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Tumor Biology |
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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