Radiation induced-tubulogenesis in endothelial cells is antagonized by the antiangiogenic properties of green tea polyphenol (-) epigallocatechin-3-gallate.
Radiation therapy is a widely-used option for the treatment of a variety of solid tumors. Although effective, ionizing radiation (IR) may give rise to various side effects, including secondary tumors. In agreement with this, recent reports have demonstrated increased invasive potential in different tumor-derived cell lines following radiation treatment. Many of the molecular effects of IR specifically on the endothelial cells involved in tumor neo-vascularization remain unknown. In this study, we found that low sublethal single doses of IR applied to human umbilical vein endothelial cells stimulated cell migration and in vitro tubulogenesis. This correlated with an increase in membrane type-1 matrix metalloproteinase (MT1-MMP) protein expression, a crucial enzyme that promotes endothelial cell migration and tube formation, and of caveolin-1, a protein that regulates tube formation. Cell adhesion was also promoted by IR, reflected in increased gene expression levels of cell surface beta(3) integrin. Pretreatment of the cells with epigallocatechin-3-gallate (EGCg), a green tea catechin that possesses anti-angiogenic properties, prevented most of the IR-induced cellular and molecular events. These observations suggest that current protocols involving radiation therapy for the treatment of cancer can paradoxically promote angiogenesis, but can be improved by combination with anti-angiogenic molecules such as EGCg to target those tumor-derived endothelial cells that escaped IR-induced apoptosis.
Annabi
Borhane
B
Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine and Université du Québec a Montreal, Montreal, Quebec, Canada.
Lee
Ying-Ta
YT
Martel
Charles
C
Pilorget
Anthony
A
Bahary
Jean-Paul
JP
Béliveau
Richard
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051242:Caveolin 1; D022461:Caveolins / Q000187:drug effects / Q000528:radiation effects; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D003094:Collagen / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects* / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000166:cytology; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D039661:Integrin beta3 / Q000187:drug effects / Q000528:radiation effects; D007797:Laminin / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects* / Q000528:radiation effects; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000528:radiation effects; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D011509:Proteoglycans / Q000378:metabolism; D011839:Radiation, Ionizing; D013662:Tea / Q000737:chemistry*; D013997:Time Factors; D011503:Transglutaminases / Q000187:drug effects / Q000528:radiation effects; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000528:radiation effects
D020533:Angiogenesis Inhibitors; C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D004338:Drug Combinations; D005419:Flavonoids; D039661:Integrin beta3; D007797:Laminin; D010636:Phenols; D059808:Polyphenols; D011509:Proteoglycans; D013662:Tea; C059485:matrigel; D002392:Catechin; D003094:Collagen; C045651:epigallocatechin gallate; D011503:Transglutaminases; C105804:transglutaminase 1; D020169:Caspases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases