Takahashi Yutaka, Teshima Teruki, Kawaguchi Naomasa, Hamada Yoshinosuke, Mori Seiji, Madachi Ayako, Ikeda Satoko, Mizuno Hirokazu, Ogata Toshiyuki, Nojima Kumie, Furusawa Yoshiya, Matsuura Nariaki
Department of Medical Engineering, School of Allied Health Sciences, Osaka University Faculty of Medicine, Osaka 565-0871, USA.
Cancer Res. 2003 Jul 15;63(14):4253-7.
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.
血管生成对于肿瘤生长和转移至关重要。由于内皮细胞基因稳定，它们很少获得对抗癌方式的抗性，因此可能是放射治疗的合适靶点。重离子放射治疗因其高致死效应作为一种有效的癌症治疗方式而受到关注，但重离子照射对与血管生成相关的体外细胞功能的影响尚未见报道。我们的研究发现，即使在亚致死剂量（0.1 Gy）下，高传能线密度碳离子照射也能抑制体外血管生成。用约110 keV/μm的290 MeV碳离子束或约1 keV/μm的4 MV X射线照射ECV304和人脐静脉血管内皮细胞（HUVEC）。碳离子照射后，它们对玻连蛋白或骨桥蛋白的黏附性和迁移受到抑制，三维培养中的毛细血管样管结构被破坏，同时基质金属蛋白酶-2活性受到抑制，黏附分子之一的αVβ3整合素下调，膜型1-基质金属蛋白酶略有上调，金属蛋白酶组织抑制剂-2显著上调。另一方面，亚致死剂量的X射线照射促进了内皮细胞的迁移，即使在16 Gy照射后，三维培养中的毛细血管样管结构仍继续发展。这些结果表明，即使在亚致死剂量下，重离子束治疗在体外血管生成的预防作用方面可能优于传统光子束治疗，并且可能在体内抑制血管生成。
