Transcriptional network governing the angiogenic, switch in human pancreatic cancer
Transcriptional network governing the angiogenic, switch in human pancreatic cancer
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DOI：
10.1073/pnas.0705505104
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发表时间：
2007-07-31
影响因子：
11.1
通讯作者：
Huber, Peter E.
中科院分区：
文献类型：
--
作者：
Abdollahi, Amir;Schwager, Christian;Huber, Peter E.
血管生成平衡向促血管生成状态的转变，称为“血管生成开关”，是癌症进展的标志。在这里，我们设计了一种策略来识别血管生成开关的遗传参与者，该策略基于人内皮细胞中基因的逆调控，以响应关键的内源性促血管生成和抗血管生成蛋白。这种方法揭示了血管稳态的全球网络模式，将已知的血管生成相关基因与以前未知的信号成分联系起来。我们还证明，血管生成开关是由多个基因组织的转录回路同时调控的。在胰腺癌患者中，我们验证了转录组衍生的“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（血管生成打开）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癌症风险增加。在小鼠基因敲除实验中，我们发现靶向去除血管生成网络的枢纽节点（过氧化物酶体增殖激活受体）显著损害血管生成和肿瘤生长。此外，在肿瘤患者中，我们发现过氧化物酶体增殖激活受体8的表达水平与肿瘤病理分期、肿瘤复发风险增加和远处转移相关。因此，我们的研究结果也可能有助于抗血管生成癌症药物的合理设计；尽管“窄”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，但该网络可能更容易受到多种或广谱抑制剂的影响，也更容易受到靶向去除已确定的血管生成“枢纽”节点的影响。
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 8 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.