Cytokine-mediated inflammation is a driver of gastric tumorigenesis. Interleukin 33 (IL-33) regulates inflammatory responses but only recently, a role of IL-33 in cancer starts to emerge. Depending on the cancer stage or type IL-33 can provoke either pro- or anti-tumoral responses.
Aims: Elucidate the function of IL-33 signalling, mast cells and macrophages in gastric cancer.
Methods: We utilise gp130FF mutant gastric cancer mice, compound mutants lacking IL33 signalling (ST2-/-), mast cells (c-kitW-sh/W-sh), macrophages (Csfr1-/-) or drug treatments to interrogate the role of IL-33 and innate immune cells in the growth of gastric cancers.
Results: IL-33 signals through its receptor ST2, which we found abundantly expressed in gp130FF tumours. Deficiency of IL33 signalling (ST2-/-) diminished gastric tumour growth, and was associated with a decrease in tumour-adjacent mast cells and tumour-associated macrophages (TAM) as well as reduced angiogenesis. Indeed, mast cell and macrophage numbers are elevated in the gp130FF-tumours compared to wild type stomachs. Genetic depletion or pharmacological inhibition of mast cells and macrophages reduced tumour burden, again associated with decreased angiogenesis. Mechanistically, we show that tumour-produced IL33 can activate gastric gp130FF mast cells, which in turn recruit pro-tumoral and pro-angiogenic macrophages to the tumour through release of chemo-attractants like Ccl2, Ccl3 and Ccl71.
Conclusion: We conclude, that tumour-derived IL33 promotes gastric cancer growth through tumour-associated mast cells and TAMs. The results of our genetic and pharmacological experiments in mice suggest that either the IL-33/ST2 signalling node or mast cells and macrophages may represent novel therapeutic targets against inflammation-associated gastric cancer.