GLYCOBIOLOGY AND EXTRACELLULAR MATRICES
Distinct Antitumor Properties of a Type IV Collagen Domain Derived from Basement Membrane*

https://doi.org/10.1074/jbc.M001956200Get rights and content
Under a Creative Commons license
open access

Vascular basement membrane is an important structural component of blood vessels. During angiogenesis this membrane undergoes many alterations and these changes are speculated to influence the formation of new capillaries. Type IV collagen is a major component of vascular basement membrane, and recently we identified a fragment of type IV collagen α2 chain with specific anti-angiogenic properties (Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H., Ramchandran, R., Torre, A., Maeshima, Y., Mier, J. W., Sukhatme, V. P., and Kalluri, R. (2000) J. Biol. Chem. 275, 1209–1215). In the present study we characterize two different antitumor activities associated with the noncollagenous 1 (NC1) domain of the α3 chain of type IV collagen. This domain was previously discovered to possess a C-terminal peptide sequence (amino acids 185–203) that inhibits melanoma cell proliferation (Han, J., Ohno, N., Pasco, S., Monboisse, J. C., Borel, J. P., and Kefalides, N. A. (1997) J. Biol. Chem. 272, 20395–20401). In the present study, we identify the anti-angiogenic capacity of this domain using several in vitro and in vivo assays. The α3(IV)NC1 inhibited in vivoneovascularization in matrigel plug assays and suppressed tumor growth of human renal cell carcinoma (786-O) and prostate carcinoma (PC-3) in mouse xenograft models associated with in vivo endothelial cell-specific apoptosis. The anti-angiogenic activity was localized to amino acids 54–132 using deletion mutagenesis. This anti-angiogenic region is separate from the 185–203 amino acid region responsible for the antitumor cell activity. Additionally, our experiments indicate that the antitumor cell activity is not realized until the peptide region is exposed by truncation of the α3(IV)NC1 domain, a requirement not essential for the anti-angiogenic activity of this domain. Collectively, these results effectively highlight the distinct and unique antitumor properties of the α3(IV)NC1 domain and the potential use of this molecule for inhibition of tumor growth.

Cited by (0)

Published, JBC Papers in Press, April 13, 2000, DOI 10.1074/jbc.M001956200

*

This work was supported in part by Grants DK-51711 and DK-55001 from the National Institutes of Health (to R. K.), the 1998 Hershey Prostate Cancer Research Award (to R. K.), the 1998 American Society of Nephrology Carl Gottschalk Research Award (to R. K.), the 1998 National Kidney Foundation Murray award (to R. K.), the 1998 Beth Israel Deaconess Medical Center Enterprise Award (to R. K.), and research funds from the Beth Israel Deaconess Medical Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of the 1999 Research Award for Young Scientists from the Inoue Foundation for Science of Japan.

§

Suppoeted by National Institutes of Health/NIDDK Grant F32 DK09946.

Supported by Deutsche Forschungsgemeinschaft Grant HO 2138/1-1.