C-Kit expression, angiogenesis, and grading in canine mast cell tumour: a unique model to study c-Kit driven human malignancies.

Rosa Patruno,Patrizia Nardulli,Domenico Ribatti,Ilaria Marech,Cosmo Damiano Gadaleta,Michele Ammendola,Rosa Angela Rubini,Claudia Gadaleta,Nicola Zizzo,Marcello Introna,Gennaro Capriuolo,Girolamo Ranieri

doi:10.1155/2014/730246

Abstract

Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well- (G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic- and predominantly focal paranuclear- (Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cell membrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans.

Highlights

The c-Kit is a protooncogene that encodes for c-Kit receptor (c-KitR), a type III tyrosine kinase protein that is the receptor for stem cell factor (SCF), a cytokine regulating important mast cell (MC) functions, such as growth, differentiation, proliferation, and degranulation [1, 2]
It has been demonstrated that human and canine MCs play an important role in tumour angiogenesis by means of angiogenic cytokines such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), fibroblast growth factor-2 (FGF), and tryptase stored in their cytoplasmic secretory granules [10,11,12]
No significant difference was found between G1 and G2 cutaneous mast cell tumour (CMCT) subgroups as concerns microvascular density (MVD), MCGD, and MCDD (Table 1)

Summary

Introduction

The c-Kit is a protooncogene that encodes for c-Kit receptor (c-KitR), a type III tyrosine kinase protein that is the receptor for stem cell factor (SCF), a cytokine regulating important mast cell (MC) functions, such as growth, differentiation, proliferation, and degranulation [1, 2]. The c-KitR consists of an extracellular domain of 5 immunoglobulin-like folds and an intracellular kinase domain separated by transmembrane and juxtamembrane domains [3]. It is expressed by MCs and their progenitors, by germ cells, and by Cajal interstitial cells [4]. The main effect of these c-Kit aberrations results in a constitutive activation of c-KitR. They seem to be implicated in both the development and the progression of CMCT that is a very common cutaneous tumour in dog [8]. A novel tyrosine kinase inhibitor, named masitinib, that targets c-KitR has been developed to treat CMCT, with the aim of translating this approach in human clinical trials [13,14,15,16]

Methods

Results

Conclusion