High density of tryptase‐positive mast cells in human colorectal cancer: a poor prognostic factor related to protease‐activated receptor 2 expression

Abstract

Tryptase(+) mast cells (MCs), abundant in the invasive front of tumours, contribute to tissue remodelling. Indeed, protease-activated receptor-2 (PAR-2) activation by MC-tryptase is considered an oncogenic event in colorectal cancer (CRC). Recently, we have suggested NHERF1 as a potential new marker in CRC. In this study, we aimed to determine the distribution of tryptase(+) MCs and PAR-2 and to examine the relationship between PAR-2 and NHERF1, investigating their reputed usefulness as tumour markers. We studied a cohort of 115 CRC specimens including primary cancer (C) and adjacent normal mucosa (NM) by immunohistochemical double staining, analyzing the protein expression of MC-tryptase, PAR-2 and cytoplasmic NHERF1. MC density was higher in NM than in C. Tumours with high TNM stage and poor grade showed the highest MC density. A higher PAR-2 immunoreactivity characterized tumours most infiltrated by MCs compared with samples with low MC density. Furthermore, PAR-2 overexpression was associated with advanced TNM stage, poor grade and lymphovascular invasion (LVI). A positive correlation existed between tryptase(+) MC density and PAR-2 expression. Cytoplasmic NHERF1 was higher in C than in NM and overexpressing tumours resulted associated with nodal and distant metastases, poor grade and LVI. PAR-2 correlated with cytoplasmic NHERF1 and the PAR-2(+)/cytoplasmic NHERF1(+) expression immunophenotype identified tumours associated with unfavourable prognosis and aggressive clinical parameters. Our data indicate that the high density of tryptase(+) MCs at invasive margins of tumours was associated with advanced stages of CRC and was strongly correlated with PAR-2 expression.

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

“…These findings are consistent with clinical observations, where high infiltration of MC has been observed in human colon cancer. 10–13,15–17 MC migration toward Caco2 was observed solely SCF-dependent. SCF is an important growth factor for MC, but also induces chemotaxis and survival.…”

“…7 MC density in CRC tissues is positively associated with poor clinical outcomes in patients 10–13,15,17 and decreased intestinal tumor growth has been observed in MC-deficient mice. 28,29 Our study further provides experimental evidence that primary human MC promote colon cancer growth by stimulating production of pro-tumorigenic mediators in a bidirectional manner.…”

“…Particularly, there are discrepancies regarding the relationship between MC density and tumor progression and clinical outcomes in patients with CRC. 7 Some studies suggested MC number is positively associated with a poor prognosis for CRC, 10–13,15,17 while other studies had contrasting findings. 14,16 This suggests that simply assessing MC number does not provide insight into MC contribution in CRC progression.…”

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

“…MCs are known to accumulate in the inflamed gut of IBD patients (16)(17)(18). Also, an increased number of MCs in tumors correlated with poor prognosis in some studies of outcome in colorectal cancer patients (19,20) and low MC infiltration correlated with lower overall survival in an earlier study (21).…”

Mast Cell-Targeted Strategies in Cancer Therapy

“…It has been well demonstrated that MCs can secrete several classical and non-classical pro-angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor-β (PDGF-β), IL-6, IL-8, thymidine phosphorylase (TP), and chymase. MCs can secrete other molecules such as tryptase and TNF-α that play a role in angiogenesis, and not in immune response [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. …”