**3. Cellular biology of mast cells**

## **3.1. Inflammatory responses of mast cells**

Mast cells play key roles for inflammatory responses through degranulation and cyto‐ kine/chemokine production and secretion [4]. However, proteases, chemical mediators, and cytokines included in mast cell granules are different according to types of mast cells. Heterogeneity among mast cells is important to precisely understand the pathophysiolog‐ ical roles of mast cells in each tissue. Connective tissue‐type mast cells include chemical mediators such as histamine that has strong biologic activity on nerve fibers and blood ves‐ sels. Histamine is known as a pruritogen that induces itch sensation resulting in scratching behavior in humans and animals. Vasoactive effects of histamine initiate inflammation at the affected sites. Scratching behavior stimulates physical degranulation of mast cells leading to exacerbation of swelling and inflammation. Exact roles of mucosal‐type mast cells are not clearly demonstrated. Since numbers of mucosal‐type mast cells are increased in the gut with parasite infection, roles in host reaction against parasite exclusion have been proposed. However, factors and mechanisms that involve in antiparasite effects of mucosal‐type mast cells are not fully explored.

#### **3.2. Heterogeneity of MCTs**

Most MCTs in dogs are consisted with histamine‐rich connective tissue‐type mast cells. Steps responsible for transformation of mast cells are summarized in **Figure 3**. Since recep‐ tors for histamine are expressed in mucosal cells of the stomach, progression of MCTs has been suggested to induce gastric ulcer and serious damage on gastric function. However, the exact and direct association of MCTs with gastric ulcer remains unclear [5, 6]. Connective tissue‐type mast cells contain tryptase and chymase that possess broad protease activities. Particularly, tryptase has been reported to regulate neovascularization. Connective tissue‐ type mast cells can also produce growth factors for vascular endothelial cells; therefore,

**Figure 3.** Malignant transformation of mast cells. For tumor formation, mast cell proliferation must be promoted by activation of ligand‐independent activation on growth factor receptors. Also, acquisition of resistance against apoptosis pathways and invasive characters may facilitate malignant expansion of MCTs.

most of the MCTs must be rich with blood vessels. Moreover, dogs with serious MCTs show deficiency in blood coagulation possibly because connective tissue‐type mast cells have plenty of heparin in their cytosol. Canine mast cells have unique chymase whose name is dog mast cell protease‐3; however, its specific role has not been fully understood [7]. A mass formed with mucosal‐type mast cells rarely develops in the gastrointestinal tract, which induces dysfunction of the gut. Influence of mucosal mast cell tumor on other organs except the gut has not been well documented.
