Mast cells positive to tryptase, endothelial cells positive to protease-activated receptor-2, and microvascular density correlate among themselves in hepatocellular carcinoma patients who have undergone surgery

Abstract

BackgroundMast cells (MCs) can stimulate angiogenesis, releasing several proangiogenic cytokines stored in their cytoplasm. In particular MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase phosphorylation. Nevertheless, no data are available concerning the relationship between MC density positive to tryptase (MCDPT), endothelial cells positive to PAR-2 forming microvascular density (PAR-2-MVD), and classical MVD (C-MVD) in hepatocellular carcinoma (HCC) angiogenesis. This study analyzed the correlation between MCDPT, PAR-2-MVD, and C-MVD, each correlated to the others and to the main clinicopathological features, in early HCC patients who underwent surgery.MethodsA series of 53 HCC patients with early stage (stage 0 according to the Barcelona Clinic Liver Cancer Staging Classification) were selected and then underwent surgery. Tumor tissue samples were evaluated by means of immunohistochemistry and image analysis methods in terms of number of MCDPT, PAR-2-MVD, and C-MVD.ResultsA significant correlation between MCDPT, PAR-2-MVD, and C-MVD groups, each correlated to the others, was found by Pearson t-test analysis (r ranged from 0.67 to 0.81; P-value ranged from 0.01 to 0.03). No other significant correlation was found.ConclusionOur in vivo pilot data suggest that MCDPT and PAR-2-MVD may play a role in HCC angiogenesis and could be further evaluated as a target of antiangiogenic therapy.

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery

“…Tryptase is an agonist of PAR-2 in vascular ECs that stimulates their proliferation. Signaling via PAR-2 on ECs elicits activation of the major members of the MAPK phosphorylation family and contributes to proliferation of ECs and angiogenesis [23,24,25,26,27,28,29,30,31,32,47,48,49,50,51]. …”

Mast Cells Positive for c-Kit Receptor and Tryptase Correlate with Angiogenesis in Cancerous and Adjacent Normal Pancreatic Tissue

“…Mast cells migration in the tumour microenvironment is induced by the expression of several growth factors, molecules and proinflammatory cytokines, such as SCF, TGF, TNF, FES kinase, protein kinase D, CXCL12, eicosanoids, chemokines and prostaglandins, and by the activation of subcellular pathways, such as ERβ/CCL2/CCR2, EMT/MMP9 and PI3K/AK. Cells in both the cancer and tumour microenvironment can participate in the production of chemotactic agents for MCs, depending on the tumour type and the specific microenvironment [ 20 , 60 , 61 , 62 , 63 , 64 , 65 ]. From a functional point of view, MCs’ activities are mainly regulated by c-Kit-R, known also as CD-117, that binds its ligand SCF, and as a consequence of this interaction, MCs can degranulate [ 7 , 25 , 66 , 67 , 68 ].…”

“…From a biological point of view, tryptase is a trypsin-like neutral serine protease and selective component of the secretory granules of all human MCs, accounting for almost 25% of cell protein (10–35 pg per mast cell) [ 15 ]. It consists of four monomers, each of which is stabilized in its active conformation and its tetrameric form by heparin–proteoglycan complexes [ 20 , 77 , 78 ]. Because of its proteolytic activity, tryptase acts as an agonist of the protease-activated receptor-2 (PAR-2), a G protein expressed on ECs that is involved in their proliferation and whose activation triggers an intracellular signal involving MAPK phosphorylation pathway [ 79 , 80 ].…”

“…It is a serine protease that has been demonstrated to enhance [ 13 , 14 , 15 ] endothelial cell (EC) and microvascular proliferation in animal models in several in vitro and in vivo studies [ 16 , 17 ]. Through its binding to protease-activated receptor-2 (PAR-2) on endothelial cells, tryptase can stimulate microvascular formation [ 18 , 19 , 20 , 21 ].…”

Tryptase mast cell density, protease-activated receptor-2 microvascular density, and classical microvascular density evaluation in gastric cancer patients undergoing surgery: possible translational relevance

“…Although our results are preliminary and they need to be confirmed to further awaited studies, it is intriguing to speculate that the inhibition of MC degranulation by means of c-Kit receptor tyrosine kinase inhibitors (e.g. masitinib) or the inhibition of tryptase by means of gabexate mesilate or nafamostat mesilate, which could be novel antiangiogenic strategies worthy of clinical investigation [ Erba et al 2001 ; Mori et al 2003 ; Humbert et al 2010 ; Marech et al 2014c ; Deplanque et al 2015 ; Ammendola et al 2016c ].…”