The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells

Nancy McLaughlin, Borhane Annabi, Kwang Sik Kim, Jean Paul Bahary, Robert Moumdjian, Richard Béliveau

Research output: Contribution to journalArticle

Abstract

Introduction: Radioresistant brain tumor vasculature is thought to hamper the efficiency of adjuvant cancer therapies. However, little is known regarding the signalling pathways involved in the angiogenic response to brain tumor-derived growth factors in irradiated human brain microvascular endothelial cells (HBMEC). The goal of this study is to assess the effect of ionizing radiation (IR) on HBMEC survival, migration and tubulogenesis. Methods: HBMEC were cultured and irradiated at sublethal single doses. Cell survival was assessed by nuclear cell counting and flow cytometry. HBMEC migration in response to brain tumor-derived growth factors (U-87 GF) and tubulogenesis were assayed using modified Boyden chambers and Matrigel, respectively. Results: We observed that single administration of 3-10 Gy IR doses only reduced cell survival by 30%. Radioresistant HBMEC overexpressed RhoA, a small GTPase protein regulating cellular adhesion and migration, and Rho-kinase (ROK), a serine-threonine protein kinase and one of RhoA's major targets. HBMEC migration was induced by vascular endothelial growth factor (VEGF), but even more so in response to sphingosine-1-phosphate (S1P) and to U-87 GF. Following IR exposure, HBMEC basal migration increased more than two-fold, whereas the response to S1P and to U-87 GF was significantly diminished. Similarly, the inhibitor of ROK Y-27632 decreased HBMEC migration in response to S1P and U-87 GF. Overexpression of RhoA decreased tubulogenesis, an effect also observed in irradiated HBMEC. Conclusion: Our results suggest that radioresistant HBMEC migration response to tumor-secreted growth factors and tubulogenesis are altered following IR. The RhoA/ROK signalling pathway is involved in the IR-altered angiogenic functions and may represent a potential molecular target for enhancing the impact of radiotherapy on tumor-associated endothelial cells.

Original languageEnglish (US)
Pages (from-to)1539-1545
Number of pages7
JournalCancer Biology and Therapy
Volume5
Issue number11
StatePublished - Nov 2006

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Brain Neoplasms
Endothelial Cells
Brain
Cell Movement
Ionizing Radiation
rho-Associated Kinases
Cell Survival
brain-derived growth factor
Radiation Dosage
Neoplasms
Monomeric GTP-Binding Proteins
Protein-Serine-Threonine Kinases
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Flow Cytometry
Radiotherapy

Keywords

  • Glioblastoma
  • Human brain endothelial cells
  • Migration
  • Radiotherapy
  • Rho proteins
  • Tubulogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

McLaughlin, N., Annabi, B., Kim, K. S., Bahary, J. P., Moumdjian, R., & Béliveau, R. (2006). The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells. Cancer Biology and Therapy, 5(11), 1539-1545.

The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells. / McLaughlin, Nancy; Annabi, Borhane; Kim, Kwang Sik; Bahary, Jean Paul; Moumdjian, Robert; Béliveau, Richard.

In: Cancer Biology and Therapy, Vol. 5, No. 11, 11.2006, p. 1539-1545.

Research output: Contribution to journalArticle

McLaughlin, N, Annabi, B, Kim, KS, Bahary, JP, Moumdjian, R & Béliveau, R 2006, 'The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells', Cancer Biology and Therapy, vol. 5, no. 11, pp. 1539-1545.
McLaughlin, Nancy ; Annabi, Borhane ; Kim, Kwang Sik ; Bahary, Jean Paul ; Moumdjian, Robert ; Béliveau, Richard. / The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells. In: Cancer Biology and Therapy. 2006 ; Vol. 5, No. 11. pp. 1539-1545.
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abstract = "Introduction: Radioresistant brain tumor vasculature is thought to hamper the efficiency of adjuvant cancer therapies. However, little is known regarding the signalling pathways involved in the angiogenic response to brain tumor-derived growth factors in irradiated human brain microvascular endothelial cells (HBMEC). The goal of this study is to assess the effect of ionizing radiation (IR) on HBMEC survival, migration and tubulogenesis. Methods: HBMEC were cultured and irradiated at sublethal single doses. Cell survival was assessed by nuclear cell counting and flow cytometry. HBMEC migration in response to brain tumor-derived growth factors (U-87 GF) and tubulogenesis were assayed using modified Boyden chambers and Matrigel, respectively. Results: We observed that single administration of 3-10 Gy IR doses only reduced cell survival by 30{\%}. Radioresistant HBMEC overexpressed RhoA, a small GTPase protein regulating cellular adhesion and migration, and Rho-kinase (ROK), a serine-threonine protein kinase and one of RhoA's major targets. HBMEC migration was induced by vascular endothelial growth factor (VEGF), but even more so in response to sphingosine-1-phosphate (S1P) and to U-87 GF. Following IR exposure, HBMEC basal migration increased more than two-fold, whereas the response to S1P and to U-87 GF was significantly diminished. Similarly, the inhibitor of ROK Y-27632 decreased HBMEC migration in response to S1P and U-87 GF. Overexpression of RhoA decreased tubulogenesis, an effect also observed in irradiated HBMEC. Conclusion: Our results suggest that radioresistant HBMEC migration response to tumor-secreted growth factors and tubulogenesis are altered following IR. The RhoA/ROK signalling pathway is involved in the IR-altered angiogenic functions and may represent a potential molecular target for enhancing the impact of radiotherapy on tumor-associated endothelial cells.",
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T1 - The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells

