Are Mast Cells MASTers in Cancer?

Abstract

Prolonged low-grade inflammation or smoldering inflammation is a hallmark of cancer. Mast cells form a heterogeneous population of immune cells with differences in their ultra-structure, morphology, mediator content, and surface receptors. Mast cells are widely distributed throughout all tissues and are stromal components of the inflammatory microenvironment that modulates tumor initiation and development. Although canonically associated with allergic disorders, mast cells are a major source of pro-tumorigenic (e.g., angiogenic and lymphangiogenic factors) and antitumorigenic molecules (e.g., TNF-α and IL-9), depending on the milieu. In certain neoplasias (e.g., gastric, thyroid and Hodgkin's lymphoma) mast cells play a pro-tumorigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of mast cells and their mediators could be cancer specific. The microlocalization (e.g., peritumoral vs intratumoral) of mast cells is another important aspect in the initiation/progression of solid and hematologic tumors. Increasing evidence in certain experimental models indicates that targeting mast cells and/or their mediators represent a potential therapeutic target in cancer. Thus, mast cells deserve focused consideration also as therapeutic targets in different types of tumors. There are many unanswered questions that should be addressed before we understand whether mast cells are an ally, adversary, or innocent bystanders in human cancers.

Keywords: angiogenesis; cancer; inflammation; lymphangiogenesis; mast cells.

Figure 1

Some of the surface receptors expressed by human mast cells. Human mast cells express the tetrameric high-affinity receptor for IgE (FcεRI) and the FcγRIIA, and their cross-linking induces the release of pro-inflammatory and immunomodulatory mediators. Mast cell expresses the KIT receptor (CD117), which is activated by stem cell factor. These cells express a plethora of receptors, such as toll-like receptor (TLR) 2, TLR4, TLR5, TLR6, receptors for chemokines (CCR2, CCR3, CXCR1, CXCR2, CXCR3, and CXCR4), two receptors for cysteinyl leukotriene (CysLTR1 and CysLTR2), two leukotriene B₄ receptors (BLT1 and BLT2), the prostaglandin D₂ receptor (CRTH2), the prostaglandin E₂ receptor (EP₂), the cannabinoid CB1 receptor, two adenosine receptors (A_2B and A₃), and histamine H4 receptor (H4R). Mast cells express receptor for various cytokines (IL-4Rα, IL-5Rα, IFN-γRα, ST2). The MAS-related G protein coupled receptor (MRGPRX2) can be activated by neuromuscular blocking drugs, neuropeptides (SP and VIP), and eosinophil cationic proteins (MBP and EPX). These cells also express receptors for vascular endothelial growth factors (VEGFR1 and VEGFR2), and VEGFR co-receptors, neuropilin-1 and neuropilin-2 (NRP1 and NRP2), for anaphylatoxins (C5aR1/CD88, C5aR2, and C3aR), and the high-affinity urokinase plasminogen activator receptor (uPAR). Human mast cells also express co-receptors for T-cell activation [CD40 ligand (CD40L), tumor necrosis factor superfamily member 4 (OX40L), inducible costimulator ligand (ICOS-L), programmed death ligands (PD-L1 and PD-L2)] [Slightly modified with permission of Springer Nature from Borriello et al. (15)].

Figure 2

Roles of mast cells in human tumors. In red boxes are indicated the tumors in which mast cells play a pro-tumorigenic role. In green boxes are those tumors in which mast cells appear to play a protective role. In mixed red/green boxes are presented tumors in which mast cells play both a pro- and antitumorigenic role in different studies.

Figure 3

Possible mechanisms by which mast cells and their mediators may play a pro-tumorigenic or an antitumorigenic role. Mast cells in tumor microenvironment can promote tumor initiation and progression through the release of ROS, angiogenic and lymphangiogenic factors, and proteases, the induction of epithelial-to-mesenchymal transition and stemness. Mast cells can also activate STAT-3, contribute to immunosuppression and macrophage M2 polarization, and stimulate proliferation of tumor cells. Mast cells can exhibit antitumor activity through direct tumor cell cytotoxicity mediated by ROS and TNF-α or indirectly through the release of heparin, IL-9, and stimulation of dendritic cell maturation.