Notch3 activation promotes invasive glioma formation in a tissue site-specific manner.
Although Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. Although Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, whereas Notch3 was 10-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RBPjk-association molecule and transactivation domains of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3.
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Tarran J
TJ
Pierfelice
Karisa C
KC
Schreck
Louis
L
Dang
Laura
L
Asnaghi
Nicholas
N
Gaiano
Charles G
CG
Eberhart
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002830:Choroid Neoplasms / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology; D051379:Mice; D019574:Optic Nerve Neoplasms / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019572:Retinal Neoplasms / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins
Mol Cell Neurosci. 1996;8(1):14-27
8923452
Am J Pathol. 2006 Oct;169(4):1206-14
17003479
Cell. 2009 Apr 17;137(2):216-33
19379690
Cancer Res. 2007 Jun 15;67(12):5579-82
17575119
Dev Biol. 2002 Sep 1;249(1):121-30
12217323
Development. 1995 Nov;121(11):3637-50
8582277
Cancer Res. 2004 Nov 1;64(21):7787-93
15520184
Neuron. 1995 Mar;14(3):487-96
7695895
Dev Biol. 2008 Sep 1;321(1):111-22
18588871
Oncogene. 2006 Jan 19;25(3):487-91
16186803
Annu Rev Pathol. 2008;3:587-613
18039126
Science. 2004 Oct 8;306(5694):269-71
15472075
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18998-9003
17148603
Stem Cells. 2010 Jan;28(1):17-28
19921751
FASEB J. 2001 Sep;15(11):2013-5
11511521
Anticancer Res. 2008 Nov-Dec;28(6A):3621-30
19189643
Cancer Cell. 2005 Oct;8(4):323-35
16226707
Neuron. 2000 May;26(2):395-404
10839358
Biochim Biophys Acta. 2008 Sep;1782(9):489-97
18625307
Breast. 2009 Oct;18 Suppl 3:S56-8
19914544
Hum Mol Genet. 2010 May 1;19(9):1791-804
20150232
Am J Pathol. 2004 Aug;165(2):695-705
15277242
Neuron. 2000 May;26(2):383-94
10839357
Development. 1999 Jul;126(13):2901-9
10357934
Mol Cell Biol. 2001 Nov;21(22):7537-44
11604490
Curr Pharm Biotechnol. 2009 Feb;10(2):154-60
19199947
Neoplasia. 2006 Dec;8(12):1072-82
17217625
Oncogene. 2008 Sep 1;27(38):5092-8
18758477
Genesis. 2009 Mar;47(3):175-87
19208436
Cancer Res. 2006 Aug 1;66(15):7445-52
16885340
Development. 2001 Apr;128(7):1099-107
11245575
Development. 1991 Dec;113(4):1435-49
1687460
Cold Spring Harb Symp Quant Biol. 2008;73:367-75
19022772
Nat Genet. 1996 Apr;12(4):376-84
8630490
Nat Neurosci. 1999 Sep;2(9):812-9
10461220
Cell. 1991 Aug 23;66(4):649-61
1831692
Cell Mol Life Sci. 2007 Nov;64(21):2746-62
17687513
Nat Genet. 2003 Mar;33(3):416-21
12590261
Dev Neurosci. 2006;28(1-2):58-69
16508304
Mech Dev. 1994 May;46(2):123-36
7918097
J Comp Neurol. 2003 Jun 23;461(2):187-204
12724837
J Biol Chem. 2006 Feb 24;281(8):5106-19
16365048
Am J Ophthalmol. 1974 Dec;78(6):972-84
4140696
J Neurosci. 1997 Feb 15;17(4):1425-34
9006984
Nucleic Acids Res. 1998 Dec 1;26(23):5448-55
9826771
J Biol Chem. 2008 May 23;283(21):14781-91
18381292
Development. 2001 Mar;128(5):689-702
11171394
Leukemia. 2005 Oct;19(10):1841-3
16079893
Mech Dev. 2001 Jun;104(1-2):3-20
11404076
Expert Opin Ther Targets. 2007 Jul;11(7):915-27
17614760
Nature. 1988 Apr 28;332(6167):834-7
3282180
Blood. 2006 Jan 15;107(2):781-5
16166587
Nucleic Acids Res. 2010 Jan;38(Database issue):D792-9
19906719
Oncogene. 2008 Sep 1;27(38):5124-31
18758481
Cancer Res. 2007 Feb 1;67(3):890-900
17283119
Mol Cell Biol. 1998 Apr;18(4):2324-33
9528802