Integrins α(v)β3 and α(v)β5 are expressed by endothelium of high- risk neuroblastoma and their inhibition is associated with increased endogenous ceramide

Anat Erdreich-Epstein, Hiroyuki Shimada, Susan Groshen, Ming Liu, Leonid S. Metelitsa, Kwang Sik Kim, Monique Stins, Robert C. Seeger, Donald L. Durden

Research output: Contribution to journalArticle

Abstract

Inhibition of the RGD-binding integrins, α(v)β3 and α(v)β5, 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 α(v)β3 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 α(v)β5 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 α(v)β3 and α(v)β5. 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 α(v)β3 and α(v)β5. This is the first report to demonstrate expression of integrins α(v)β3 and α(v)β5 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.

Original languageEnglish (US)
Pages (from-to)712-721
Number of pages10
JournalCancer Research
Volume60
Issue number3
StatePublished - Feb 1 2000
Externally publishedYes

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Ceramides
Neuroblastoma
Integrins
Endothelium
Endothelial Cells
Vitronectin
Microvessels
Apoptosis
Neoplasms
Cell Death
Cyclic Peptides
Mitogen-Activated Protein Kinase Kinases
Brain
Second Messenger Systems
Fibronectins
Chromatin
Animal Models
Cell Culture Techniques
Lipids
Peptides

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Integrins α(v)β3 and α(v)β5 are expressed by endothelium of high- risk neuroblastoma and their inhibition is associated with increased endogenous ceramide. / Erdreich-Epstein, Anat; Shimada, Hiroyuki; Groshen, Susan; Liu, Ming; Metelitsa, Leonid S.; Kim, Kwang Sik; Stins, Monique; Seeger, Robert C.; Durden, Donald L.

In: Cancer Research, Vol. 60, No. 3, 01.02.2000, p. 712-721.

Research output: Contribution to journalArticle

Erdreich-Epstein, A, Shimada, H, Groshen, S, Liu, M, Metelitsa, LS, Kim, KS, Stins, M, Seeger, RC & Durden, DL 2000, 'Integrins α(v)β3 and α(v)β5 are expressed by endothelium of high- risk neuroblastoma and their inhibition is associated with increased endogenous ceramide', Cancer Research, vol. 60, no. 3, pp. 712-721.
Erdreich-Epstein, Anat ; Shimada, Hiroyuki ; Groshen, Susan ; Liu, Ming ; Metelitsa, Leonid S. ; Kim, Kwang Sik ; Stins, Monique ; Seeger, Robert C. ; Durden, Donald L. / Integrins α(v)β3 and α(v)β5 are expressed by endothelium of high- risk neuroblastoma and their inhibition is associated with increased endogenous ceramide. In: Cancer Research. 2000 ; Vol. 60, No. 3. pp. 712-721.
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abstract = "Inhibition of the RGD-binding integrins, α(v)β3 and α(v)β5, 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 α(v)β3 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 α(v)β5 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 α(v)β3 and α(v)β5. 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 α(v)β3 and α(v)β5. This is the first report to demonstrate expression of integrins α(v)β3 and α(v)β5 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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AU - Erdreich-Epstein, Anat

AU - Shimada, Hiroyuki

AU - Groshen, Susan

AU - Liu, Ming

AU - Metelitsa, Leonid S.

AU - Kim, Kwang Sik

AU - Stins, Monique

AU - Seeger, Robert C.

AU - Durden, Donald L.

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N2 - Inhibition of the RGD-binding integrins, α(v)β3 and α(v)β5, 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 α(v)β3 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 α(v)β5 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 α(v)β3 and α(v)β5. 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 α(v)β3 and α(v)β5. This is the first report to demonstrate expression of integrins α(v)β3 and α(v)β5 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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