The p75 neurotrophin receptor is a central regulator of glioma invasion.
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.
Johnston
Angela L M
AL
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Lun
Xueqing
X
Rahn
Jennifer J
JJ
Liacini
Abdelhamid
A
Wang
Limei
L
Hamilton
Mark G
MG
Parney
Ian F
IF
Hempstead
Barbara L
BL
Robbins
Stephen M
SM
Forsyth
Peter A
PA
Senger
Donna L
DL
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
D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D049452:Green Fluorescent Proteins; D020742:rhoA GTP-Binding Protein
Cancer Res. 2003 Sep 15;63(18):5821-8
14522905
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83
14645703
J Neurosci. 2003 Dec 10;23(36):11373-81
14673001
J Neurosci. 2004 Jan 14;24(2):542-6
14724254
Nature. 2004 Feb 26;427(6977):843-8
14985763
J Neurosci. 2004 May 5;24(18):4363-72
15128850
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8774-9
15161978
Nature. 2004 Aug 26;430(7003):1034-9
15329723
Cancer Res. 2004 Oct 1;64(19):7011-21
15466194
Neuron. 1990 Apr;4(4):487-92
2157470
Proc Natl Acad Sci U S A. 1990 Jul;87(14):5454-8
2164684
Neuron. 1991 May;6(5):845-58
2025430
J Biol Chem. 1991 Jun 25;266(18):12099-104
1646820
EMBO J. 1992 Mar;11(3):917-22
1547788
Clin Exp Metastasis. 1994 Nov;12(6):405-15
7923993
Endocrinology. 1995 Jan;136(1):262-8
7828539
Invasion Metastasis. 1994-1995;14(1-6):372-84
7657530
Cancer Res. 1996 Feb 15;56(4):694-9
8630997
Neurosurgery. 1996 Aug;39(2):235-50; discussion 250-2
8832660
Prostate. 1997 Mar 1;30(4):274-9
9111606
J Cell Biol. 1998 Feb 23;140(4):911-23
9472042
Oncogene. 1998 Jun 25;16(25):3253-60
9681823
Prostate. 2000 Feb 1;42(2):150-60
10617873
Nature. 2000 Aug 3;406(6795):532-5
10952316
J Neurosci. 2000 Oct 15;20(20):7706-15
11027232
Cancer Res. 2000 Dec 1;60(23):6617-22
11118044
Cancer Lett. 2001 Mar 10;164(1):51-60
11166915
J Clin Oncol. 2001 Feb 1;19(3):689-96
11157019
Int J Oncol. 2001 Feb;18(2):287-95
11172594
Cancer Res. 2001 May 15;61(10):4190-6
11358844
J Natl Cancer Inst. 2001 Jun 20;93(12):903-12
11416111
J Neurosci. 2001 Jul 15;21(14):5121-9
11438587
Clin Cancer Res. 2001 Aug;7(8):2480-9
11489830
Cancer Res. 2001 Sep 15;61(18):6885-91
11559565
J Neurooncol. 2001 Jun;53(2):129-47
11716066
J Neurooncol. 2001 Jun;53(2):161-76
11716068
Science. 2001 Nov 30;294(5548):1945-8
11729324
J Neurobiol. 2001 Dec;49(4):314-25
11745667
Brain Pathol. 2002 Jan;12(1):108-16
11771519
J Neurooncol. 2002 Jan;56(1):59-67
11949828
J Cell Biol. 2002 May 13;157(4):565-70
12011108
Curr Opin Neurobiol. 2002 Jun;12(3):260-7
12049931
Prog Neurobiol. 2002 Jun;67(3):203-33
12169297
Glia. 2002 Sep;39(3):193-206
12203386
Cell. 1992 Dec 11;71(6):973-85
1458542
J Neurosci. 1999 May 15;19(10):4155-68
10234043
Int J Cancer. 1999 Jul 2;82(1):112-20
10360829
Ann Neurol. 1999 Aug;46(2):183-8
10443883
Cancer Res. 1999 Sep 1;59(17):4228-32
10485462
Nature. 2004 Nov 18;432(7015):396-401
15549107
J Mol Histol. 2004 Nov;35(8-9):749-58
15609087
J Neurooncol. 2004 Nov;70(2):217-28
15674479
Neoplasia. 2005 Jan;7(1):7-16
15720813
Cancer Res. 2005 Mar 1;65(5):1678-86
15753362
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9
15827123
Nature. 2005 Jul 28;436(7050):518-24
16049480
Biochem Biophys Res Commun. 2005 Nov 4;336(4):1227-33
16171788
Cancer Res. 2006 Jan 1;66(1):159-67
16397228
Neuron. 1999 Nov;24(3):585-93
10595511
Int J Cancer. 1993 Oct 21;55(4):692-9
8407001
Mol Cell Biol. 1994 Jan;14(1):759-67
8264643
Mol Biol Cell. 1993 Nov;4(11):1205-16
8305739
Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2795-9
8146193
J Biol Chem. 2002 Sep 13;277(37):34295-302
12097334
Nat Neurosci. 2002 Nov;5(11):1131-6
12404007
Nature. 2002 Nov 7;420(6911):74-8
12422217
J Neurosci. 2002 Dec 1;22(23):10368-76
12451136
Mol Cancer Ther. 2002 Nov;1(13):1229-36
12479704
Cancer Res. 2003 Apr 1;63(7):1602-7
12670911
Nat Rev Neurosci. 2003 Apr;4(4):299-309
12671646
J Clin Oncol. 2003 Apr 15;21(8):1624-36
12697889
Nat Neurosci. 2003 May;6(5):461-7
12692556
Nat Neurosci. 2003 May;6(5):435-6
12715005
Science. 2003 May 9;300(5621):949
12738854
Oncogene. 2003 Jun 5;22(23):3616-23
12789270
J Cell Biol. 2003 Jul 21;162(2):233-43
12860969
Cancer J. 2003 May-Jun;9(3):214-21
12952306
J Cell Sci. 2003 Nov 1;116(Pt 21):4409-17
13130092