TY - JOUR
T1 - Tumstatin, the NC1 domain of α3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth
AU - Hamano, Yuki
AU - Kalluri, Raghu
N1 - Funding Information:
This study was supported by NIH Grants DK 55001, DK 62987, and research funds associated with Center for Matrix Biology at the BIDMC. Dr. Yuki Hamano was supported by the Stop and Shop Pediatric Brain Tumor Foundation. We also acknowledge the generous financial donations to Kalluri Laboratory from Ann L. and Herbert J. Siegel philanthropic Jewish Communal fund and the Joseph Lubrano Memorial Goldfield Family Charitable trust fund.
PY - 2005/7/29
Y1 - 2005/7/29
N2 - Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen α3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to αVβ3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors.
AB - Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen α3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to αVβ3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors.
KW - Angiogenic switch
KW - Endogenous angiogenesis
KW - Extracellular matrix
KW - Inhibitor
KW - Tumstatin
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U2 - 10.1016/j.bbrc.2005.05.130
DO - 10.1016/j.bbrc.2005.05.130
M3 - Review article
C2 - 15979458
AN - SCOPUS:20544438078
SN - 0006-291X
VL - 333
SP - 292
EP - 298
JO - Biochemical and biophysical research communications
JF - Biochemical and biophysical research communications
IS - 2
ER -