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Updated: May 6, 2026
A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma
Winnie W Lo1, Jay S Wunder, Brendan C Dickson
1Department of Molecular Genetics, University of Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Background:
During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma.
Methods:
Small-molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small-molecule Smoothened (SMO) antagonist, IPI-926 (saridegib), also was examined in patient-derived xenograft models.
Results:
An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma-associated oncogene 2 (GLI2) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand-independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand-dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand-dependent Hedgehog signaling was identified. IPI-926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand-dependent models.
Conclusions:
The current results indicate that both ligand-dependent and ligand-independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI-926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma.
Insights
Dysregulated Hedgehog signaling, both ligand-dependent and independent, is implicated in osteosarcoma. Targeting this pathway, particularly with SMO antagonist IPI-926, shows potential for novel cancer therapeutics.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The Hedgehog signaling pathway is crucial for chondrocyte proliferation and differentiation during bone development.
- Dysregulation of the Hedgehog pathway is investigated as a potential therapeutic target in osteosarcoma.
Purpose of the Study:
- To investigate the mechanisms of Hedgehog pathway dysregulation in osteosarcoma.
- To evaluate the efficacy of Hedgehog pathway blockade as a therapeutic strategy for osteosarcoma.
Main Methods:
- Utilized small-molecule agonists and antagonists to modulate Hedgehog pathway components in osteosarcoma cell lines.
- Examined the efficacy of a Smoothened (SMO) antagonist, IPI-926 (saridegib), in patient-derived xenograft models.
- Assessed pathway activation through gene expression analysis of Hedgehog ligands and target genes.
Main Results:
- Identified an inverse correlation between glioma-associated oncogene 2 (GLI2) levels and pathway induction, suggesting ligand-independent activation in some osteosarcoma cells.
- Demonstrated that cells with high Indian hedgehog (IHH) expression were sensitive to both SMO and GLI inhibition, indicating ligand-dependent activation.
- Observed that IPI-926 inhibited tumor-stroma Hedgehog signaling and showed antitumor efficacy in ligand-dependent xenograft models.
Conclusions:
- Osteosarcoma exhibits both ligand-dependent and ligand-independent Hedgehog pathway dysregulation.
- This study is the first to report Hedgehog signaling crosstalk between osteosarcoma tumor and stroma.
- Hedgehog pathway inhibitors, like IPI-926, warrant further investigation as potential targeted therapies for osteosarcoma.
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