Published in:Journal of Hepato-Biliary-Pancreatic Sciences
Language:
English
DOI:
10.1002/jhbp.107
ISSN:
1868-6974;
1868-6982
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Innovative treatment concepts targeting essential signaling pathways may offer new chances for patients suffering from cholangiocarcinoma (<jats:styled-content style="fixed-case">CCC</jats:styled-content>). For that, we performed a systematic molecular genetic analysis concerning the <jats:styled-content style="fixed-case">H</jats:styled-content>edgehog activity in human <jats:styled-content style="fixed-case">CCC</jats:styled-content> samples and analyzed the effect of <jats:styled-content style="fixed-case">Hh</jats:styled-content> inhibition on <jats:styled-content style="fixed-case">CCC</jats:styled-content> cells <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Activation of the <jats:styled-content style="fixed-case">Hh</jats:styled-content> pathway was analyzed in 50 human <jats:styled-content style="fixed-case">CCC</jats:styled-content> samples using quantitative polymerase chain reaction (q<jats:styled-content style="fixed-case">PCR</jats:styled-content>). The efficacy of <jats:styled-content style="fixed-case">Hh</jats:styled-content> inhibition using cyclopamine and <jats:styled-content style="fixed-case">BMS</jats:styled-content>‐833923 was evaluated <jats:italic>in vitro</jats:italic>. In addition, the effect of <jats:styled-content style="fixed-case">BMS</jats:styled-content>‐833923, alone or in combination with gemcitabine, was analyzed <jats:italic>in vivo</jats:italic> in a murine subcutaneous xenograft model.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Expression analysis revealed a significant activation of the <jats:styled-content style="fixed-case">Hh</jats:styled-content>‐signaling pathway in nearly 50% of <jats:styled-content style="fixed-case">CCC</jats:styled-content>s. <jats:styled-content style="fixed-case">Hh</jats:styled-content> inhibition resulted in a significant decrease in cell proliferation of <jats:styled-content style="fixed-case">CCC</jats:styled-content> cells. Moreover, a distinct inhibition of tumor growth could be seen as a result of a combined therapy with <jats:styled-content style="fixed-case">BMS</jats:styled-content>‐833923 and gemcitabine in <jats:styled-content style="fixed-case">CCC</jats:styled-content> xenografts.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The results of our study suggest that the <jats:styled-content style="fixed-case">Hh</jats:styled-content> pathway plays a relevant role at least in a subset of human <jats:styled-content style="fixed-case">CCC</jats:styled-content>. Inhibition of this pathway may represent a possible treatment option for <jats:styled-content style="fixed-case">CCC</jats:styled-content> patients in which the <jats:styled-content style="fixed-case">Hh</jats:styled-content> pathway is activated.</jats:p></jats:sec>