AU - McLaughlin, Nancy

AU - Annabi, Borhane

AU - Kim, Kwang Sik

AU - Bahary, Jean Paul

AU - Moumdjian, Robert

AU - Béliveau, Richard

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N2 - Introduction: Radioresistant brain tumor vasculature is thought to hamper the efficiency of adjuvant cancer therapies. However, little is known regarding the signalling pathways involved in the angiogenic response to brain tumor-derived growth factors in irradiated human brain microvascular endothelial cells (HBMEC). The goal of this study is to assess the effect of ionizing radiation (IR) on HBMEC survival, migration and tubulogenesis. Methods: HBMEC were cultured and irradiated at sublethal single doses. Cell survival was assessed by nuclear cell counting and flow cytometry. HBMEC migration in response to brain tumor-derived growth factors (U-87 GF) and tubulogenesis were assayed using modified Boyden chambers and Matrigel, respectively. Results: We observed that single administration of 3-10 Gy IR doses only reduced cell survival by 30%. Radioresistant HBMEC overexpressed RhoA, a small GTPase protein regulating cellular adhesion and migration, and Rho-kinase (ROK), a serine-threonine protein kinase and one of RhoA's major targets. HBMEC migration was induced by vascular endothelial growth factor (VEGF), but even more so in response to sphingosine-1-phosphate (S1P) and to U-87 GF. Following IR exposure, HBMEC basal migration increased more than two-fold, whereas the response to S1P and to U-87 GF was significantly diminished. Similarly, the inhibitor of ROK Y-27632 decreased HBMEC migration in response to S1P and U-87 GF. Overexpression of RhoA decreased tubulogenesis, an effect also observed in irradiated HBMEC. Conclusion: Our results suggest that radioresistant HBMEC migration response to tumor-secreted growth factors and tubulogenesis are altered following IR. The RhoA/ROK signalling pathway is involved in the IR-altered angiogenic functions and may represent a potential molecular target for enhancing the impact of radiotherapy on tumor-associated endothelial cells.

AB - Introduction: Radioresistant brain tumor vasculature is thought to hamper the efficiency of adjuvant cancer therapies. However, little is known regarding the signalling pathways involved in the angiogenic response to brain tumor-derived growth factors in irradiated human brain microvascular endothelial cells (HBMEC). The goal of this study is to assess the effect of ionizing radiation (IR) on HBMEC survival, migration and tubulogenesis. Methods: HBMEC were cultured and irradiated at sublethal single doses. Cell survival was assessed by nuclear cell counting and flow cytometry. HBMEC migration in response to brain tumor-derived growth factors (U-87 GF) and tubulogenesis were assayed using modified Boyden chambers and Matrigel, respectively. Results: We observed that single administration of 3-10 Gy IR doses only reduced cell survival by 30%. Radioresistant HBMEC overexpressed RhoA, a small GTPase protein regulating cellular adhesion and migration, and Rho-kinase (ROK), a serine-threonine protein kinase and one of RhoA's major targets. HBMEC migration was induced by vascular endothelial growth factor (VEGF), but even more so in response to sphingosine-1-phosphate (S1P) and to U-87 GF. Following IR exposure, HBMEC basal migration increased more than two-fold, whereas the response to S1P and to U-87 GF was significantly diminished. Similarly, the inhibitor of ROK Y-27632 decreased HBMEC migration in response to S1P and U-87 GF. Overexpression of RhoA decreased tubulogenesis, an effect also observed in irradiated HBMEC. Conclusion: Our results suggest that radioresistant HBMEC migration response to tumor-secreted growth factors and tubulogenesis are altered following IR. The RhoA/ROK signalling pathway is involved in the IR-altered angiogenic functions and may represent a potential molecular target for enhancing the impact of radiotherapy on tumor-associated endothelial cells.

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KW - Migration

KW - Radiotherapy

KW - Rho proteins

KW - Tubulogenesis

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