Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Abstract

Tryptase‐positive mast cells populate melanomas, but it is not known whether tryptase impacts on melanoma progression. Here we addressed this and show that melanoma growth is significantly higher in tryptase‐deficient (Mcpt6−/−) versus wild‐type mice. Histochemical analysis showed that mast cells were frequent in the tumor stroma of both wild‐type and Mcpt6−/− mice, and also revealed their presence within the tumor parenchyma. Confocal microscopy analysis revealed that tryptase was taken up by the tumor cells. Further, tryptase‐positive granules were released from mast cells and were widely distributed within the tumor tissue, suggesting that tryptase could impact on the tumor microenvironment. Indeed, gene expression analysis showed that the absence of Mcpt6 caused decreased expression of numerous genes, including Cxcl9, Tgtp2, and Gbp10, while the expression of 5p‐miR3098 was enhanced. The levels of CXCL9 were lower in serum from Mcpt6−/− versus wild‐type mice. In further support of a functional impact of tryptase on melanoma, recombinant tryptase (Mcpt6) was taken up by cultured melanoma cells and caused reduced proliferation. Altogether, our results indicate a protective role of mast cell tryptase in melanoma growth.

Phenotypic and Histological Distribution Analysis Identify Mast Cell Heterogeneity in Non-Small Cell Lung Cancer

“…This result is in agreement with some previous studies [19,45]. It is worthy to note that MC tryptase might also have a beneficial impact as it has been reported previously in melanoma [46,47]. However, and surprisingly, no clear advantages were shown in our study for patients exhibiting strong CD103 + MC profile.…”

Mast Cell β-Tryptase Is Enzymatically Stabilized by DNA

“…In recent studies we have challenged the established notion of tryptase being confined to secretory granules, by showing that tryptase also can be found within the nucleus of murine mast cells, and also in human tumor cells exposed to human tryptase [13][14][15][16]. In the nucleus, tryptase was shown to proteolytically degrade several nuclear compounds such as histones and lamin B1, and we also showed that tryptase can regulate gene expression and proliferation [13,14,16].…”

Carboxypeptidase A3—A Key Component of the Protease Phenotype of Mast Cells

“…The possibility of the protease transferring as a part of postcellular structures to targets allows specific biological effects to be carried out at considerable distances from the site of initial degranulation, and, in some cases, to create quite extensive inductive fields with a high concentration of MC CPA3, in particular, in patients with melanoma in the skin or in the tonsil with chronic inflammation [9] (Figure 4p-r). Compared to individual granules, fragments of the MC cytoplasm can be considered as a prolongation of the effector action of specific proteases [48,73,119].…”

“…The classification of human MC is based on the content of specific proteases-chymase and tryptase [5,6]. At the same time, along with them, carboxypeptidase A3 (CPA3) is no less abundant component of the mast cell secretome [7][8][9][10][11]. CPA3 is involved in the pathogenesis of cancer, inflammatory diseases of the gastrointestinal tract, respiratory and cardiovascular systems, disorders of the musculoskeletal system, as well as in immunogenesis.…”