Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin.
We demonstrate a physiological role for tumstatin, a cleavage fragment of the alpha3 chain of type IV collagen (Col IValpha3), which is present in the circulation. Mice with a genetic deletion of Col IValpha3 show accelerated tumor growth associated with enhanced pathological angiogenesis, while angiogenesis associated with development and tissue repair are unaffected. Supplementing Col IValpha3-deficient mice with recombinant tumstatin to a normal physiological concentration abolishes the increased rate of tumor growth. The suppressive effects of tumstatin require alphaVbeta3 integrin expressed on pathological, but not on physiological, angiogenic blood vessels. Mice deficient in matrix metalloproteinase-9, which cleaves tumstatin efficiently from Col IValpha3, have decreased circulating tumstatin and accelerated growth of tumor. These results indicate that MMP-generated fragments of basement membrane collagen can have endogenous function as integrin-mediated suppressors of pathologic angiogenesis and tumor growth.
Hamano
Yuki
Y
Center for Matrix Biology, Department of Medicine and Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Zeisberg
Michael
M
Sugimoto
Hikaru
H
Lively
Julie C
JC
Maeshima
Yohei
Y
Yang
Changqing
C
Hynes
Richard O
RO
Werb
Zena
Z
Sudhakar
Akulapalli
A
Kalluri
Raghu
R
D000818:Animals; D001324:Autoantigens / Q000494:pharmacology / Q000502:physiology*; D001485:Basement Membrane / Q000737:chemistry; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D024141:Collagen Type IV / Q000494:pharmacology / Q000502:physiology*; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism; D000939:Epitopes; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008115:Liver Regeneration; D008168:Lung / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000196:embryology / Q000254:growth & development; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D011270:Pregnancy, Animal; D011509:Proteoglycans / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014945:Wound Healing
D001324:Autoantigens; D024141:Collagen Type IV; D004338:Drug Combinations; D000939:Epitopes; D039302:Integrin alphaVbeta3; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; C057112:type IV collagen alpha3 chain; C059485:matrigel; D003094:Collagen; D020780:Matrix Metalloproteinase 9