Kamiya K, Konno H, Tanaka T, Baba M, Matsumoto K, Sakaguchi T, Yukita A, Asano M, Suzuki H, Arai T, Nakamura S
Second Department of Surgery, Hamamatsu University School of Medicine.
Jpn J Cancer Res. 1999 Jul;90(7):794-800. doi: 10.1111/j.1349-7006.1999.tb00817.x.
Induction of apoptosis by antiangiogenic therapy has been suggested as a new anticancer strategy. To clarify the mechanism of the antitumor effect achieved by inhibition of vascular endothelial growth factor (VEGF), which is a major mediator of angiogenesis, we used an orthotopic transplantation model of human gastric carcinoma line (MT2) treated with a monoclonal VEGF neutralizing antibody (VEGF Ab). We histologically examined the microvessel density (MVD) and the apoptotic index (AI) in this model. Transplanted tumor growth was significantly inhibited by the VEGF Ab (P = 0.03), and there was a significant decrease in the number of mice with liver metastasis (P = 0.004). The MVD detected by immunohistochemical staining with ER-MP12 antibody was 33.6 +/- 8.0 in the control group and 21.1 +/- 5.4 in the treated group, and the difference was significant (P < 0.0001). The AI values of the control and treated groups were 4.73 +/- 1.11 and 7.26 +/- 1.62, respectively, and this difference is also significant (P < 0.0001). However, the expression of VEGF mRNA in transplanted tumors did not show a significant difference between the control and treated groups. These results suggest that the antitumor effect of the VEGF Ab on human gastric carcinoma is exerted by inducing mild hypoxia followed by apoptosis, which does not influence VEGF mRNA expression in the carcinoma.
抗血管生成疗法诱导细胞凋亡已被认为是一种新的抗癌策略。为了阐明通过抑制血管内皮生长因子（VEGF）（血管生成的主要介质）所实现的抗肿瘤作用机制，我们使用了用单克隆VEGF中和抗体（VEGF Ab）处理的人胃癌细胞系（MT2）原位移植模型。我们对该模型中的微血管密度（MVD）和凋亡指数（AI）进行了组织学检查。VEGF Ab显著抑制了移植瘤的生长（P = 0.03），并且肝转移小鼠的数量显著减少（P = 0.004）。用ER-MP12抗体进行免疫组化染色检测的对照组MVD为33.6±8.0，治疗组为21.1±5.4，差异具有统计学意义（P < 0.0001）。对照组和治疗组的AI值分别为4.73±1.11和7.26±1.62，这种差异也具有统计学意义（P < 0.0001）。然而，移植瘤中VEGF mRNA的表达在对照组和治疗组之间没有显著差异。这些结果表明，VEGF Ab对人胃癌的抗肿瘤作用是通过诱导轻度缺氧继而引发细胞凋亡来实现的，而这并不影响癌组织中VEGF mRNA的表达。
