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

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.

Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer

“…They described the presence of mast cells near blood vessels in bone metastases from gastric cancer and found a correlation between mast cell density and microvascular density. The latter observation led to suggest that tryptase inhibitors or KIT tyrosine kinase inhibitors could represent a novel strategy to inhibit tumour-induced angiogenesis and osteoclastic bone resorption [210].…”

“…Mast cell density in tumour microenvironment was associated with poor prognosis [129,168,170,198,199,218], tumour angiogenesis [169,198,199,204,219] and the formation of lymph node [168,219] and bone metastases [209]. These observations led to suggest that angiogenesis blockade could represent a promising target for the treatment of gastric cancer [207,210,231,232]. The results of several clinical trials indicate that anti-angiogenic agents improve overall survival, progression-free survival and disease control rate in gastric cancer [233].…”

Novel therapeutic compounds for prostate adenocarcinoma treatment

“…[ 38 ] As is well known, activities of cell surface serine proteases may promote tumor progression. [ 77 ] In this view, the antineoplastic effects of gabexate have been evaluated in treatments of several advanced tumor types including metastatic colorectal cancer, [ 78 ] gastric cancer with bone metastases [ 79 ] and pancreatic cancer. [ 80 ] Interestingly, an in vitro study indicated that only the invasiveness and metastatic processes were impacted by treatment with gabexate, but the proliferation of the tumor cell line was free from the effect.…”

Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases

“…It has been demonstrated that bone tumor enhances the PAR-2 expression in sensory nerves [ 116 ]. In addition, recent studies have revealed that tumor-infiltrating mast cells in bone metastatic tumors of gastric cancer promote bone metastatic growth, osteolytic lesions, and CIBP by stimulating angiogenesis [ 117 , 118 ].…”