Mast cells in health and disease
MCs, first described in 1878, are an important part of the immune system [1]. They arise from pluripotent bone marrow progenitor cells and mature under the influence of c-kit ligand and stem cell factor (SCF) and other growth factors (e. g. cytokines) provided by the microenvironment of the tissue in which they are to establish [2]. They are central to initial pathogen response and can mainly be found in the skin and the mucous membranes [3]. MCs are convoluted in numerous physiological and pathological conditions, including angiogenesis, tissue remodeling, wound healing, IgE-dependent allergic disease, infection-induced immune response, and autoimmune inflammatory disease [4]. They contain granules with a wide variety of biologically active substances, including prostaglandins/leukotrienes, vasoactive amines, such as histamine, and proteases [mainly mast cell tryptase (MCT) and chymas] [3]. Like other immune cells, e. g. T lymphocytes [5], macrophages [6], and neutrophils [7], MCs can be encountered in different functional subpopulations, depending on their granular content [8]. MCT cells exclusively express MCT within their granules and can primarily be found in lung tissue [8], while MCTC cells also contain chymase and carboxypeptidase A3 in addition to MCT within their granules (mainly located in the skin and mucous membranes) [8].
Different mast cell functions during tumor progression
MCs play a critical role during several malignoma progression. Tumor-promoting [9, 10] and tumor-inhibiting [11–13] effects have been delineated in various tumor entities. These properties depend on whether MCs contact the tumor cells or reside in the tumor microenvironment (TME) [14–16]. In Hodgkin's lymphoma [17, 18], malignant melanoma [19, 20], and various types of carcinoma, such as esophageal carcinoma [21], adenocarcinoma of the lung [10], and carcinomas of the gastrointestinal tract [22, 23], a poorer patients` prognosis has increased MC density in the TME. It may be due to MCs’ releasing angiogenic factors (e. g., VEGF) from their granules into the TME, thus supporting angiogenesis. The histamine release can induce tumor cell proliferation [24, 25]. Matrix metalloproteinases (MMPs) and proteases (mainly MCT and chymase) are released, modulating the extracellular matrix and promoting tumor invasion and metastasis [11, 24, 25]. MCs can inhibit the immune response by releasing IL-10 and TGF-β, thus promoting tumor spread [11].
Contrarily, high intratumoral MC density (close contact between both cell types) has been linked to improved prognosis in patients with prostate carcinoma [26, 27], colorectal carcinoma [28, 29], and clear cell renal cell carcinoma [29]. MCs have a TNF-induced cytotoxic effect on tumor cells [11] and promote tumor cell apoptosis [25]. Releases of CCL5, CXCL8, CXCL10, and IL-6 can recruit and activate various immune cells, thereby inhibiting tumor growth [11]. MCs can generate reactive oxygen (ROO-, OH-, H2O2) and nitrogen (ONOO-) radicals, besides granzymes, inhibiting tumor growth in high concentrations or having a direct cytotoxic effect [30, 31].
An example of MC localization in the TME and partly intratumorally is shown in Figure 1 using an oral squamous cell carcinoma (OSCC).
