Pilot assessment of vascular endothelial growth factor receptors and trafficking pathways in recurrent and metastatic canine subcutaneous mast cell tumours.

Lucas Da Silva,Jennifer J Thompson,Robert A Foster,Carlos E Fonseca‐Alves,Renee L Amorim,Geoffrey A Wood,Brenda L Coomber

doi:10.1002/vms3.66

Abstract

Canine subcutaneous mast cell tumour (scMCT) shows less aggressive biological behaviour than cutaneous MCT. Vascular endothelial growth factor receptor 2 (VEGFR2) is expressed by neoplastic cells in canine scMCT, but the relevance of this signalling pathway for disease pathobiology is not clear. The objective of this study was to quantify VEGF‐A, VEGFR2, pVEGFR2, the VEGF co‐receptor Neuropilin 1 (NRP‐1) and the E3 ubiquitin protein ligase c‐Cbl in canine scMCT, and to evaluate their association with disease outcome. Immunohistochemical staining for biomarkers was quantified from 14 cases of canine scMCT using manual and computer‐assisted methods. Kaplan–Meier curves were generated for disease‐free survival (DFS) and compared using Mantel–Cox log‐rank analysis. Cases with high levels of neoplastic cell VEGFR2, pVEGFR2 or c‐CBL immunoreactivity had significantly reduced DFS. All cases displayed neoplastic cells positive for VEGF‐A, which was significantly associated with pVEGFR2 immunoreactivity. There were also significant positive correlations between VEGFR2 and pVEGFR2, and between c‐CBL and pVEGFR2 levels. This pilot study demonstrates the potential utility of these markers in a subset of scMCT in dogs.

Highlights

Mast cell tumours (MCTs), account for 7–21% of all canine skin cancer (Welle et al 2008) and there are subcutaneous and dermal types
We report that a subset of recurrent canine subcutaneous MCTs were heterogeneous in their expression of Vascular endothelial growth factor receptor 2 (VEGFR2), with membranous, cytoplasmic, or nuclear immunolocalization in neoplastic cells
Neoplastic cells from a variety of cancer types use VEGFR2 as an autocrine growth factor, and may employ a similar process to that observed in endothelial cells

Summary

Introduction

Mast cell tumours (MCTs), account for 7–21% of all canine skin cancer (Welle et al 2008) and there are subcutaneous and dermal ( called cutaneous) types. Activation of the receptor tyrosine kinase KIT plays a role in normal mast cell growth and development, as well as in malignant transformation (London et al 1999; Webster et al 2007; Warland & Dobson 2013). Studies with the c-KIT gene have indicated a key role in dermal MCT development and progression (London et al 1999; Jones et al 2004; Webster et al 2007; Warland & Dobson 2013; Patruno et al 2014). Its role in subcutaneous MCT is less well understood (Thompson et al 2011a, 2016)

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