Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.
Syndecan-1 (Sdc1) is a matrix receptor shown to associate via its extracellular domain with the alpha(v)beta(3) and alpha(v)beta(5) integrins, potentially regulating cell adhesion, spreading, and invasion of cells expressing these integrins. Using Sdc1 deletion mutants expressed in human mammary carcinoma cells, we identified the active site within the Sdc1 core protein and derived a peptide inhibitor called synstatin (SSTN) that disrupts Sdc1's interaction with these integrins. Because the alpha(v)beta(3) and alpha(v)beta(5) integrins are critical in angiogenesis, a process in which a role for Sdc1 has been uncertain, we used human vascular endothelial cells in vitro to show that the Sdc1 regulatory mechanism is also required for integrin activation on these cells. We found Sdc1 expressed in the vascular endothelium during microvessel outgrowth from aortic explants in vitro and in mouse mammary tumors in vivo. Moreover, we show that SSTN blocks angiogenesis in vitro or when delivered systemically in a mouse model of angiogenesis in vivo, and impairs mammary tumor growth in an orthotopic mouse tumor model. Thus, Sdc1 is a critical regulator of these two important integrins during angiogenesis and tumorigenesis, and is inhibited by the novel SSTN peptide.
Beauvais
DeannaLee M
DM
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Ell
Brian J
BJ
McWhorter
Andrea R
AR
Rapraeger
Alan C
AC
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D019030:Receptors, Vitronectin / Q000378:metabolism*; D053668:Syndecan-1 / Q000037:antagonists & inhibitors*
D039302:Integrin alphaVbeta3; D010455:Peptides; D019030:Receptors, Vitronectin; D053668:Syndecan-1; C064660:integrin alphaVbeta5; D005346:Fibroblast Growth Factors