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

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.

SUBMITTER: Patruno R

PROVIDER: S-EPMC4036613 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Patruno Rosa R Marech Ilaria I Zizzo Nicola N Ammendola Michele M Nardulli Patrizia P Gadaleta Claudia C Introna Marcello M Capriuolo Gennaro G Rubini Rosa Angela RA Ribatti Domenico D Gadaleta Cosmo Damiano CD Ranieri Girolamo G Ranieri Girolamo G

BioMed research international 20140512

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 cel ...[more]

PMID: 24900982

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Project description:Canine mast cell tumour proliferation depends to a large extent on the activity of KIT, a tyrosine kinase receptor. Inhibitors of the KIT tyrosine kinase have recently been introduced and successfully applied as a therapeutic agent for this tumour type. However, little is known on the downstream target genes of this signalling pathway and molecular changes after inhibition. Transcriptome analysis of the canine mast cell tumour cell line C2 treated for up to 72 hours with the tyrosine kinase inhibitor masitinib identified significant changes in the expression levels of approximately 3500 genes representing 16% of the canine genome. Approximately 40% of these genes had increased mRNA expression levels including genes associated with the pro-proliferative pathways of B- and T-cell receptors, chemokine receptors, steroid hormone receptors and EPO-, RAS and MAP kinase signalling. Proteome analysis of C2 cells treated for 72 hours identified 24 proteins with changed expression levels, most of which being involved in gene transcription, e.g. EIA3, EIA4, TARDBP, protein folding, e.g. HSP90, UCHL3, PDIA3 and protection from oxidative stress, GSTT3, SELENBP1. Transcriptome and proteome analysis of neoplastic canine mast cells treated with masitinib confirmed the strong important and complex role of KIT in these cells. Approximately 16% of the total canine genome and thus the majority of the active genes were significantly transcriptionally regulated. Most of these changes were associated with reduced proliferation and metabolism of treated cells. Interestingly, several pro-proliferative pathways were up-regulated which may represent attempts of masitinib treated cells to activate alternative pro-proliferative pathways. These pathways may contain hypothetical targets for a combination therapy with masitinib to further improve its therapeutic effect. The present study aimed at identifying the transcriptional and translational responses of neoplastic canine mast cells to the tyrosine kinase inhibitor masitinib. To this end, C2 cells, a cell line with a tandem duplication in the juxtamembrane unit and thus constitutively activated KIT, were treated with masitinib and changes in the global mRNA and protein expression levels were characterized.

Dataset Information

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

Publications

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

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