The tissue mast cell is recognized for its role in a number of inflammatory events. Rodent mast cells also have been demonstrated to kill tumor cells in vitro, and studies in mice suggest that mast cells may have an important tumoricidal role in vivo. To date, however, little is known about the specificity of mast cell-tumor target recognition in killing, the kinetics of the cytolytic process, the mechanisms responsible for mast cell mediated cytotoxicity, or the forces that alter this tumoricidal activity. Although studies exploring the in vivo antitumor role for the mast cell have been initiated, further experiments are necessary. Therefore, an in-depth, systematic investigation of mast cell-mediated cytotoxicity is proposed. Both rat serosal and human cutaneous mast cells will be employed for these in vitro studies because of morphologic and functional differences. Specifically, the events that lead to mast cell-mediated cytotoxicity will be investigated. Tumor cell lines and freshly-isolated human skin tumors susceptible to mast cell killing will be established and used for future studies. The kinetics of mast cell binding to and lysis of targets will be assessed. The importance of time, temperature, divalent cation concentrations, and mast cell-tumor target conjugate formation will be explored. The role of different cell surface receptors in the cytotoxic process and potential mediators of mast cell cytolysis including: cytokines (TNF, LT, cytolysins/perforins), proteolytic enzymes, soluble proteins, oxygen intermediates, arachidonic acid metabolites, and mastoplasts will be investigated. The effects of glucocorticoids, endotoxin, lymphokines and UV light on mast cell killing will be examined. Alterations in mast cell and tumor target morphology during in vitro cytotoxicity will be assessed by electron microscopy and compared to mast cell skin tumor morphologic changes in vivo. Mast cell-mediated cytostasis against lytic-resistant targets will be characterized functionally and morphologically. The in vivo relevance of the mast cell tumoricidal process will be extended by transplanting mast cells in the skin of mast cell-deficient mice and monitoring dermal tumor growth. Taken together, these studies should enhance our understanding of the mechanisms responsible for mast cell killing of tumors, provide new insight into the similarities and differences between rat and human mast cell-mediated cytotoxicity, and potentially extend our knowledge of the mast cell's role in host defense mechanisms.
| Chan, I J; Tharp, M D (1994) Rat mast cell protease I alters cell metabolism. J Invest Dermatol 103:84-7 |
| Tharp, M D; Kasper, C; Thiele, D et al. (1989) Studies of connective tissue mast cell-mediated cytotoxicity. J Invest Dermatol 93:423-8 |
