Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis
Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis
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DOI：
10.1038/nature02009
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发表时间：
2003-10-23
期刊：
影响因子：
64.8
通讯作者：
Hebrok, M
中科院分区：
文献类型：
--
作者：
Thayer, SP;di Magliano, MP;Hebrok, M
刺猬信号通路——胚胎胰腺发育过程中的一个重要通路，其调节异常与多种癌症有关——可能也是人类胰腺癌的一个重要介导因子（1 - 8）。在此我们报道，音猬因子（一种分泌型刺猬配体）在胰腺腺癌及其前体病变：胰腺上皮内瘤变（PanIN）中异常表达。Pdx - Shh小鼠（其中Shh在胰腺内胚层中错误表达）的胰腺形成异常的管状结构，这是人类PanIN - 1和 - 2的表型模拟。此外，这些类似PanIN的病变也包含K - ras突变且过表达HER - 2/neu，这些基因突变在人类胰腺癌进展的早期被发现。再者，刺猬信号通路在从原发性和转移性胰腺腺癌建立的细胞系中仍然活跃。值得注意的是，环巴胺对刺猬信号通路的抑制在体外和体内都诱导了一部分胰腺癌细胞系的凋亡并阻断了其增殖。这些数据表明该通路可能在这种癌症的发生中具有早期关键作用，并且刺猬信号通路的维持对于异常增殖和肿瘤发生是重要的。
Hedgehog signalling-an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer-may also be an important mediator in human pancreatic carcinoma(1-8). Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.