Integrin alpha 6 regulates glioblastoma stem cells.
Cancer stem cells (CSCs) are a subpopulation of tumor cells suggested to be critical for tumor maintenance, metastasis, and therapeutic resistance. Prospective identification and targeting of CSCs are therefore priorities for the development of novel therapeutic paradigms. Although CSC enrichment has been achieved with cell surface proteins including CD133 (Prominin-1), the roles of current CSC markers in tumor maintenance remain unclear. We examined the glioblastoma stem cell (GSC) perivascular microenvironment in patient specimens to identify enrichment markers with a functional significance and identified integrin alpha6 as a candidate. Integrin alpha6 is coexpressed with conventional GSC markers and enriches for GSCs. Targeting integrin alpha6 in GSCs inhibits self-renewal, proliferation, and tumor formation capacity. Our results provide evidence that GSCs express high levels of integrin alpha6, which can serve not only as an enrichment marker but also as a promising antiglioblastoma therapy.
Lathia
Justin D
JD
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
Gallagher
Joseph
J
Heddleston
John M
JM
Wang
Jialiang
J
Eyler
Christine E
CE
Macswords
Jennifer
J
Wu
Qiulian
Q
Vasanji
Amit
A
McLendon
Roger E
RE
Hjelmeland
Anita B
AB
Rich
Jeremy N
JN
D000071916:AC133 Antigen; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D010641:Phenotype
D000071916:AC133 Antigen; D019138:Antibodies, Blocking; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D039503:Integrin alpha6; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse
Oncogene. 2009 Apr 16;28(15):1807-11
19287454
J Neurosci Res. 1992 Aug;32(4):494-506
1356158
Stem Cells. 2007 Oct;25(10):2524-33
17628016
Cancer Cell. 2007 Jan;11(1):69-82
17222791
Cancer Res. 2008 Oct 1;68(19):7882-6
18829544
Lab Invest. 2008 Aug;88(8):808-15
18560366
Cancer Cell. 2009 Feb 3;15(2):135-47
19185848
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83
14645703
PLoS Biol. 2009 Aug;7(8):e1000176
19688041
Nature. 2006 Dec 7;444(7120):756-60
17051156
Histopathology. 1996 Jun;28(6):521-8
8803595
Neuron. 2001 Aug 16;31(3):367-79
11516395
J Clin Oncol. 2008 Dec 1;26(34):5610-7
18981465
Cell Stem Cell. 2009 Aug 7;5(2):168-77
19664991
Stem Cells. 2007 Sep;25(9):2146-57
17569787
Cancer Cell. 2005 Oct;8(4):323-35
16226707
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14720-5
11121071
J Neurosci Methods. 2009 Jan 30;176(2):192-9
19215724
Cancer Cell. 2006 May;9(5):391-403
16697959
Cancer Cell. 2009 Jun 2;15(6):501-13
19477429
Nature. 2006 Dec 7;444(7120):761-5
17151667
Cancer Res. 2006 Aug 1;66(15):7445-52
16885340
Cancer Res. 2003 Sep 15;63(18):5821-8
14522905
Cell Stem Cell. 2009 May 8;4(5):440-52
19427293
Nature. 2008 Oct 23;455(7216):1129-33
18948956
Cancer Res. 2008 Aug 1;68(15):6043-8
18676824
Nature. 2004 Nov 18;432(7015):396-401
15549107
BMC Neurosci. 2008 Jul 23;9:71
18651950
Cell Stem Cell. 2007 Nov;1(5):555-67
18371393
Cell Stem Cell. 2009 Jun 5;4(6):568-80
19497285
J Biol Chem. 2006 Dec 29;281(52):40450-60
17085437
PLoS One. 2008;3(11):e3769
19020659
Oncogene. 2004 Dec 16;23(58):9392-400
15558011
Cancer Res. 2007 May 1;67(9):4010-5
17483311
Development. 2004 Jul;131(14):3433-44
15226259
Cancer Res. 2006 Aug 15;66(16):7843-8
16912155
Cancer Res. 2008 Oct 1;68(19):7711-7
18829523
Curr Biol. 1998 Aug 27;8(17):983-6
9742403
Cereb Cortex. 2003 Mar;13(3):219-24
12571112
Dev Dyn. 2007 Dec;236(12):3267-82
17937403
Am J Pathol. 1993 Jul;143(1):154-63
8317546
Cell. 2002 Sep 20;110(6):673-87
12297042
Nature. 2001 Nov 1;414(6859):105-11
11689955
Nat Rev Cancer. 2007 Oct;7(10):733-6
17882276
Int J Cancer. 2008 Feb 15;122(4):761-8
17955491
Stem Cells. 2006 Sep;24(9):2078-84
16690778
Cell. 2000 Jan 7;100(1):57-70
10647931
Mol Cancer. 2006 Dec 02;5:67
17140455
J Comp Neurol. 2007 Dec 20;505(6):630-43
17948866
J Neuroimmunol. 1995 Mar;57(1-2):143-53
7535788
Cancer Res. 2007 Jul 15;67(14):6796-805
17638891
Cancer Res. 2004 Oct 1;64(19):7011-21
15466194
Stem Cells. 2008 Dec;26(12):3027-36
18802038
Glia. 2002 Sep;39(3):193-206
12203386
Neurosurgery. 2008 Feb;62(2):505-14; discussion 514-5
18382330
J Mol Med (Berl). 2008 Sep;86(9):1025-32
18535813
Stem Cells. 2008 Jun;26(6):1414-24
18403755
Science. 2003 Oct 17;302(5644):393; author reply 393
14563990
Cell Stem Cell. 2008 Sep 11;3(3):289-300
18786416