Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts.
Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts.
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发表时间：
2003-09
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通讯作者：
M. Bockhorn;Y. Tsuzuki;Lei Xu;A. Frilling;C. Broelsch;D. Fukumura
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作者：
M. Bockhorn;Y. Tsuzuki;Lei Xu;A. Frilling;C. Broelsch;D. Fukumura
目的探讨抗血管内皮细胞生长因子(VEGF)治疗对人胰腺癌原位移植瘤血管功能、基因表达及生长的影响，为新的肿瘤治疗提供临床前资料。实验设计将人胰腺癌PANC-1小块植入严重联合免疫缺陷雄性小鼠的胰腺内。给动物注射抗人血管内皮生长因子抗体A.4.6.1(300微克，每3天一次)。或在肿瘤植入后4-8周出现非特异性免疫球蛋白。然后通过活体显微镜检测血管密度、直径、通透性和肿瘤生长情况。随后，获取肿瘤组织，利用包含96个肿瘤血管生成相关基因的微阵列试剂盒检测血管生成基因的表达谱。结果抗血管内皮生长因子抗体显著抑制原位PANC-1肿瘤的血管生成和生长。抗血管内皮生长因子治疗组血管密度(67.80±10.6 cm/cm(2))明显小于对照组(146.7±10.0 cm/cm(2))。然而，抗血管内皮生长因子抗体治疗对血管内径和通透性无明显影响。治疗组胰腺肿瘤明显小于对照组。基因芯片和随后的Northern印迹和半定量逆转录-聚合酶链式反应分析显示，经抗血管内皮生长因子治疗后，PANC-1肿瘤中血管生成相关基因的表达减少(成纤维细胞生长因子1、转化生长因子β1、血小板衍生生长因子α、erb2和c-ets1)，而增加(胎盘生长因子、低氧诱导因子α和endoglin)。结论抗血管内皮生长因子抗体治疗对原位胰腺癌血管功能及血管生成基因表达有不同程度的影响，对血管生成及生长有抑制作用。抗血管内皮生长因子策略在胰腺癌治疗中显示出良好的应用前景。
PURPOSE The objectives of this study were to investigate the effects of anti-vascular endothelial growth factor (VEGF) treatment on various vascular functions, gene expression, and growth of orthotopic human pancreatic cancer xenografts and thus to provide useful preclinical data for novel cancer treatments. EXPERIMENTAL DESIGN Small pieces of a human pancreatic carcinoma, PANC-1, were implanted into the pancreas of male severe combined immunodeficient mice. The animals were treated with anti-human VEGF antibody A.4.6.1 (300 micro g, every 3 days i.p.) or a nonspecific IgG between 4 and 8 weeks after tumor implantation. Then, vascular density, diameter, permeability, and tumor growth were determined by intravital microscopy. Subsequently, tumors were harvested, and angiogenic gene expression profile was determined by a microarray kit including 96 genes involved in tumor angiogenesis. RESULTS Anti-VEGF antibody significantly reduced angiogenesis and growth of orthotopic PANC-1 tumors. In the anti-VEGF treatment group, the vessel density was significantly smaller (67.8 +/- 10.6 cm/cm(2)) than that seen in the control group (146.7 +/- 10.0 cm/cm(2)). However, vessel diameter and permeability were not altered significantly by anti-VEGF antibody treatment. The pancreatic tumors in the treated group were significantly smaller than those in the control group. Microarray and subsequent Northern blot and semiquantitative reverse transcription-PCR analyses revealed both a decrease (fibroblast growth factor 1, transforming growth factor beta1, platelet-derived growth factor alpha, erbB2, and c-ets1,) and an increase (placenta growth factor, hypoxia-inducible factor alpha, and endoglin) in expression of angiogenesis-related genes in the PANC-1 tumors by anti-VEGF treatment. CONCLUSIONS Anti-VEGF antibody treatment has differential effects on vessel functions as well as angiogenic gene expression and inhibitory effects on angiogenesis and growth of the orthotopic pancreatic tumor. Anti-VEGF strategy appears promising for pancreatic cancer treatment.