Tumour-endothelium interactions in co-culture: coordinated changes of gene expression profiles and phenotypic properties of endothelial cells.
Tumour angiogenesis is a complex process based upon a sequence of interactions between tumour cells and endothelial cells. To model tumour/endothelial-cell interactions, we co-cultured U87 human glioma cells with human umbilical vein endothelial cells (HUVECs). U87 cells induced an 'activated' phenotype in HUVECs, including an increase in proliferation, migration and net-like formation. Activation was observed in co-cultures where cells were in direct contact and physically separated, suggesting an important role for soluble factor(s) in the phenotypic and genotypic changes observed. Expressional profiling of tumour-activated endothelial cells was evaluated using cDNA arrays and confirmed by quantitative PCR. Matching pairs of receptors/ligands were found to be coordinately expressed, including TGFbetaRII with TGFbeta3, FGFRII and cysteine-rich fibroblast growth factor receptor (CRF-1) with FGF7 and FGF12, CCR1, CCR3, CCR5 with RANTES and calcitronin receptor-like gene (CALCRL) with adrenomedullin. Consistent with cDNA array data, immunohistochemical staining of expressed proteins revealed the upregulation of Tie-2 receptor in vitro and in vivo. Our data suggest that tumour-induced activation of quiescent endothelial cells involves the expression of angiogenesis-related receptors and the induction of autocrine growth loops. We suggest that tumour cells release growth factors that induce endothelial cells to express specific ligands and their cognate receptors coordinately.
Khodarev
Nikolai N
NN
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
Yu
Jianqing
J
Labay
Edwardine
E
Darga
Thomas
T
Brown
Charles K
CK
Mauceri
Helena J
HJ
Yassari
Reza
R
Gupta
Nalin
N
Weichselbaum
Ralph R
RR
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D043168:Angiostatins; D019898:Autocrine Communication / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology*; D015870:Gene Expression / Q000502:physiology; D005910:Glioma; D006801:Humans; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D010958:Plasminogen / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D018121:Receptors, Cytokine / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D017468:Receptors, Fibroblast Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D043168:Angiostatins; D010958:Plasminogen; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2