Glioblastoma cells block radiation-induced programmed cell death of endothelial cells.
We demonstrate that human umbilical vein endothelial cells (HUVEC) grown in co-culture (CC) with U87 glioblastoma cells transfected with green fluorescent protein (GFP-U87) exhibit resistance to radiation-mediated apoptosis. cDNA macroarray analysis reveals increases in the accumulation of RNAs for HUVEC genes encoding cell adhesion molecules, growth factor-related proteins, and cell cycle regulatory/DNA repair proteins. An increase in protein expression of integrin alphav, integrin beta1, MAPK(p42), Rad51, DNA-PK(CS), and ataxia telangiectasia gene (ATM) was detected in HUVEC grown in CC with GFP-U87 cells compared with HUVEC grown in mono-culture. Treatment with anti-VEGF antibody decreases the expression of integrin alphav, integrin beta1, DNA-PK(CS) and ATM with a corresponding increase in ionizing radiation (IR)-induced apoptosis. These data support the concept that endothelial cells growing in the tumor microenvironment may develop resistance to cytotoxic therapies due to the up-regulation by tumor cells of endothelial cells genes associated with survival.
Brown
Charles K
CK
Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
Khodarev
Nikolai N
NN
Yu
Jianqing
J
Moo-Young
Tricia
T
Labay
Edwardine
E
Darga
Thomas E
TE
Posner
Mitchell C
MC
Weichselbaum
Ralph R
RR
Mauceri
Helena J
HJ
D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004260:DNA Repair; D018076:DNA, Complementary / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000473:pathology* / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000166:cytology; D005909:Glioblastoma / Q000473:pathology* / Q000532:radiotherapy; D049452:Green Fluorescent Proteins; D006801:Humans; D007259:Infrared Rays; D039564:Integrin alphaV / Q000096:biosynthesis; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D019012:Integrin beta1 / Q000096:biosynthesis; D008164:Luminescent Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051135:Rad51 Recombinase; D011878:Radiotherapy; D011995:Recombination, Genetic; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase