**2.2. Proliferation of mast cells**

diseases has been identified, and mast cells are estimated as the most important target in medical treatment of allergy. Although malignancies of mast cell are uncommon disorders in humans, veterinary clinicians frequently encounter mast cell tumors (MCTs) in dogs and cats. The frequency of cutaneous MCTs has been reported to reach 20% of all tumors raised in the skin of dogs. Most of the malignant mast cells existed in a mass have granules in their cytosol, containing pruritogens, inflammatory factors, and various proteases (**Figure 1**). In this chapter, recent information on both basics in mast cell biology and clinical approaches

**Figure 1.** Typical histologic features of surgically removed canine MCTs stained with toluidine blue solution. A mass is consisted with numbers of differenced mast cells that show metachromasia. Connective tissues colored in light blue

Mast cell progenitors are differentiated from pluripotent hematopoietic stem cells in bone marrow. Being different from other granulocytes, mast cells are transported by blood stream to peripheral tissues as mononuclear immature cells without granules in their cytosol [1]. In peripheral tissues, mast cell precursors complete their differentiation and distribution being ready for the host defense (**Figure 2**). According to characters of microenvironment of each peripheral tissue, final types of mature mast cells are altered. In the skin, they differenced into connective tissue‐type mast cells that include heparin proteoglycan and abundant granules in cytosol. Various kinds of proteases and chemical mediators are in granules of connective tissue‐type mast cells by which sever inflammation is induced when they are released at the affected sites. Heparin proteoglycan‐positive mast cells can be detected with not only tolu‐ idine blue but also berberine sulfate and safranin O. In contrast, mast cells that reach to and invade in mucosal tissues differentiate into mucosal‐type mast cells. Mucosal‐type mast cells include chondroitin sulfate as proteoglycan, and cytosolic granules are very few. Chondroitin

for canine MCTs is outlined.

78 Canine Medicine - Recent Topics and Advanced Research

can be identified.

**2.1. Differentiation of mast cells**

**2. Differentiation and proliferation of mast cells**

Factors that involve in mast cell proliferation are not fully understood. In mice, mast cells proliferate in response to interleukin (IL)‐3, IL‐9, and stem cell factor (SCF). Both IL‐6 and SCF are essential factors for proliferation and survival of human mast cells. Though less is known regarding development of canine mast cells, SCF has been reported to induce proliferation and survival, as well as migration and activation of canine mast cells [2, 3]. The IL dependency varies according to a species from which mast cells are derived. However, SCF is the most important factor for proliferation, differentiation, and survival of mast cells in humans and animals. SCF is the ligand for KIT receptors expressed on cell surface of mast cells. Since mast cells are differentiated from KIT‐positive cell lineage and KIT is retained on the surface of not only immature precursors but also mature mast cells, influence of SCF on mast cells must be crucial for their proliferation and differentiation. In fact, gain‐of‐function mutations in the *KIT* gene have been identified in mast cells with factor‐independent tumorigenic proliferation in humans, rodents, and dogs. Meanwhile, over 50% of canine MCTs and most of the feline MCTs show *KIT*gen mutation‐independent development. Recent observations have revealed that not only SCF but also other cytokines and growth factors including epidermal growth factor, vascular endothelial growth factor, and nerve growth factor may facilitate prolifera‐ tion, differentiation, and survival of mast cells. Unfortunately, investigation on development of canine mast cells has been insufficient.
