Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.
Carcinogenesis. 2011 Apr;32(4):445-51. doi: 10.1093/carcin/bgq280. Epub 2010 Dec 24.
To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis.
PubMed search (2000-2010) and literature based references.
Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment.
Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.
系统综述 hedgehog 信号通路在胰腺癌发生中的作用。
检索 PubMed（2000-2010 年）和基于文献的参考文献。
首先，2009 年一项对胰腺癌的遗传分析发现，包括 hedgehog 在内的 12 种核心细胞信号通路在 67-100%的病例中发生了遗传改变。其次，用环巴胺（hedgehog 信号通路成分 smoothened 的天然拮抗剂）进行的体外和体内治疗研究表明，抑制 hedgehog 可以阻断胰腺癌的转移。第三，实验证据表明， sonic hedgehog（Shh）与胰腺癌中的间质增生有关。这一点很重要，因为靶向 Shh 途径可能有助于化疗药物的传递，因为胰腺癌往往有致密的纤维性基质，从外部压迫肿瘤血管，导致肿瘤内循环低灌注。局部晚期胰腺癌患者可能从 smoothened 拮抗剂治疗中获益最大。第四，研究发现 hedgehog 通过配体依赖性激活发生在胰腺癌的肿瘤基质微环境中，这是一种对肿瘤发生的旁分泌效应。最后，在胰腺癌中，具有 CD44+CD24+ESA+免疫表型的细胞选择富含癌症起始干细胞的群体。与正常胰腺上皮细胞相比，CD44+CD24+ESA+细胞中的 Shh 增加了 46 倍。破坏胰腺癌起始干细胞的药物是癌症治疗的一种潜在新策略。
异常的 hedgehog 信号发生在胰腺癌的发生中，靶向跨膜受体 smoothened 的治疗方法可以阻断 hedgehog 信号，并可能改善胰腺癌患者的预后。
