title: The p75 neurotrophin receptor is a central regulator of glioma invasion.
abstract: The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75(NTR)) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75(NTR) dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75(NTR)-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75(NTR) as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.
authors: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors: Angela L M
authors: AL
authors: Johnston
authors: Xueqing
authors: X
authors: Lun
authors: Jennifer J
authors: JJ
authors: Rahn
authors: Abdelhamid
authors: A
authors: Liacini
authors: Limei
authors: L
authors: Wang
authors: Mark G
authors: MG
authors: Hamilton
authors: Ian F
authors: IF
authors: Parney
authors: Barbara L
authors: BL
authors: Hempstead
authors: Stephen M
authors: SM
authors: Robbins
authors: Peter A
authors: PA
authors: Forsyth
authors: Donna L
authors: DL
authors: Senger
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009414:Nerve Growth Factors / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D049452:Green Fluorescent Proteins; D020742:rhoA GTP-Binding Protein
references: Cancer Res. 2003 Sep 15;63(18):5821-8
references: 14522905
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83
references: 14645703
references: J Neurosci. 2003 Dec 10;23(36):11373-81
references: 14673001
references: J Neurosci. 2004 Jan 14;24(2):542-6
references: 14724254
references: Nature. 2004 Feb 26;427(6977):843-8
references: 14985763
references: J Neurosci. 2004 May 5;24(18):4363-72
references: 15128850
references: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8774-9
references: 15161978
references: Nature. 2004 Aug 26;430(7003):1034-9
references: 15329723
references: Cancer Res. 2004 Oct 1;64(19):7011-21
references: 15466194
references: Neuron. 1990 Apr;4(4):487-92
references: 2157470
references: Proc Natl Acad Sci U S A. 1990 Jul;87(14):5454-8
references: 2164684
references: Neuron. 1991 May;6(5):845-58
references: 2025430
references: J Biol Chem. 1991 Jun 25;266(18):12099-104
references: 1646820
references: EMBO J. 1992 Mar;11(3):917-22
references: 1547788
references: Clin Exp Metastasis. 1994 Nov;12(6):405-15
references: 7923993
references: Endocrinology. 1995 Jan;136(1):262-8
references: 7828539
references: Invasion Metastasis. 1994-1995;14(1-6):372-84
references: 7657530
references: Cancer Res. 1996 Feb 15;56(4):694-9
references: 8630997
references: Neurosurgery. 1996 Aug;39(2):235-50; discussion 250-2
references: 8832660
references: Prostate. 1997 Mar 1;30(4):274-9
references: 9111606
references: J Cell Biol. 1998 Feb 23;140(4):911-23
references: 9472042
references: Oncogene. 1998 Jun 25;16(25):3253-60
references: 9681823
references: Prostate. 2000 Feb 1;42(2):150-60
references: 10617873
references: Nature. 2000 Aug 3;406(6795):532-5
references: 10952316
references: J Neurosci. 2000 Oct 15;20(20):7706-15
references: 11027232
references: Cancer Res. 2000 Dec 1;60(23):6617-22
references: 11118044
references: Cancer Lett. 2001 Mar 10;164(1):51-60
references: 11166915
references: J Clin Oncol. 2001 Feb 1;19(3):689-96
references: 11157019
references: Int J Oncol. 2001 Feb;18(2):287-95
references: 11172594
references: Cancer Res. 2001 May 15;61(10):4190-6
references: 11358844
references: J Natl Cancer Inst. 2001 Jun 20;93(12):903-12
references: 11416111
references: J Neurosci. 2001 Jul 15;21(14):5121-9
references: 11438587
references: Clin Cancer Res. 2001 Aug;7(8):2480-9
references: 11489830
references: Cancer Res. 2001 Sep 15;61(18):6885-91
references: 11559565
references: J Neurooncol. 2001 Jun;53(2):129-47
references: 11716066
references: J Neurooncol. 2001 Jun;53(2):161-76
references: 11716068
references: Science. 2001 Nov 30;294(5548):1945-8
references: 11729324
references: J Neurobiol. 2001 Dec;49(4):314-25
references: 11745667
references: Brain Pathol. 2002 Jan;12(1):108-16
references: 11771519
references: J Neurooncol. 2002 Jan;56(1):59-67
references: 11949828
references: J Cell Biol. 2002 May 13;157(4):565-70
references: 12011108
references: Curr Opin Neurobiol. 2002 Jun;12(3):260-7
references: 12049931
references: Prog Neurobiol. 2002 Jun;67(3):203-33
references: 12169297
references: Glia. 2002 Sep;39(3):193-206
references: 12203386
references: Cell. 1992 Dec 11;71(6):973-85
references: 1458542
references: J Neurosci. 1999 May 15;19(10):4155-68
references: 10234043
references: Int J Cancer. 1999 Jul 2;82(1):112-20
references: 10360829
references: Ann Neurol. 1999 Aug;46(2):183-8
references: 10443883
references: Cancer Res. 1999 Sep 1;59(17):4228-32
references: 10485462
references: Nature. 2004 Nov 18;432(7015):396-401
references: 15549107
references: J Mol Histol. 2004 Nov;35(8-9):749-58
references: 15609087
references: J Neurooncol. 2004 Nov;70(2):217-28
references: 15674479
references: Neoplasia. 2005 Jan;7(1):7-16
references: 15720813
references: Cancer Res. 2005 Mar 1;65(5):1678-86
references: 15753362
references: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9
references: 15827123
references: Nature. 2005 Jul 28;436(7050):518-24
references: 16049480
references: Biochem Biophys Res Commun. 2005 Nov 4;336(4):1227-33
references: 16171788
references: Cancer Res. 2006 Jan 1;66(1):159-67
references: 16397228
references: Neuron. 1999 Nov;24(3):585-93
references: 10595511
references: Int J Cancer. 1993 Oct 21;55(4):692-9
references: 8407001
references: Mol Cell Biol. 1994 Jan;14(1):759-67
references: 8264643
references: Mol Biol Cell. 1993 Nov;4(11):1205-16
references: 8305739
references: Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2795-9
references: 8146193
references: J Biol Chem. 2002 Sep 13;277(37):34295-302
references: 12097334
references: Nat Neurosci. 2002 Nov;5(11):1131-6
references: 12404007
references: Nature. 2002 Nov 7;420(6911):74-8
references: 12422217
references: J Neurosci. 2002 Dec 1;22(23):10368-76
references: 12451136
references: Mol Cancer Ther. 2002 Nov;1(13):1229-36
references: 12479704
references: Cancer Res. 2003 Apr 1;63(7):1602-7
references: 12670911
references: Nat Rev Neurosci. 2003 Apr;4(4):299-309
references: 12671646
references: J Clin Oncol. 2003 Apr 15;21(8):1624-36
references: 12697889
references: Nat Neurosci. 2003 May;6(5):461-7
references: 12692556
references: Nat Neurosci. 2003 May;6(5):435-6
references: 12715005
references: Science. 2003 May 9;300(5621):949
references: 12738854
references: Oncogene. 2003 Jun 5;22(23):3616-23
references: 12789270
references: J Cell Biol. 2003 Jul 21;162(2):233-43
references: 12860969
references: Cancer J. 2003 May-Jun;9(3):214-21
references: 12952306
references: J Cell Sci. 2003 Nov 1;116(Pt 21):4409-17
references: 13130092