Abstract
Mast cell tumors (MCTs) are one of the most common cutaneous malignancies in dogs. Previous studies have reported expression of mast cell–specific proteases chymase and tryptase in canine cutaneous MCTs and in connective tissue and mucosal mast cells. In humans and rodents, mast cells express an additional specific protease, carboxypeptidase A3 (CPA3). In this article, we describe CPA3 immunoreactivity in connective tissue, visceral, mucosal, and neoplastic mast cells in dogs. Positive immunolabeling for CPA3 was observed in nonneoplastic mast cells in 20/20 formalin-fixed paraffin-embedded normal tissues (skin, liver, spleen, intestine), and in 63/63 MCTs irrespective of their histological grade. CPA3 protein expression was comparable to that of c-kit in both the nonneoplastic and neoplastic mast cells. Three distinct labeling patterns (membranous, diffuse, and focal cytoplasmic) were observed for CPA3 in MCTs. The focal cytoplasmic labeling pattern was associated with high-grade MCTs staged with the Kiupel 2-tier grading criteria. We propose CPA3 as a novel immunohistochemical marker for canine mast cells in health and disease.
Highlights
Mast cell tumors (MCTs) are one of the most common cutaneous malignancies in dogs
carboxypeptidase A3 (CPA3) is encoded by a single gene (CPA3) spanning over 32 kb and in humans and mice is located on chromosome 3 and in rats on chromosome 2.34 In dog the CPA3 gene is located on chromosome 23
Results the CPA3 antibody marked one strong band from the MCTs and human mast cell homogenates but no signal was detected in muscle tissue
Summary
Mast cell tumors (MCTs) are one of the most common cutaneous malignancies in dogs. Previous studies have reported expression of mast cell–specific proteases chymase and tryptase in canine cutaneous MCTs and in connective tissue and mucosal mast cells. CPA3 expression is considered to be restricted to mast cell secretory granules, with the exception of reported CPA3 expression on RNA level in basophils of patients with allergic conditions.[25,37] CPA3 belongs to the peptidase family M14 (carboxypeptidase A family), and to pancreatic CPA, it is an exopeptidase cleaving Cterminal amino acid residues from proteins and peptides.[32] CPA3 in humans is typically co-expressed in mast cells expressing both tryptase and chymase[33] but is expressed in only tryptase-positive mast cells associated with allergic diseases.[1,7] In mice and rats, connective tissue mast cells express all 3 proteases (chymase, tryptase, and CPA3), while mucosal mast cells only express chymase.[2,33] CPA3 in mast cells is stored in secretory granules and is tightly bound to negatively charged proteoglycans, especially heparin.[33] CPA3 appears to be essential for secretory granule homeostasis. A variety of functional substrates for CPA3 have been recognized in vitro, including apolipoprotein B,23 neurotensin,[14,35] and angiotensin I.13 The physiological relevance of these functions remains unknown
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