Abdollahi Amir, Schwager Christian, Kleeff Jörg, Esposito Irene, Domhan Sophie, Peschke Peter, Hauser Kai, Hahnfeldt Philip, Hlatky Lynn, Debus Jürgen, Peters Jeffrey M, Friess Helmut, Folkman Judah, Huber Peter E
Department of Radiation Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg Medical School, Heidelberg 69120, Germany.
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12890-5. doi: 10.1073/pnas.0705505104. Epub 2007 Jul 24.
A shift of the angiogenic balance to the proangiogenic state, termed the "angiogenic switch," is a hallmark of cancer progression. Here we devise a strategy for identifying genetic participants of the angiogenic switch based on inverse regulation of genes in human endothelial cells in response to key endogenous pro- and antiangiogenic proteins. This approach reveals a global network pattern for vascular homeostasis connecting known angiogenesis-related genes with previously unknown signaling components. We also demonstrate that the angiogenic switch is governed by simultaneous regulations of multiple genes organized as transcriptional circuitries. In pancreatic cancer patients, we validate the transcriptome-derived switch of the identified "angiogenic network:" The angiogenic state in chronic pancreatitis specimens is intermediate between the normal (angiogenesis off) and neoplastic (angiogenesis on) condition, suggesting that aberrant proangiogenic environment contributes to the increased cancer risk in patients with chronic pancreatitis. In knockout experiments in mice, we show that the targeted removal of a hub node (peroxisome proliferative-activated receptor delta) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor delta expression levels are correlated with advanced pathological tumor stage, increased risk for tumor recurrence, and distant metastasis. Our results therefore also may contribute to the rational design of antiangiogenic cancer agents; whereas "narrow" targeted cancer drugs may fail to shift the robust angiogenic regulatory network toward antiangiogenesis, the network may be more vulnerable to multiple or broad-spectrum inhibitors or to the targeted removal of the identified angiogenic "hub" nodes.
血管生成平衡向促血管生成状态的转变，即所谓的“血管生成开关”，是癌症进展的一个标志。在此，我们设计了一种策略，基于人类内皮细胞中基因对关键内源性促血管生成和抗血管生成蛋白的反向调节，来识别血管生成开关的基因参与者。这种方法揭示了一种血管稳态的全局网络模式，将已知的血管生成相关基因与先前未知的信号成分联系起来。我们还证明，血管生成开关受多个基因作为转录回路组织的同时调节。在胰腺癌患者中，我们验证了转录组衍生的已识别“血管生成网络”的开关：慢性胰腺炎标本中的血管生成状态介于正常（血管生成关闭）和肿瘤（血管生成开启）状态之间，这表明异常的促血管生成环境导致慢性胰腺炎患者患癌风险增加。在小鼠的基因敲除实验中，我们表明血管生成网络的一个枢纽节点（过氧化物酶体增殖物激活受体δ）的靶向去除显著损害血管生成和肿瘤生长。此外，在肿瘤患者中，我们表明过氧化物酶体增殖物激活受体δ的表达水平与晚期病理肿瘤分期、肿瘤复发风险增加和远处转移相关。因此，我们的结果也可能有助于抗血管生成癌症药物的合理设计；鉴于“窄谱”靶向癌症药物可能无法将强大的血管生成调节网络转向抗血管生成，该网络可能更容易受到多种或广谱抑制剂或对已识别的血管生成“枢纽”节点的靶向去除的影响。
