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Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

机译：刺猬是胰腺癌肿瘤发生的早期和晚期介体

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摘要

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. 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-2eu, 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 rant proliferation and tumorigenesis.
机译：刺猬信号是胚胎胰腺发育过程中的重要途径，其调控失调与多种形式的癌症有关，也可能是人类胰腺癌的重要介体。在这里，我们报告声波刺猬，一种分泌的刺猬配体，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小鼠的胰腺（其中Shh在胰腺内胚层中错误表达）的胰腺发育异常的肾小管结构，即人PanIN-1和-2的表型。此外，这些PanIN样病变还包含K-ras突变和过表达HER-2 / neu，这是在人类胰腺癌进展早期发现的基因突变。此外，刺猬信号在从原发性和转移性胰腺腺癌建立的细胞系中保持活跃。值得注意的是，在体外和体内，环巴胺对刺猬蛋白信号通路的抑制诱导了胰腺癌细胞系子集中的凋亡并阻断了增殖。这些数据表明，该途径可能在这种癌症的发生中具有早期和关键作用，并且刺猬信号的维持对于蚂蚁增殖和肿瘤发生很重要。

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