Mast cell-mediated tumor-cell cytotoxicity. Role of the peroxidase system.

Abstract

Mast cells have been demonstrated in increased numbers in certain neoplasms in humans (1-3) and in both spontaneous tumors and those induced by carcinogenic agents in animals (4, 5). Eosinophils are often closely associated with mast cells in inflammatory reactions, and these cells also are present in increased numbers in some neoplasms (6). The role of these inflammatory cells in the host defense against tumors is unknown.A number of distinct peroxidases exist in mammalian tissues which differ in primary structure and in their heme prosthetic group. When combined with H202 and a halide, peroxidases are toxic to a variety of targets including tumor cells. Peroxidases shown to have tumoricidal activity in vitro include the milk peroxidase (lactoperoxidase) (7), the neutrophil (and monocyte) peroxidase (myeloperoxidase) (8), and the eosinophil peroxidase (EPO) x (9). Mast cell granules (MCG) contain a small amount of peroxidase activity (10), and this activity is considerably increased by the firm binding of the positively charged EPO to the surface of the negatively charged MCG (11). H202 at relatively high concentrations can induce mast cell degranulation (12, 13). When the H202 concentration is lowered to a level where it is ineffective alone, noncytotoxic mast cell secretion is initiated on the supplementation of the H202 with EPO and a halide (14). We report here that mast cells are toxic to a line of mouse aseites lymphoma cells when combined with H202 and a halide. The H202 initiates mast cell secretion; the released granules with their endogenous peroxidase are toxic to the tumor cells in the presence of H202 and a halide. In addition, the binding of EPO to the MCG greatly potentiates their tumoricidal activity. Special Reagents. Compound 48/80, guaiacol (anhydrous), and Triton X-100 were obtained from Sigma Chemical Co., St. Louis, Mo.; glutaraldehyde from Polysciences, Inc., Warrington, Pa.; osmium tetroxide from Scientific Chemical Co., Huntington Beach, Calif.; and sodium chloride (Suprapur) was obtained from Matheson Coleman and Bell, Norwood, Ohio. All other reagents were of the highest commercial grade available. EPO was partially purified from Materials and Methods

Activation of basophil and mast cell histamine release by eosinophil granule major basic protein.

“…That eosinophils may, however, also potentiate basophil and mast cell functions is shown by findings that relatively low concentrations of eosinophil peroxidase in the presence of hydrogen peroxide and a halide induce noncytotoxic degranulation of rat peritoneal mast cells (37) and also enhance mast cell tumoricidal activity (38). The results presented here extend possible activation by eosinophils to include the effect of MBP on human basophils and also rat mast cells.…”

Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer

“…It has been reported that the incidence of metastases as well as the appearance of tumours correlates inversely with tissue histamine level and mast cell count (Burtin et al, 1985). Interestingly, isolated mast cells were shown to inactivate tumour cells selectively in vitro (Henderson et al, 1981). These findings suggest that mast cells may play a role in inhibiting tumour metastases and suppressing growth of primary tumours.…”

“…The role of mast cells in tumour growth has been studied extensively in experimental tumours (Fisher and Fisher, 1965;Tanooka et al, 1982;Burtin et al, 1985), however, the significance of mast cell infiltration around human tumours has not been well studied, even though accumulation of mast cells around tumours was first reported a decade ago (Dimitriadou and Koutsilieris, 1997). Most studies have shown that mast cells prevent tumour growth (Farram and Nelson, 1980;Henderson et al, 1981;Ghiara et al, 1985;Benyon et al, 1991). In contrast, in a heterocyclic amine-induced rat PCa model, Nakai et al (2007) reported increased infiltration of stromal mast cell in the ventral prostate, with increased prostatic epithelial proliferation, suggesting that mast cells may have beneficial roles in progression of PCa (Nakai et al, 2007).…”

Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part I)

“…On the other hand, mast cell granules released during inflammation may contribute to the tissue irritation caused by other eosinophil proteins. It has been suggested that mast cells, which normally contain a small amount of granular peroxidase activity [244], may internalize exogenous EPO using a vesicular transport system and incorporate the peroxidase in their cytoplasmic granules [243,246,247].…”

“…It has been shown that EPO binds to the negativelycharged mast cell granule to form a complex that retains toxic activity to bacteria [242] and tumour cells [243] when supplemented with H 2 O 2 and a halide [242,244]. Since EPO at high H 2 O 2 concentrations and the EPO/H 2 O 2 / halide complex at lower H 2 O 2 concentrations can initiate mast cell granule release [245], it is conceivable that mast cells and eosinophils may act synergistically to improve host defence.…”