Vascular endothelial growth factor mediated angiogenic potential of pancreatic ductal carcinomas enhanced by hypoxia: An in vitro and in vivo study
Vascular endothelial growth factor mediated angiogenic potential of pancreatic ductal carcinomas enhanced by hypoxia: An in vitro and in vivo study
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缺氧增强血管内皮生长因子介导的胰腺导管癌血管生成潜力：体外和体内研究
DOI：
10.1002/ijc.10753
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发表时间：
2002
影响因子：
6.4
通讯作者：
G. Klöppel
中科院分区：
文献类型：
--
作者：
B. Sipos;Dirk Weber;H. Ungefroren;H. Kalthoff;André Zühlsdorff;C. Luther;Virág Török;G. Klöppel
胰腺导管腺癌中的血管生成依赖于血管生成因子如血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的存在，并且被认为是由缺氧刺激的。我们通过筛选VEGF和bFGF的mRNA和蛋白表达以及在常氧和低氧（5%或0.2%O2）条件下VEGF释放到培养基中来检测9种胰腺导管癌起源细胞系的血管生成潜力。使用2-D和3-D内皮细胞试验测定血管生成活性。此外，VEGF的表达和肿瘤血管化的研究，在人胰腺癌组织原位异种移植和切除标本。所有的细胞系表达（mRNA，蛋白质）和分泌VEGF，而bFGF只发现在3个细胞系，并分泌到培养基中的低浓度。除了优势亚型VEGF 121、VEGF 165和VEGF 189外，还检测到最近描述的2种亚型VEGF 145和VEGF 183。重度缺氧（0.2%O2）可使7/9细胞VEGF mRNA表达增加，中度缺氧（5%O2）可使5/9细胞VEGF蛋白分泌增加。来自7/9、6/9、8/9和7/9细胞系的条件培养基分别在常氧（24和48小时）或低氧（24小时，0.2%和48小时5%O2）条件下刺激内皮细胞增殖。来自4/9个细胞系的条件培养基也在常氧条件下诱导毛细血管样发芽，6/9在缺氧（0.2% O2）条件下诱导毛细血管样发芽。在异种移植的癌组织中，发现缺血性坏死区域周围的微血管密度没有增加。在切除的导管癌肿瘤坏死VEGF表达和微血管密度仅增加，分别在3/12和2/13例。总之，在体外，大多数胰腺导管癌表现出明显的与VEGF相关的血管生成潜力，正如二维和三维内皮细胞增殖所证明的那样，这可能会受到严重缺氧的促进。令人惊讶的是，周围坏死的肿瘤区域，这应该是缺氧，只有很少表现出预期的微血管密度和VEGF表达的增加。© 2002 Wiley利斯公司
Angiogenesis in pancreatic ductal adenocarcinomas depends on the presence of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thought to be stimulated by hypoxia. We tested the angiogenic potential of 9 cell lines of pancreatic ductal carcinoma origin by screening mRNA and protein expression of VEGF and bFGF and the release of VEGF into culture medium under normoxic and hypoxic (5% or 0.2% O2) conditions. Angiogenic activity was determined using 2‐ and 3‐D endothelial cell assays. Furthermore, VEGF expression and tumor vascularization were studied in human pancreatic carcinoma tissues from orthotopic xenografts and resection specimens. All cell lines expressed (mRNA, protein) and secreted VEGF, whereas bFGF was only found in 3 cell lines and was secreted into the medium in low concentrations. In addition to the dominant isoforms VEGF121,VEGF165 and VEGF189, 2 isoforms described recently, VEGF145 and VEGF183, were detected. Severe hypoxia (0.2% O2), but not moderate hypoxia (5% O2) raised VEGF mRNA expression and protein secretion in 7/9 and 5/9 cell lines, respectively. Conditioned media from 7/9, 6/9, 8/9 and 7/9 cell lines stimulated endothelial cell proliferation under normoxic (24 and 48 hr) or hypoxic (24 hr, 0.2% and 48 hr 5% O2) conditions, respectively. Conditioned media from 4/9 cell lines also induced capillary‐like sprouting under normoxic conditions and from 6/9 under hypoxic (0.2% O2) conditions. In xenografted carcinoma tissues microvessel density was found not to be increased around areas of ischemic necrosis. In resected ductal carcinomas showing tumor necrosis VEGF expression and microvessel density were only increased in 3/12 and 2/13 cases, respectively. In conclusion, in vitro most pancreatic ductal carcinomas show a distinct VEGF related angiogenic potential, as demonstrated by 2‐ and 3‐D endothelial cell proliferation, which may be promoted by severe hypoxia. Surprisingly, perinecrotic tumor areas, which are supposed to be hypoxic, only rarely showed the expected increase in microvessel density and VEGF expression. © 2002 Wiley‐Liss, Inc.
影响因子：
11.2
作者：
Y. Yamanaka;H. Friess;M. Büchler;H. Beger;E. Uchida;M. Onda;M. Kobrin;M. Korc
通讯作者：
Y. Yamanaka;H. Friess;M. Büchler;H. Beger;E. Uchida;M. Onda;M. Kobrin;M. Korc
影响因子：
11.2
作者：
N. Beasley;C. Wykoff;P. Watson;R. Leek;H. Turley;K. Gatter;J. Pastorek;G. Cox;P. Ratcliffe;A. Harris
通讯作者：
N. Beasley;C. Wykoff;P. Watson;R. Leek;H. Turley;K. Gatter;J. Pastorek;G. Cox;P. Ratcliffe;A. Harris