Published online Oct 7, 2015. doi: 10.3748/wjg.v21.i37.10493
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.
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.