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PMID: 12842087 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin.

Cancer cell ·Vol. 3 ·No. 6 ·2003-06-00 ·Pages 589-601

Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, Yang C, Hynes RO, Werb Z, Sudhakar A, Kalluri R

Abstract

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.

MeSH Terms
Animals Autoantigens/pharmacology,physiology Basement Membrane/chemistry Carcinoma, Lewis Lung/metabolism,pathology,prevention & control Cell Division Collagen/metabolism Collagen Type IV/pharmacology,physiology Drug Combinations Endothelium, Vascular/metabolism Epitopes Female Heterozygote Homozygote Humans Integrin alphaVbeta3/metabolism Laminin/metabolism Liver Regeneration Lung/metabolism Matrix Metalloproteinase 9/genetics,metabolism Mice Mice, Inbred C57BL Mice, Knockout/embryology,growth & development Neovascularization, Pathologic Neovascularization, Physiologic Pregnancy Pregnancy, Animal Proteoglycans/metabolism Recombinant Proteins/pharmacology Survival Rate Tumor Cells, Cultured Wound Healing
Chemicals
Autoantigens Collagen Type IV Drug Combinations Epitopes Integrin alphaVbeta3 Laminin Proteoglycans Recombinant Proteins type IV collagen alpha3 chain matrigel Collagen Matrix Metalloproteinase 9
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Hamano Yuki
Center for Matrix Biology, Department of Medicine and Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Zeisberg Michael
Sugimoto Hikaru
Lively Julie C
Maeshima Yohei
Yang Changqing
Hynes Richard O
Werb Zena
Sudhakar Akulapalli
Kalluri Raghu
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1535-6108
DOI
10.1016/s1535-6108(03)00133-8
Published
2003-06-00
Pages
589-601
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2775452
Subset
IM
Grants
NHLBI NIH HHS · HL 66105 · United States
NIDDK NIH HHS · DK 55001 · United States
NIDDK NIH HHS · R01 DK055001-02 · United States
NCI NIH HHS · P01 CA072006-08 · United States
NIDDK NIH HHS · R01 DK081576 · United States
NCI NIH HHS · CA 72006 · United States
NIDDK NIH HHS · R01 DK055001 · United States
NIDDK NIH HHS · DK 51711 · United States
NIDDK NIH HHS · R01 DK051711-03 · United States
NCI NIH HHS · P01 CA072006 · United States
NHLBI NIH HHS · P01 HL066105 · United States
Corrections
CommentIn
PMID: 12842077
External Links
PubMed source DOI: 10.1016/s1535-6108(03)00133-8 PMC Full Text View journal details
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