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Tumor Biology |
Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School [P. C. C., A. T., G. K., Y. M., H. H., K. T., R. V., E. D. Z., S. H., P. K. S., M. B. E., M. D., M. S., M. P., V. P. S., R. K.], and Dana Farber Cancer Institute and Harvard Medical School [D. W. K.], Boston, Massachusetts 02215, and Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 60637 [R. R. W.]
Vascular basement membrane is an important structural component of blood
vessels and has been shown to interact with and modulate vascular
endothelial behavior during angiogenesis. During the inductive phase of
tumor angiogenesis, this membrane undergoes many degradative and
structural changes and reorganizes to a native state around newly
formed capillaries in the resolution phase. Such matrix changes are
potentially associated with molecular modifications that include
expression of matrix gene products coupled with conformational changes,
which expose cryptic protein modules for interaction with the vascular
endothelium. We speculate that these interactions provide important
endogenous angiogenic and anti-angiogenic cues. In this report, we
identify an important anti-angiogenic vascular basement
membrane-associated protein, the 26-kDa NC1 domain of the
1 chain of type IV collagen, termed arresten. Arresten
was isolated from human placenta and produced as a recombinant molecule
in Escherichia coli and 293 embryonic kidney cells. We
demonstrate that arresten functions as an anti-angiogenic molecule by
inhibiting endothelial cell proliferation, migration, tube formation,
and Matrigel neovascularization. Arresten inhibits the growth of two
human xenograft tumors in nude mice and the development of tumor
metastases. Additionally, we show that the anti-angiogenic activity of
arresten is potentially mediated via mechanisms involving cell surface
proteoglycans and the 1ß1 integrin on
endothelial cells. Collectively, our results suggest that arresten is a
potent inhibitor of angiogenesis with a potential for therapeutic use.
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