper JSchiavon GPepe-Caprio AZhou L: Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell 140:4774902010

59

Lin NUCarey LALiu MCYounger JCome SEEwend M: Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26:199319992008

60

Linskey ME: Stereotactic radiosurgery versus stereotactic radiotherapy for patients with vestibular schwannoma: a Leksell Gamma Knife Society 2000 debate. J Neurosurg 93:Suppl 390952000

61

Linthicum FH JrBrackmann DE: Bilateral acoustic tumors. A diagnostic and surgical challenge. Arch Otolaryngol 106:7297331980

62

Louis DNRamesh VGusella JF: Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathol 5:1631721995

63

Lu JFBruno REppler SNovotny WLum BGaudreault J: Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 62:7797862008

64

MacCollin MRamesh VJacoby LBLouis DNRubio MPPulaski K: Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet 55:3143201994

65

Maitra SKulikauskas RMGavilan HFehon RG: The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol 16:7027092006

66

Marchionni MAGoodearl ADChen MSBermingham-McDonogh OKirk CHendricks M: Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362:3123181993

67

Maurel PSalzer JL: Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity. J Neurosci 20:463546452000

68

Mautner VFLindenau MBaser MEHazim WTatagiba MHaase W: The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 38:8808861996

69

Mautner VFNguyen RKutta HFuensterer CBokemeyer CHagel C: Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol 12:14182010

70

McCall CMMiliani de Marval PLChastain PD IIJackson SCHe YJKotake Y: Human immunodeficiency virus type 1 Vpr-binding protein VprBP, a WD40 protein associated with the DDB1-CUL4 E3 ubiquitin ligase, is essential for DNA replication and embryonic development. Mol Cell Biol 28:562156332008

71

McClatchey AFehon R: Merlin and the ERM proteins--regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol 19:1982062009

72

McLaughlin MEKruger GMSlocum KLCrowley DMichaud NAHuang J: The Nf2 tumor suppressor regulates cell-cell adhesion during tissue fusion. Proc Natl Acad Sci U S A 104:326132662007

73

Medina PJGoodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther 30:142614472008

74

Mérel PHoang-Xuan KSanson MMoreau-Aubry ABijlsma EKLazaro C: Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas. Genes Chromosomes Cancer 13:2112161995

75

Meyer TACanty PAWilkinson EPHansen MRRubinstein JTGantz BJ: Small acoustic neuromas: surgical outcomes versus observation or radiation. Otol Neurotol 27:3803922006

76

Moffat DAIrving RM: The molecular genetics of vestibular schwannoma. J Laryngol Otol 109:3813841995

77

Moore MJGoldstein DHamm JFiger AHecht JRGallinger S: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:196019662007

78

Morrison HSherman LSLegg JBanine FIsacke CHaipek CA: The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev 15:9689802001

79

Morrison HSperka TManent JGiovannini MPonta HHerlich P: Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the action of Ras and Rac. Cancer Res 67:5205272007

80

Morrissey TKLevi ADNuijens ASliwkowski MBunge RP: Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. Proc Natl Acad Sci U S A 92:143114351995

81

Neff BAWelling DBAkhmametyeva EChang LS: The molecular biology of vestibular schwannomas: dissecting the pathogenic process at the molecular level. Otol Neurotol 27:1972082006

82

Okada TLopez-Lago MGiancotti FG: Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J Cell Biol 171:3613712005

83

Okada TYou LGiancotti FG: Shedding light on Merlin's wizardry. Trends Cell Biol 17:2222292007

84

Pearson MAReczek DBretscher AKarplus PA: Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101:2592702000

85

Pelton PDSherman LSRizvi TAMarchionni MAWood PFriedman RA: Ruffling membrane, stress fiber, cell spreading and proliferation abnormalities in human Schwannoma cells. Oncogene 17:219522091998

86

Plotkin SRHalpin CMcKenna MJLoeffler JSBatchelor TTBarker FG II: Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol 31:113511432010

87

Plotkin SRStemmer-Rachamimov AOBarker FG IIHalpin CPadera TPTyrrell A: Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 361:3583672009

88

Propp JMMcCarthy BJDavis FGPreston-Martin S: Descriptive epidemiology of vestibular schwannomas. Neuro Oncol 8:1112006

89

Qian XKarpova TSheppard AMMcNally JLowy DR: E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J 23:173917482004

90

Qiu RGChen JMcCormick FSymons M: A role for Rho in Ras transformation. Proc Natl Acad Sci U S A 92:11781117851995

91

Rouleau GAMerel PLutchman MSanson MZucman JMarineau C: Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:5155211993

92

Ruttledge MHSarrazin JRangaratnam SPhelan CMTwist EMerel P: Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 6:1801841994

93

Sainio MZhao FHeiska LTurunen Oden Bakker MZwarthoff E: Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin-containing cytoskeleton. J Cell Sci 110:224922601997

