Pharmacological Inhibition of Sonic Hedgehog Signaling Suppresses Tumor Development in a Murine Model of Intrahepatic Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCC) is the second most primary liver cancer with an aggressive biological behavior, and its incidence increases steadily. An aberrant up-regulation of the sonic hedgehog signaling pathway has been reported in a variety of hepatic diseases including hepatic inflammation, fibrosis, as well as cancer. In this study, we determined the effect of a sonic hedgehog inhibitor, vismodegib, on the development of CCC. Through database analyses, we found sonic hedgehog signaling was up-regulated in human CCC, based on overexpression of its target genes, GLI1 and GLI2. Further, human CCC cells were highly sensitive to the treatment with vismodegib in vitro. Based on the data, we investigated the in vivo anti-cancer efficacy of vismodegib in CCC employing a murine model of CCC developed by hydrodynamic tail vein injection method. In the murine model, CCC induced by constitutively active forms of TAZ and PI3K exhibited up-regulated sonic hedgehog signaling. Treatment of vismodegib significantly suppressed tumor development in the murine CCC model, based on comparison of gross morphologies and liver weight/body weight. It is expected that pharmacological inhibition of sonic hedgehog signaling would be an effective molecular target therapy for CCC.

Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma‐associated oncogene homolog 1 and chemokine CCL2

“…Aberrant activation of the Hh signaling pathway has been shown to positively regulate tumorigenesis in human cancers, including CCA 42,43 . Inhibitors of the Hh pathway also been reported to suppress the development of CCA 44 . After collecting the supernatant from CCA cells and exploring the changes in its composition using a cytokine array, we observed that the regulation of CCL2 by EHF was particularly significant.…”

“… 42 , 43 Inhibitors of the Hh pathway also been reported to suppress the development of CCA. 44 After collecting the supernatant from CCA cells and exploring the changes in its composition using a cytokine array, we observed that the regulation of CCL2 by EHF was particularly significant. CCL2, also known as MCP‐1, recruits macrophages from the bloodstream to the microenvironment by binding to CCR2 on the macrophages.…”

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

“…Itraconazole in cholangiocarcinoma: 5-LO and its leukotriene products contribute to the growth of cholangiocarcinoma [207][208][209]. Hh signaling is a core growth-driving element in cholangiocarcinoma, and prominently so in the stem subset [210][211][212][213][214][215]. 5-LO is one of the drivers of both myeloid-derived suppressor cell immunosuppression and stemness in cholangiocarcinoma [216].…”