title: Heavy ion irradiation inhibits in vitro angiogenesis even at sublethal dose.
abstract: Angiogenesis is essential for tumor growth and metastasis. Because endothelial cells are genetically stable, they rarely acquire resistance to anticancer modalities, and could, thus, be a suitable target for radiation therapy. Heavy ion radiation therapy has attracted attention as an effective modality for cancer therapy because of its highly lethal effects, but the effects of heavy ion irradiation on in vitro cell function associated with angiogenesis have not been reported. Our study found that in vitro angiogenesis was inhibited by high linear energy transfer carbon ion irradiation even at sublethal dose (0.1 Gy). ECV304 and HUVEC human umbilical vascular endothelial cells were irradiated with 290 MeV carbon ion beams of approximately 110 keV/ micro m or 4 MV X-ray of approximately 1 keV/ micro m. Their adhesiveness and migration to vitronectin or osteopontin were inhibited, and capillary-like tube structures in three-dimensional culture were destroyed after carbon ion irradiation concomitant with the inhibition of matrix metalloproteinase-2 activity, down-regulation of alphaVbeta3 integrin, which is one of the adhesion molecules, slight up-regulation of membrane type1- matrix metalloproteinase, and significant up-regulation of tissue inhibitor of metalloproteinase-2. On the other hand, sublethal X-ray irradiation promoted migration of endothelial cells, and the capillary-like tube structure in three-dimensional culture progressed even after 16 Gy irradiation. These results provide an implication that heavy ion beam therapy could be superior to conventional photon beam therapy in preventive effects on in vitro angiogenesis even at sublethal dose, and might inhibit angiogenesis in vivo.
authors.affiliation: Department of Medical Engineering, School of Allied Health Sciences, Osaka University Faculty of Medicine, Osaka 565-0871, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Teruki
authors.initials: T
authors.lastname: Teshima
authors.forename: Naomasa
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Hamada
authors.forename: Seiji
authors.initials: S
authors.lastname: Mori
authors.forename: Ayako
authors.initials: A
authors.lastname: Madachi
authors.forename: Satoko
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizuno
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ogata
authors.forename: Kumie
authors.initials: K
authors.lastname: Nojima
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
mesh_terms: D002196:Capillaries / Q000033:anatomy & histology / Q000528:radiation effects; D002448:Cell Adhesion / Q000528:radiation effects; D002465:Cell Movement / Q000528:radiation effects; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D020450:Heavy Ions; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000378:metabolism; D018499:Linear Energy Transfer; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology / Q000528:radiation effects*; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000378:metabolism; D019096:Vitronectin / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D019096:Vitronectin; D053495:Osteopontin; D020778:Matrix Metalloproteinase 2