Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo.
Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.
Roth
Jennifer M
JM
Department of Radiation Oncology, New York University School of Medicine, 400 East 34th St., New York, NY 10016, USA.
Akalu
Abebe
A
Zelmanovich
Anat
A
Policarpio
Desiree
D
Ng
Bruce
B
MacDonald
Shannon
S
Formenti
Silvia
S
Liebes
Leonard
L
Brooks
Peter C
PC
D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002642:Chick Embryo; D024141:Collagen Type IV / Q000737:chemistry* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D012878:Skin Neoplasms / Q000378:metabolism
D024141:Collagen Type IV; D008024:Ligands; D011994:Recombinant Proteins
J Biol Chem. 2004 Jan 16;279(3):2091-100
14583633
Trends Genet. 2004 Jan;20(1):33-43
14698617
Expert Rev Anticancer Ther. 2004 Feb;4(1):129-40
14748663
Cancer Res. 2004 Mar 1;64(5):1773-80
14996739
Oncologist. 2004;9(2):182-7
15047922
Mol Cells. 2004 Apr 30;17(2):188-202
15179030
Nat Rev Mol Cell Biol. 2004 Oct;5(10):816-26
15459662
Science. 1994 Apr 22;264(5158):569-71
7512751
Dev Biol. 1994 Jul;164(1):10-23
8026615
Cell. 1994 Dec 30;79(7):1157-64
7528107
J Clin Invest. 1995 Oct;96(4):1815-22
7560073
Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7
7568133
Eur J Cancer. 1996 Dec;32A(14):2423-9
9059330
J Biol Chem. 1997 Aug 15;272(33):20395-401
9252346
Cell. 1998 Feb 6;92(3):391-400
9476898
Genes Dev. 1998 Oct 1;12(19):3008-19
9765203
Clin Cancer Res. 1998 Nov;4(11):2625-34
9829725
Cancer Res. 1999 Jun 1;59(11):2724-30
10363998
J Biol Chem. 2000 Jan 14;275(2):1209-15
10625665
J Biol Chem. 2000 Mar 17;275(11):8051-61
10713126
Cell. 2000 Mar 31;101(1):47-56
10778855
Cancer Res. 2000 May 1;60(9):2520-6
10811134
J Biol Chem. 2000 Jul 14;275(28):21340-8
10766752
Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10026-31
10944199
Exp Cell Res. 2000 Nov 25;261(1):52-68
11082275
J Cell Biol. 2001 Sep 3;154(5):1069-79
11535623
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):389-94
11752408
Cancer Res. 2002 Mar 15;62(6):1876-83
11912168
Cell. 2002 May 3;109(3):335-46
12015983
Semin Cancer Biol. 2002 Apr;12(2):105-12
12027582
J Biol Chem. 2002 Aug 23;277(34):31142-53
11970952
Cell. 2002 Sep 20;110(6):673-87
12297042
Am J Pathol. 2002 Oct;161(4):1429-37
12368215
J Cell Sci. 2002 Nov 15;115(Pt 22):4201-14
12376553
Trends Cell Biol. 2003 Jan;13(1):51-6
12480340
Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8
12516034
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4766-71
12682293
J Biol Chem. 2003 Jun 6;278(23):20612-7
12663662
Nat Rev Cancer. 2003 Jun;3(6):422-33
12778132
Cancer Res. 2003 Jun 1;63(11):2705-15
12782571
Trends Cell Biol. 2003 Jul;13(7):366-75
12837607
Cell. 2003 Jul 11;114(1):33-45
12859896
N Engl J Med. 2003 Jul 31;349(5):427-34
12890841
J Biol Chem. 2003 Sep 26;278(39):37632-6
12876280
Oncogene. 2003 Dec 8;22(56):9022-9
14663480
Biochem Biophys Res Commun. 2003 Dec 19;312(3):801-5
14680836
J Biol Chem. 2004 Jan 23;279(4):2772-80
14610079