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Integrins _vß₃ and _vß₅ Are Expressed by Endothelium of High-Risk Neuroblastoma and Their Inhibition Is Associated with Increased Endogenous Ceramide¹

Divisions of Hematology-Oncology [A. E-E., M. L., L. S. M., R. C. S., D. L. D.] and Infectious Diseases [K. S. K., M. F. S.], Neil Bogart Memorial Laboratories, and Departments of Pediatrics and Pathology [H. S.], Children’s Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, California 90027; and Department of Preventive Medicine [S. G.], University of Southern California School of Medicine and the Children’s Cancer Group, Arcadia, California 91066

Inhibition of the RGD-binding integrins, _vß₃ and _vß₅, prevents endothelial cell anchorage and induces endothelial apoptosis, which results in disruption of tumor angiogenesis and inhibition of tumor growth in animal models. In this study, we demonstrate by immunohistochemical analysis that integrin _vß₃ was expressed by 61% (mean) of microvessels in high-risk neuroblastomas (stage IV and MYCN-amplified stage III; n = 28) but only by 18% (mean) of microvessels in low-risk tumors (stages I and II and non-MYCN-amplified stage III; n = 12). Integrin _vß₅ was found on 60% (mean) of microvessels in 21 Stage IV tumors. These data suggest that neuroblastomas may be targeted for antiangiogenic treatment directed against endothelial integrins _vß₃ and _vß₅. In cell culture, inhibition of integrin-dependent endothelial cell anchorage to vitronectin by RGDfV, an RGD function-blocking cyclic peptide, induced apoptosis in bovine brain endothelial cells compared with the control peptide, RADfV (37.5% versus 8.7%, respectively), as detected by chromatin condensation and nuclear fragmentation. Treatment with RGDfV but not with RADfV, which prevented attachment of endothelial cells to vitronectin or fibronectin, was associated with up to a 50% increase in endogenous ceramide, a lipid second messenger that can mediate cell death. Furthermore, exogenous C₂-ceramide was cytotoxic to bovine brain endothelial cells and induced activation of C-jun N-terminal kinase (JNK), a MAP kinase that can be activated in stress-induced apoptosis pathways. This suggests that ceramide may function in detachment-induced endothelial cell apoptosis, originating from inhibition of vitronectin binding to integrins such as _vß₃ and _vß₅. This is the first report to demonstrate expression of integrins _vß₃ and _vß₅ by microvascular endothelium of a childhood tumor and association of their expression with neuroblastoma aggressiveness. Furthermore, our data provide the first suggestion that inhibition of endothelial cell anchorage, resulting from specific blockade of RGD-binding integrins, increases endogenous ceramide, which may contribute to endothelial cell death.

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