Related Experiment Video
Updated: May 25, 2026
Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models
Published on: May 17, 2024
Elevated expression of IRS2 in the progression from neurofibroma to malignant peripheral nerve sheath tumor
Christiana M Shaw1, Stephen R Grobmyer, Deniz A Ucar
1Division of Surgical Oncology, Department of Surgery, University of Florida College of Medicine, 1600 SW Archer Road, P.O. Box 100109, Gainesville, FL 32610-0109, USA.
Background/Aim:
Novel drugs to inhibit insulin receptor substrate (IRS) and focal adhesion kinase (FAK) pathways are emerging and will be sarcoma subtype-specific. As a result, defining expression of proteins in these pathways; in select tumors is important in order to formulate therapeutic approaches to malignant peripheral nerve sheath tumors (MPNSTs).
Materials And Methods:
Fifty-three patients with MPNSTs or neurofibromas (NFs), who were treated at our institution from 1994-2005, were identified. Tumor immonohistochemical staining for multiple key oncogenic proteins was performed and the sections were evaluated in a blinded fashion by a sarcoma pathologist (JDR) and correlated with survival.
Results:
A total of 88% of MPNSTs expressed IRS2 compared to 48% of NFs. IRS2 expression was significantly higher in MPNSTs than in NFs (p=0.0009). However, IRS1 expression was significantly higher in NFs than MPNSTs (p=0.03). A trend toward an increase in FAK expression in MPNSTs was seen (p=0.11). No difference was seen between MPNSTs and NFs when evaluating the expression of phosphorylated focal adhesions kinase, vascular endothelial growth factor 3, insulin like growth factor receptor 1, neurofibromatosis 1. Univariate analysis of survival indicated that IRS2 and NF1 protein expression, patient age and tumor size were significantly correlated with outcome.
Conclusion:
MPNSTs have an elevated level of IRS2 and FAK and lower level of IRS1 compared to NFs These data demonstrate for the first time that IRS2 and FAK may be associated with malignant transformation of neurofibromas.
Insights
Malignant peripheral nerve sheath tumors (MPNSTs) show higher insulin receptor substrate 2 (IRS2) and focal adhesion kinase (FAK) levels than neurofibromas (NFs). These findings suggest IRS2 and FAK may drive MPNST development.
Area of Science:
- Oncology
- Molecular Biology
- Sarcoma Research
Background:
- Novel targeted therapies for sarcomas are emerging, requiring subtype-specific protein expression data.
- Understanding the molecular pathways in malignant peripheral nerve sheath tumors (MPNSTs) is crucial for developing effective treatments.
Purpose of the Study:
- To define the expression of key proteins in the insulin receptor substrate (IRS) and focal adhesion kinase (FAK) pathways in MPNSTs and neurofibromas (NFs).
- To correlate protein expression with patient survival outcomes.
Main Methods:
- Immunohistochemical staining was performed on 53 MPNST and NF tumor samples.
- Stained sections were evaluated by a sarcoma pathologist in a blinded manner.
- Protein expression levels were correlated with patient survival data.
Main Results:
- MPNSTs exhibited significantly higher IRS2 expression (88%) compared to NFs (48%) (p=0.0009).
- IRS1 expression was significantly higher in NFs than in MPNSTs (p=0.03).
- A trend towards increased FAK expression was observed in MPNSTs (p=0.11).
- IRS2 and NF1 protein expression, patient age, and tumor size correlated significantly with survival.
Conclusions:
- MPNSTs demonstrate elevated IRS2 and FAK levels, and lower IRS1 levels compared to NFs.
- These data suggest that IRS2 and FAK may play a role in the malignant transformation of neurofibromas into MPNSTs.
