Department of General, Visceral and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany.
Pancreas. 2012 Mar;41(2):222-9. doi: 10.1097/MPA.0b013e31822896dd.
Activation of the hedgehog signal transduction pathway, triggered by hedgehog binding to the transmembrane receptor patched 1 (PTCH1) or by mutations in the PTCH1 gene, plays an important role in the development of various tumors.
To investigate whether the Hedgehog signaling pathway is also active in human pancreatic adenocarcinomas, we determined the expression levels of the known Hedgehog target genes PTCH1 and GLI-1 in pancreatic tumors. To determine whether alterations in the PTCH1 gene are responsible for this pathway activation, we screened pancreatic carcinomas for mutations in PTCH. To investigate the contribution of hedgehog signaling to the tumorigenicity of pancreatic tumor cells, we blocked the Hedgehog pathway in cultured tumor cells and xenografts using the steroidal alkaloid cyclopamine and the small-molecule Hedgehog inhibitor Hh-Antag.
We identified single nucleotide polymorphisms (SNPs) within the PTCH1 gene but no somatic PTCH1 mutations. Pathway-blockage resulted in a significant dose-dependent reduction of tumor cell growth in vitro and in vivo. Moreover, combined treatment with cyclopamine and the conventional antimetabolite gemcitabine revealed a synergistic effect on the reduction of tumor growth in pancreatic adenocarcinoma xenografts.
Inhibition of Hedgehog signaling could be a promising approach for the treatment of pancreatic adenocarcinomas.
hedgehog 信号转导通路的激活，由 hedgehog 与跨膜受体 patched 1（PTCH1）结合或由 PTCH1 基因突变触发，在各种肿瘤的发展中起着重要作用。
为了研究 Hedgehog 信号通路是否也存在于人类胰腺腺癌中，我们测定了已知的 Hedgehog 靶基因 PTCH1 和 GLI-1 在胰腺肿瘤中的表达水平。为了确定 PTCH1 基因突变是否导致该通路的激活，我们筛选了胰腺腺癌中的 PTCH1 基因突变。为了研究 hedgehog 信号对胰腺肿瘤细胞致瘤性的贡献，我们使用甾体生物碱环巴胺和小分子 Hedgehog 抑制剂 Hh-Antag 在培养的肿瘤细胞和异种移植中阻断 Hedgehog 通路。
我们在 PTCH1 基因中发现了单核苷酸多态性（SNP），但没有体细胞 PTCH1 突变。通路阻断导致体外和体内肿瘤细胞生长呈显著的剂量依赖性减少。此外，环巴胺和常规抗代谢物吉西他滨联合治疗对胰腺腺癌异种移植瘤生长的抑制作用具有协同作用。
抑制 Hedgehog 信号可能是治疗胰腺腺癌的一种有前途的方法。
