Possible biological and translational significance of mast cells density in colorectal cancer

Abstract

Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34(+) hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated (mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor (c-KitR) and tryptase (an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density (MCD) role in colorectal cancer (CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors (imatinib, masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) with the aim to prevent CRC progression.

Keywords: Angiogenesis; Colorectal cancer; Mast cell density; Proteinase-activated receptor-2; Tryptase; Tryptase inhibitors; Tumor progression; Vascular endothelial growth factor; c-Kit receptor; c-Kit receptor tyrosine kinase inhibitors.

Figure 1

Close relationship between mast cells and angiogenesis-mediated tumor progression. FGF-2: Fibroblast growth factor-2; VEGF: Vascular endothelial growth factor; PDGF-β: Platelet-derived growth factor-β; EGF: Epidermal growth factor; IL: Interleukin; GM-CSF: Granulocyte/macrophage colony stimulating factor; TNF-α: Tumor necrosis factor-α; ECM: Extracellular matrix; MMP: Matrix metalloproteinase.

Figure 2

In both intestinal and endothelial cells, the tryptase/proteinase-activated receptor-2 and vascular endothelial growth factor/vascular endothelial growth factor receptor axes, induced by mast cells, lead to tumor angiogenesis and intestinal cell growth. Note that targeting mast cells with molecular agents (c-KitR tyrosine kinase and tryptase inhibitors) could prevent angiogenesis-mediated colorectal cancer progression. c-KitR: c-Kit receptor; PAR-2: Proteinase-activated receptor-2; VEGFR: Vascular endothelial growth factor receptor; SCF: Stem cell factor: VEGF: Vascular endothelial growth factor; NHERF-1: Na⁺/H⁺ exchanger regulatory factor-1; MEKK-1: Mitogen-activated protein kinase/extracellular signal-related kinase-1; MEKK-4: Mitogen-activated protein kinase/ extracellular signal-related kinase-4; JNK: c-Jun N-terminal kinase; c-Jun: Jun proto-oncogene; SAPK: Mitogen-activated protein kinase-9; GEF: Rho/rac guanine nucleotide exchange factor; Rho: Rhodopsin transcription termination factor; SOS: Son of sevenless protein; Grb2: Growth factor receptor-bound protein 2; Shc: Shc transforming protein kinase; Ras: Ras protein kinase; Raf: Raf protein kinase; Mitogen-activated protein kinase/extracellular signal-related kinase-1/2; Erk: Elk-related tyrosine kinase; DAG: Diacylglycerol; IP-3: Inositol triphosphate; PK-C: Protein kinase-C; COX-2: Cyclooxygenase-2; PGE2: Prostaglandin E2; PGES-1: Prostaglandin E synthase-1; PK-A: Protein kinase-A.