Mast cells and macrophages are part of bone marrow derived cell-infiltrates, which play a significant role in the initiation and progression of cancer. Preclinical studies have demonstrated a role for tumour-associated macrophages (TAMs) and mast cells in tumour stroma remodelling, promotion of angiogenesis and stimulation of tumour cell growth. Increased numbers of TAMs and mast cells in the tumour stroma have been correlated to human gastric cancer progression and angiogenesis. We have previously characterized the gp130Y757F/Y757F (hereafter gp130FF) mouse as a robust model for inflammation-associated gastric tumourigenesis, in which disease arises from excessive gp130/Stat3 activation in response to IL6-family cytokines .
Gp130FF mice have increased numbers of mast cells and macrophages in the tumour associated gastric submucosa when compared to normal submucosa in gp130wt mice. Genetic depletion of mast cells in the gp130FF led to abated tumour formation, which indicates a tumour-promoting activity of mast cells in the gp130FF gastric tumour model. Furthermore, treatment of mice with established gastric adenomas with an inhibitor of mast cell degranulation (cromolyn) decreased the overall tumour burden and polyp size in treated mice compared to controls. Similarly, therapeutic depletion of macrophages with clodrosomes (clodronate-containing liposomes) decreased tumour burden in gp130FF mice. Preliminary data indicate that the therapeutic targeting of mast cells and macrophages decreased cancer cell proliferation, and vascularisation. Finally, inhibition of mast cells and macrophages with the novel c-kit and c-fms kinase specific inhibitor PLXX3397 blocked growth of gastric tumours in gp130FF mice.
Our study demonstrates tumour-promoting activities of mast cells and macrophages in a mouse model of gastric cancer. Genetic and pharmacological inhibition of mast cells and macrophages was able to reduce tumour-associated angiogenesis and overall tumour burden. Our results suggest that targeting tumour-associated mast cells and macrophages in human gastric cancer may have beneficial effects on patient survival.