The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma: Laboratory investigation

Eric M. Thompson, Nathaniel L. Whitney, Y. Jeffrey Wu, Edward Neuwelt

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Object. Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor-1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods. Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results. Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p <0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p <0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p <0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p <0.05) and in normoxic D283 cells (p <0.01). Neither cell line demonstrated increased HIF-1a expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p <0.05). Conclusions. Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting av integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalJournal of Neurosurgery: Pediatrics
Volume11
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Integrin alpha Chains
Medulloblastoma
Integrins
Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor A
Phenotype
Cell Line
Cell Movement
Cell Proliferation
Oxygen
Cell Hypoxia
intetumumab
Brain Neoplasms
Hypoxia
Monoclonal Antibodies

Keywords

  • α integrin
  • c-Myc
  • Hypoxia
  • Hypoxia-inducible factor-1α
  • Intetumumab
  • Medulloblastoma
  • Oncology

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery
  • Pediatrics, Perinatology, and Child Health

Cite this

The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma : Laboratory investigation. / Thompson, Eric M.; Whitney, Nathaniel L.; Wu, Y. Jeffrey; Neuwelt, Edward.

In: Journal of Neurosurgery: Pediatrics, Vol. 11, No. 1, 01.2013, p. 60-67.

Research output: Contribution to journalArticle

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abstract = "Object. Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor-1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods. Cells were grown at 21{\%} and 1{\%} O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results. Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p <0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p <0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p <0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p <0.05) and in normoxic D283 cells (p <0.01). Neither cell line demonstrated increased HIF-1a expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p <0.05). Conclusions. Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting av integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.",
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T1 - The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma

T2 - Laboratory investigation

AU - Thompson, Eric M.

AU - Whitney, Nathaniel L.

AU - Wu, Y. Jeffrey

AU - Neuwelt, Edward

PY - 2013/1

Y1 - 2013/1

N2 - Object. Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor-1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods. Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results. Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p <0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p <0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p <0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p <0.05) and in normoxic D283 cells (p <0.01). Neither cell line demonstrated increased HIF-1a expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p <0.05). Conclusions. Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting av integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.

AB - Object. Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor-1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods. Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results. Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p <0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p <0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p <0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p <0.05) and in normoxic D283 cells (p <0.01). Neither cell line demonstrated increased HIF-1a expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p <0.05). Conclusions. Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting av integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.

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KW - c-Myc

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KW - Hypoxia-inducible factor-1α

KW - Intetumumab

KW - Medulloblastoma

KW - Oncology

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