94

Schuknecht HF: Pathology of the Ear ed 2PhiladelphiaLea & Febiger1993

95

Scoles DRBaser MEPulst SM: A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes. Neurology 47:5445461996

96

Seizinger BRMartuza RLGusella JF: Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature 322:6446471986

97

Shaw RJPaez JGCurto MYaktine APruitt WMSaotome I: The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell 1:63722001

98

Shimizu TSeto AMaita NHamada KTsukita STsukita S: Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain. J Biol Chem 277:10332103362002

99

Slattery WH IIIFisher LMIqbal ZOppenhiemer M: Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects. Otol Neurotol 25:8118172004

100

Solares CAPanizza B: Vestibular schwannoma: an understanding of growth should influence management decisions. Otol Neurotol 29:8298342008

101

Speck OHughes SCNoren NKKulikauskas RMFehon RG: Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity. Nature 421:83872003

102

Stangerup SETos MCaye-Thomasen PTos TKlökker MThomsen J: Increasing annual incidence of vestibular schwannoma and age at diagnosis. J Laryngol Otol 118:6226272004

103

Stangerup SETos MThomsen JCaye-Thomasen P: True incidence of vestibular schwannoma?. Neurosurgery 67:133513402010

104

Strasnick BGlasscock ME IIIHaynes DMcMenomey SOMinor LB: The natural history of untreated acoustic neuromas. Laryngoscope 104:111511191994

105

Sughrue MEYeung AHRutkowski MJCheung SWParsa AT: Molecular biology of familial and sporadic vestibular schwannomas: implications for novel therapeutics. A review. J Neurosurg 114:3593662009

106

Takahashi KSasaki TMammoto ATakaishi KKameyama TTsukita S: Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem 272:23371233751997

107

Takahashi KSuzuki K: Density-dependent inhibition of growth involves prevention of EGF receptor activation by E-cadherin-mediated cell-cell adhesion. Exp Cell Res 226:2142221996

108

Tos MCharabi SThomsen J: Incidence of vestibular schwannomas. Laryngoscope 109:7367401999

109

Tos MStangerup SECayé-Thomasen PTos TThomsen J: What is the real incidence of vestibular schwannoma?. Arch Otolaryngol Head Neck Surg 130:2162202004

110

Tos MThomsen J: Epidemiology of acoustic neuromas. J Laryngol Otol 98:6856921984

111

Tos MThomsen JCharabi S: Incidence of acoustic neuromas. Ear Nose Throat J 71:3913931992

112

Trofatter JAMacCollin MMRutter JLMurrell JRDuyao MPParry DM: A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:7918001993

113

Turner CE: Paxillin interactions. J Cell Sci 113:Pt 23413941402000

114

Twist ECRuttledge MHRousseau MSanson MPapi LMerel P: The neurofibromatosis type 2 gene is inactivated in schwannomas. Hum Mol Genet 3:1471511994

115

Uesaka TShono TSuzuki SONakamizo ANiiro HMizoguchi M: Expression of VEGF and its receptor genes in intracranial schwannomas. J Neurooncol 83:2592662007

116

Vadlamudi RAdam LTalukder AMendelsohn JKumar R: Serine phosphorylation of paxillin by heregulin-beta1: role of p38 mitogen activated protein kinase. Oncogene 18:725372641999

117

Vartanian TGoodearl AViehöver AFischbach G: Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3. J Cell Biol 137:2112201997

118

von Recklinghausen F: Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen BerlinA. Hirschundel1882

119

Welling DB: Clinical manifestations of mutations in the neurofibromatosis type 2 gene in vestibular schwannomas (acoustic neuromas). Laryngoscope 108:1781891998

120

Welling DBGuida MGoll FPearl DKGlasscock MEPappas DG: Mutational spectrum in the neurofibromatosis type 2 gene in sporadic and familial schwannomas. Hum Genet 98:1891931996

121

Wilkinson JSReid HArmstrong GR: Malignant transformation of a recurrent vestibular schwannoma. J Clin Pathol 57:1091102004

122

Wishart J: Case of tumours in the skull, dura mater, and brain. Edinburg Med Surg J 18:3933971822

123

Wong ETBrem S: Taming glioblastoma: targeting angiogenesis. J Clin Oncol 25:470547062007

124

World Health Organization/National Neurofibromatosis Foundation: Prevention and control of neurofibromatosis: memorandum from a joint WHO/NNFF meeting. Bull World Health Organ 70:1731821992

125

Yamakami IKobayashi EIwadate YSaeki NYamaura A: Hypervascular vestibular schwannomas. Surg Neurol 57:1051122002

126

Yeung AHSughrue MEKane AJTihan TCheung SWParsa AT: Radiobiology of vestibular schwannomas: mechanisms of radioresistance and potential targets for therapeutic sensitization. Neurosurg Focus 27:6E22009

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 71 71 24
Full Text Views 171 171 14
PDF Downloads 128 128 11
EPUB Downloads 0 0 0

PubMed

Google Scholar