Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer
Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer
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DOI：
10.1136/gut.2007.148189
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发表时间：
2008-10-01
期刊：
影响因子：
24.5
通讯作者：
Maitra, A.
中科院分区：
文献类型：
--
作者：
Feldmann, G.;Habbe, N.;Maitra, A.
背景和目的：胰腺癌是人类最严重的恶性肿瘤之一。目前的治疗策略在控制晚期转移性疾病方面几乎是无效的。最近的证据表明，Hedgehog信号通路在大多数胰腺癌中被异常地重新激活，并且Hedgehog阻断具有预防疾病进展和转移扩散的潜力。研究方法：在此显示，Hedgehog途径在胰腺癌的Pdx 1-Cre; LsL-Kras（G12 D）; Ink 4a/Arf（lox/lox）转基因小鼠模型中被激活。Hedgehog途径抑制对存活的影响通过连续应用小分子环巴胺（smoothened拮抗剂）来确定。对过表达Gli 1的非恶性人胰腺导管细胞进行微阵列分析，以筛选可能参与胰腺癌进展的下游Hedgehog靶基因。结果如下：在本文所用的转基因小鼠模型中，用环巴胺抑制Hedgehog显著延长了中位生存期（67 vs 61天; p= 0.026）。体外数据表明，刺猬激活可能至少部分归因于致癌Kras信号。微阵列分析确定了26个潜在的Hedgehog靶基因，这些基因以前在胰腺癌中被发现过表达。其中BIRC 3、COL 11 A1、NNMT、PLAU和TGM 2这5个基因在之前的多个全局基因表达分析中被描述为上调。结论：这项研究提供了另一条证据，表明Hedgehog信号传导是开发胰腺癌新疗法的有效靶点，可能值得在临床环境中进行评估。
Background and aims: Pancreatic cancer is among the most dismal of human malignancies. Current therapeutic strategies are virtually ineffective in controlling advanced, metastatic disease. Recent evidence suggests that the Hedgehog signalling pathway is aberrantly reactivated in the majority of pancreatic cancers, and that Hedgehog blockade has the potential to prevent disease progression and metastatic spread. Methods: Here it is shown that the Hedgehog pathway is activated in the Pdx1-Cre; LsL-Kras(G12D); Ink4a/Arf(lox/lox) transgenic mouse model of pancreatic cancer. The effect of Hedgehog pathway inhibition on survival was determined by continuous application of the small molecule cyclopamine, a smoothened antagonist. Microarray analysis was performed on non-malignant human pancreatic ductal cells overexpressing Gli1 in order to screen for downstream Hedgehog target genes likely to be involved in pancreatic cancer progression. Results: Hedgehog inhibition with cyclopamine significantly prolonged median survival in the transgenic mouse model used here (67 vs 61 days; p= 0.026). In vitro data indicated that Hedgehog activation might at least in part be ascribed to oncogenic Kras signalling. Microarray analysis identified 26 potential Hedgehog target genes that had previously been found to be overexpressed in pancreatic cancer. Five of them, BIRC3, COL11A1, NNMT, PLAU and TGM2, had been described as upregulated in more than one global gene expression analysis before. Conclusion: This study provides another line of evidence that Hedgehog signalling is a valid target for the development of novel therapeutics for pancreatic cancer that might be worth evaluating soon in a clinical setting.