Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis
Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis
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DOI：
10.1073/pnas.0813203106
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发表时间：
2009-03-17
影响因子：
11.1
通讯作者：
de Sauvage, Frederic J.
中科院分区：
文献类型：
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作者：
Tian, Hua;Callahan, Christopher A.;de Sauvage, Frederic J.
Hedgehog（Hh）通路与胰腺癌有关，但其作用仍有争议。为了描述能够响应Hh配体刺激的细胞群体，我们表达了Smoothened（SmoM 2）的致癌等位基因，以细胞自主激活小鼠胰腺中的Hh信号传导。令人惊讶的是，我们发现SmoM 2在上皮细胞中的表达不能激活该通路，并且对胰腺发育或肿瘤形成没有影响。相反，间充质中SmoM 2的激活导致Hh通路激活，表明只有肿瘤间质才有能力抑制Hh信号。使用Ptc-LacZ报告小鼠，我们表明，在各种小鼠胰腺癌模型中，Hh信号传导在表达Hh的肿瘤上皮周围的基质细胞中是活跃的。通过显微切割组织样品的定量RT-PCR证实了人胰腺癌和转移癌标本的肿瘤间质中Hh通路的激活。这些数据支持Hh介导的肿瘤发生的旁分泌模型，其中肿瘤细胞分泌Hh配体以诱导邻近基质中的促肿瘤Hh靶基因。
The Hedgehog (Hh) pathway has been implicated in pancreatic cancer but its role remains controversial. To delineate the cell populations able to respond to Hh ligand stimulation, we expressed an oncogenic allele of Smoothened (SmoM2) to cell autonomously activate Hh signaling in the mouse pancreas. Surprisingly, we found that expression of SmoM2 in epithelial cells was not able to activate the pathway and had no impact on pancreatic development or neoplasia. In contrast, activation of SmoM2 in the mesenchyme led to Hh pathway activation, indicating that only the tumor stroma is competent to transduce the Hh signal. Using a Ptc-LacZ reporter mouse, we show that Hh signaling is active in stromal cells surrounding Hh-expressing tumor epithelium in various mouse pancreatic cancer models. Activation of the Hh pathway in the tumor stroma of human pancreatic and metastatic cancer specimens was confirmed by quantitative RT-PCR of microdissected tissue samples. These data support a paracrine model of Hh-mediated tumorigenesis, in which tumor cells secrete Hh ligand to induce tumor-promoting Hh target genes in adjacent stroma.