Canonical wnt signaling is required for pancreatic carcinogenesis.
Canonical wnt signaling is required for pancreatic carcinogenesis.
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DOI：
10.1158/0008-5472.can-12-4384
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发表时间：
2013-08-01
期刊：
影响因子：
11.2
通讯作者：
Pasca di Magliano M
中科院分区：
文献类型：
--
作者：
Zhang Y;Morris JP 4th;Yan W;Schofield HK;Gurney A;Simeone DM;Millar SE;Hoey T;Hebrok M;Pasca di Magliano M
Wnt配体表达和Wnt/β-连环蛋白途径的激活与胰腺导管腺癌相关，但Wnt活性是否是胰腺癌发展所必需的仍不清楚。在这里，我们报告了三种不同的方法来抑制Wnt/β-catenin途径在一个建立的胰腺癌转基因小鼠模型的结果。首先，我们发现β-catenin空细胞不能经历腺泡到导管化生，这是一个与癌前PanIN病变发展相关的过程。其次，我们通过诱导表达Dkk 1（经典Wnt通路的内源性分泌抑制剂），阐述了配体介导的Wnt信号传导的特定作用。最后，我们用OMP-18 R5靶向Wnt通路，OMP-18 R5是一种与多种Frizzled受体相互作用的治疗性抗体。总之，这些方法表明，配体介导的Wnt/β-catenin途径的激活是启动胰腺癌所必需的。此外，他们确定Wnt信号传导对胰腺癌的进展也至关重要，这一发现具有潜在的治疗意义。
Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant PanIN lesions. Second, we addressed the specific role of ligandmediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Lastly, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches demonstrated that ligandmediated activation of the Wnt/β-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications.