C-Kit receptor and tryptase expressing mast cells correlate with angiogenesis in breast cancer patients.

Ilaria Marech,Pietro Gadaleta,Giovambattista De Sarro,Christian Leporini,Girolamo Ranieri,Rosalba Dentamaro,Cosmo Damiano Gadaleta,Giuseppe Passantino,Silvana Leo,Maria Luposella,Valeria Zuccalà,Rosario Sacco,Rosa Patruno,Ammad Ahmad Farooqi,Mariangela Porcelli,Michele Ammendola,Nicola Zizzo

doi:10.18632/oncotarget.23722

Abstract

C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic-pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients. It has been found a strong correlation between MVD and MCDPT, and MCs-c-KitR, MVD and MCs density positive to tryptase (MCDPT), and MCs-c-KitR and MCDPT by Pearson correlation. These data suggest an involvement of both MCDPT and MCs-c-KitR in BC tumor angiogenesis. Furthermore, BC tissue expressing c-KitR could be a putative predictive factor to c-KitR-TK inhibitors. In this way, selected patients with higher MCs-c-KitR could be candidate to receive c-KitR-TK inhibitors (e.g. masitinib, sunitinib) or tryptase inhibitors (e.g. nafamostat mesilate, gabexate mesilate).

Highlights

C-KitR is the transmembrane tyrosine kinase (TK) receptor (c-KitR-TK) for stem cell factor (SCF), a cytokine regulating important functions of mast cells (MCs) such as proliferation and degranulation that in turn stimulate angiogenesis [1, 2]
In in vivo studies it has been shown that MCs density positive to tryptase (MCDPT) is strongly related to angiogenesis in several animal and human malignancies [2, 28, 33, 36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]
Data obtained from tumor tissue using light microscopy and image analysis system (Quantimet500 Leica, Wetzlar, Germany) [33] show the following mean ± 1 s.d.: MCDPT 7.49±2.81 (Figure 1A), microvascular density (MVD) 29.41 ± 6.63 (Figure 1B), MCs-c-KitR 8.75 ± 3.26 (Figure 1C) and

Summary

Introduction

C-KitR is the transmembrane tyrosine kinase (TK) receptor (c-KitR-TK) for stem cell factor (SCF), a cytokine regulating important functions of MCs such as proliferation and degranulation that in turn stimulate angiogenesis [1, 2]. Several published studies showed that EBCCs positive to c-KitR (EBCCsc-KitR) are low (from 10% to 29%) or absent in invasive breast cancer (IBC) [3,4,5,6,7,8,9,10,11]. C-KitR overexpression in IBC appeared to be an indicator of high-grade cancer resulting in poor prognosis [18] This evidence suggests that c-KitR expression may play a role in BC progression. For what concern the role of EBCCs-c-KitR and tumor angiogenesis, very little data have been published and only one study explored the relationship between EBCCs-c-KitR and microvascular density (MVD) demonstrating a negative correlation [3]. With concern to early BC patients, we already demonstrated a strong correlation between high serum tryptase levels before surgery (STLBS) and MVD, STLBS and MCDPT, MCDPT and MVD [40]

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