Hedgehog Pathway Inhibition Reduces Liver Fibrosis and Cancer in Mice
Author Information
Author(s): Philips George M., Chan Isaac S., Swiderska Marzena, Schroder Vanessa T., Guy Cynthia, Karaca Gamze F., Moylan Cynthia, Venkatraman Talaignair, Feuerlein Sebastian, Syn Wing-Kin, Jung Youngmi, Witek Rafal P., Choi Steve, Michelotti Gregory A., Rangwala Fatima, Merkle Elmar, Lascola Christopher, Diehl Anna Mae
Primary Institution: Duke University Medical Center
Hypothesis
Activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and hepatocellular carcinoma (HCC).
Conclusion
Inhibiting Hh signaling safely reverses liver fibrosis and reduces tumor burden in mice with advanced liver disease.
Supporting Evidence
- Treatment with GDC-0449 significantly inhibited hepatic Hh activity.
- GDC-0449 reduced liver fibrosis and promoted regression of intra-hepatic HCCs.
- Mice treated with GDC-0449 showed decreased expression of pro-fibrogenic factors.
- Histological analysis showed significant regression of primary and metastatic HCC.
- Accumulation of Hh-responsive cells was observed in Mdr2−/− mice.
- Serum levels of AST and ALT were consistently higher in Mdr2−/− mice than controls.
- GDC-0449 treatment was well tolerated with no significant increase in mortality.
- Immunohistochemical analysis showed decreased progenitor markers in treated mice.
Takeaway
This study shows that blocking a specific pathway in mice can help shrink liver tumors and reduce liver damage.
Methodology
Mice were treated with the Hh signaling antagonist GDC-0449, and effects on liver fibrosis and tumor burden were assessed using various techniques including immunohistochemistry and MRI.
Limitations
The study was conducted in a mouse model, which may not fully replicate human conditions.
Participant Demographics
Mdr2−/− mice and age-matched wild type controls.
Statistical Information
P-Value
p<0.05
Statistical Significance
p<0.05
Digital Object Identifier (DOI)
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