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Receptor Tyrosine Kinase Expression Profiles in Canine Cutaneous and Subcutaneous Mast Cell Tumors
J J Thompson1, J A Morrison1, D L Pearl1
1University of Guelph, Ontario Veterinary College, Guelph, Canada.
Abstract:
The receptor tyrosine kinase (RTK) KIT is a major focus of current research into canine mast cell tumors (MCTs). Little is known about the role of other RTKs, such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). These RTKs are dysregulated in many human and animal cancers and are key regulators of tumor angiogenesis. The aims of this study were to assess the expression and activation (phosphorylation) status of KIT, VEGFR2, and PDGFR (α and β) in canine MCTs and to examine associations with various clinical outcomes. c-KITmutational status and KIT cellular localization pattern were also evaluated for these tumors. Twenty-seven MCTs, consisting of 5 subcutaneous and 22 cutaneous tumors, from 25 dogs were evaluated. MCT biopsies, cultured mast cells, and skin from the surgical margin were analyzed through Western blotting. MCT biopsies were also used for KIT immunohistochemical labeling and polymerase chain reaction for c-KITmutational analysis. MCT had heterogeneous expression profiles for all 3 RTKs, which varied in intensity and activation status. Statistical analyses showed phosphorylated KIT, VEGFR2, and KIT cellular localization to be predictive of decreased survival time, disease-free interval, and increased metastatic rate. Expression of VEGFR2 and KIT diffuse cytoplasmic labeling were also significantly associated with increased rate of local recurrence. The results of the study show that phosphorylated KIT, KIT, VEGFR2, and PDGFRβ, in addition to KIT localization, may be valuable prognostic determinants in MCTs and should be further studied to improve diagnostic and therapeutic modalities.
Insights
Phosphorylated KIT, VEGFR2, and KIT localization predict poorer outcomes in canine mast cell tumors (MCTs). These receptor tyrosine kinases (RTKs) may serve as valuable prognostic markers for MCTs.
Area of Science:
- Veterinary oncology
- Molecular biology
- Cancer research
Background:
- Canine mast cell tumors (MCTs) are frequently studied, with a focus on the receptor tyrosine kinase (RTK) KIT.
- The roles of other RTKs, like vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), in canine MCTs are less understood.
- These RTKs are implicated in human and animal cancers and are crucial for tumor angiogenesis.
Purpose of the Study:
- To evaluate the expression and phosphorylation status of KIT, VEGFR2, and PDGFR (α and β) in canine MCTs.
- To investigate the association of these RTKs with clinical outcomes, including survival, disease-free interval, metastasis, and local recurrence.
- To analyze c-KIT mutational status and KIT cellular localization patterns in canine MCTs.
Main Methods:
- Western blotting of MCT biopsies, cultured mast cells, and surgical margin skin.
- Immunohistochemical labeling for KIT on MCT biopsies.
- Polymerase chain reaction for c-KIT mutational analysis.
- Evaluation of 27 MCTs from 25 dogs.
Main Results:
- Canine MCTs exhibited heterogeneous expression and activation profiles for KIT, VEGFR2, and PDGFRs.
- Phosphorylated KIT, VEGFR2, and KIT cellular localization were predictive of decreased survival time and disease-free interval.
- Increased metastatic rates were associated with phosphorylated KIT, VEGFR2, and KIT cellular localization.
- VEGFR2 expression and diffuse cytoplasmic KIT labeling correlated with a higher rate of local recurrence.
Conclusions:
- Phosphorylated KIT, VEGFR2, PDGFRβ, and KIT localization are potential prognostic indicators for canine MCTs.
- These findings suggest these RTKs could be valuable in improving diagnostic and therapeutic strategies for canine MCTs.
- Further research is warranted to fully elucidate the prognostic significance of these RTKs in canine MCTs.
