Targeting mast cells in gastric cancer with special reference to bone metastases

World J Gastroenterol. 2015 Oct 7;21(37):10493-501. doi: 10.3748/wjg.v21.i37.10493.

Abstract

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

Publication types

  • Review

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary*
  • Bone Resorption
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Disease Progression
  • Gabexate / therapeutic use
  • Guanidines / therapeutic use
  • Humans
  • Imatinib Mesylate / therapeutic use
  • Immune System
  • Mast Cells / cytology*
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic
  • Proto-Oncogene Proteins c-kit / metabolism
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology*
  • Thiazoles / therapeutic use
  • Tryptases / metabolism

Substances

  • Antigens, CD34
  • Guanidines
  • NF-kappa B
  • Thiazoles
  • Gabexate
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • Tryptases
  • masitinib
  • nafamostat