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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2015; 21(37): 10493-10501
Published online Oct 7, 2015. doi: 10.3748/wjg.v21.i37.10493
Targeting mast cells in gastric cancer with special reference to bone metastases
Christian Leporini, Michele Ammendola, Ilaria Marech, Giuseppe Sammarco, Rosario Sacco, Cosmo Damiano Gadaleta, Caroline Oakley, Emilio Russo, Giovambattista De Sarro, Girolamo Ranieri
Christian Leporini, Emilio Russo, Giovambattista De Sarro, Department of Health Science, Clinical Pharmacology and Pharmacovigilance Unit and Pharmacovigilance’s Centre Calabria Region, University of Catanzaro “Magna Graecia” Medical School, Viale Europa - Germaneto, 88100 Catanzaro, Italy
Michele Ammendola, Giuseppe Sammarco, Rosario Sacco, Department of Medical and Surgery Sciences, Clinical Surgery Unit, University of Catanzaro “Magna Graecia” Medical School, 88100 Catanzaro, Italy
Ilaria Marech, Cosmo Damiano Gadaleta, Caroline Oakley, Girolamo Ranieri, Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, “Giovanni Paolo II”, 70124 Bari, Italy
Author contributions: Leporini C, Ammendola M, Marech I and Ranieri G conceived the review and performed the critical review of the literature; Sammarco G, Sacco R, Gadaleta CD, Russo E and De Sarro G contributed to the literature research and data analysis; all authors wrote the manuscript and Oakley C edited the manuscript.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Michele Ammendola, MD, Department of Medical and Surgery Sciences, Clinical Surgery Unit, University of Catanzaro “Magna Graecia” Medical School, Viale Europa - Germaneto, 88100 Catanzaro, Italy.
Telephone: +39-961-3694191 Fax: +39-961-3647556
Received: April 5, 2015
Peer-review started: April 7, 2015
First decision: April 23, 2015
Revised: June 15, 2015
Accepted: August 25, 2015
Article in press: August 25, 2015
Published online: October 7, 2015

Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases.

Keywords: Bone metastases, Gastric cancer, Receptor activator of nuclear factor-κB, Angiogenesis, Osteoclastic bone resorption, Tryptase inhibitors, c-Kit receptor tyrosine kinase inhibitors, Anti-angiogenic therapy

Core tip: The activation of the stem cell factor/c-Kit receptor (c-KitR) pathway in mast cells (MCs), and tryptase release upon MCs degranulation have a pivotal role in tumor angiogenesis in several human malignancies. MCs positive to tryptase (MCPT) have been implicated in primary gastric cancer (GC) angiogenesis. Our preliminary findings indicated that bone metastasis angiogenesis from GC is also supported by infiltrating MCPTs. Overall, the evidence provides a rationale to evaluate c-KitR inhibitors that block MCs degranulation, or tryptase inhibitors that inhibit tryptase and/or the Proteinase-Activated Receptor-2 pathway, in clinical trials for bone metastasis GC patients.