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Published on: October 27, 2014
No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone
Elisabeth F P Peterse1, Arjen H G Cleven1, Yvonne De Jong1
1Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Background:
Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study.
Methods:
Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines.
Results:
Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the same tumour, suggesting that in vitro culturing upregulates IGF1R expression.
Conclusions:
The results from this study indicate that the IGF pathway is not essential for chondrosarcoma growth, migration or chemoresistance. Furthermore, IGF1R is only minimally expressed in chondrosarcoma primary tumours. Therefore, the IGF pathway is not expected to be an effective therapeutic target for chondrosarcoma of bone.
Insights
The insulin-like growth factor (IGF) pathway is not essential for chondrosarcoma growth or chemoresistance. Minimal IGF pathway expression in primary tumors suggests it is not an effective therapeutic target for bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chondrosarcoma is a bone tumor lacking effective systemic treatments.
- The role of the insulin-like growth factor (IGF) pathway in chondrosarcoma requires further investigation for potential therapeutic targeting.
Purpose of the Study:
- To explore the role of the IGF pathway in chondrosarcoma.
- To determine if the IGF pathway can be a therapeutic target for chondrosarcoma.
Main Methods:
- Assessed IGF1R signaling mediators and IRS1 phosphorylation in chondrosarcoma cell lines using qRT-PCR and western blot.
- Treated cell lines with an IGF1R/IR dual inhibitor (OSI-906) and assessed proliferation and migration.
- Evaluated combination therapy with doxorubicin and OSI-906.
- Determined IGF1R expression in primary tumors and cell lines via immunohistochemistry.
Main Results:
- IGF1R signaling mediators were heterogeneously expressed, with active signaling in a subset of cell lines.
- Inhibition of IGF1R signaling affected downstream Akt but not MAPK or S6 activity.
- IGF1R/IR inhibitors did not impact chondrosarcoma cell proliferation or migration, even with doxorubicin combination.
- Primary tumors showed minimal IGF1R expression compared to cell lines, suggesting in vitro upregulation.
Conclusions:
- The IGF pathway is not essential for chondrosarcoma growth, migration, or chemoresistance.
- IGF1R is minimally expressed in primary chondrosarcoma tumors.
- The IGF pathway is unlikely to be an effective therapeutic target for chondrosarcoma of bone.
