title: EphA2 blockade enhances the anti-endothelial effect of radiation and inhibits irradiated tumor cell-induced migration of endothelial cells.
abstract: EphA2 tyrosine kinase plays an important role in tumor angiogenesis, but whether targeting this pathway can affect response to ionizing radiation (IR) remains unknown.
  
  
  
  We investigated, using a soluble EphA2-Fc chimera, whether EphA2 inhibition could sensitize A549 and MCF-7 tumor cells, as well as human umbilical vein endothelial cells (HUVEC) and dermal microvascular endothelial cells (HDMEC), to IR.
  
  
  
  EphA2-Fc resulted in a greater response of endothelial cells (EC) to IR than either treatment alone. EphA2-Fc significantly increased apoptosis and decreased clonogenic survival, tube formation and migration in irradiated EC after stimulation with vascular endothelial growth factor (VEGF), without an affecting their proliferation. No difference in proliferation or survival was found in A549 and MCF-7 tumor cells. In a co-culture model, EphA2-Fc inhibited an irradiated A549 cell-induced increase in EC migration. VEGF supplementation, as well as condiotioned medium from irradiated A549 cells, phosphorylated EphA2 in EC. The latter was abrogated by EphA2-Fc.
  
  
  
  EC were most sensitive to a combination of EphA2 inhibition and radiotherapy. The induction of paracrine growth factors and activation of EphA2 in EC suggest a protective mechanism that tumors probably use to attenuate IR-induced antivascular effects. Our data justify further investigation to explore targeting EphA2 in tumor radiosensitivity in vivo.
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Phillips University Marburg, Marburg, Germany Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Phillips University Marburg, Marburg, Germany Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Florentine
authors.initials: F
authors.lastname: Kamlah
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Phillips University Marburg, Marburg, Germany Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hänze
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Phillips University Marburg, Marburg, Germany Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Engenhart-Cabillic
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Phillips University Marburg, Marburg, Germany Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Phillips University Marburg, Marburg, Germany Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: An
keywords: A549 cells; EphA2; VEGF; angiogenesis; endothelial cells; irradiation