Role of Mast Cells in Shaping the Tumor Microenvironment

Abstract

Early mast cell (MC) infiltration has been reported in a wide range of human and animal tumors particularly malignant melanoma and breast and colorectal cancer. The consequences of their presence in the tumor microenvironment (TME) or at their margins still remain unclear as it is associated with a good or poor prognosis based on the type and anatomical site of the tumor. Within the tumor, MC interactions occur with infiltrated immune cells, tumor cells, and extracellular matrix (ECM) through direct cell-to-cell interactions or release of a broad range of mediators capable of remodeling the TME. MCs actively contribute to angiogenesis and induce neovascularization by releasing the classical proangiogenic factors including VEGF, FGF-2, PDGF, and IL-6, and nonclassical proangiogenic factors mainly proteases including tryptase and chymase. MCs support tumor invasiveness by releasing a broad range of matrix metalloproteinases (MMPs). MC presence within the tumor gained additional significance when it was assumed that controlling its activation by tyrosine kinase inhibitors (imatinib and masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) or controlling their interactions with other cell types may have therapeutic benefit.

Keywords: Cancer; Extracellular matrix; Immunosuppression; Mast cell; Tumor.

Fig. 1

MC orchestration of immune responses in tumor. MC involvement and the role of their mediators in immunity against tumor cells. MCs are able to release a wide variety of cytokines including IL-1, IL-4, IL-8, IL-6, MCP-3, MCP-4, TNF-α, IFN-γ, LTB4, TGF-β, and chymase which support and promote the inflammation, inhibit tumor cell growth, and induce the apoptosis of tumor cell (in green). MC-released mediators mainly IL-8, VEGF, FGF-2, NGF, heparin, tryptase, chymase, and TGF-β support neoangiogenesis (in red). Furthermore, IL-10, histamine, TNF-α, and adenosine possess immunosuppressive properties (in blue)

Fig. 2

Cells of innate and specific immune system are involved in tumor biology. The role of tumor-residing or recruited cells of both innate and specific immune system in progression and suppression of tumor growth. The positive loop among tumor MCs, Tregs, and MDSCs has been shown. CD8+ recognizes tumor cells and eliminates them by releasing granzyme and perforin. Recruited monocytes give rise to other cell types mainly MDSC, TAM, and TAN. MCs induce the mobilization and infiltration of MDSCs to tumor through CCL2/CCR2 axis. MDSCs attract Treg cells and support their immunosuppressive activity by production of IL-17. Tregs in return produce IL-9 which acts as a survival factor of MCs

Fig. 3

The recruitment of MCs in tumor is organized by a complicated ligand-receptor network. a Chemokine network involved in MC recruitment to TME (chemokines are shown in red). b The protocol used by Huang to determine the tumor-released SCF as the main chemokine involved in MC recruitment

Fig. 4

Possible interactions of MCs and tumor cells and cell-to-cell interaction with other immune cells. Possible interactions between MCs and tumor cells include releasing mediators (tumor growth–supporting MC mediators are shown in red and tumor-suppressing MC mediators are listed in green) and direct cell-to-cell contacts that result in activation or suppression of cells