Background & Aims: Inflammasomes are key regulators of innate immunity, and despite their known involvement in chronic inflammatory disorders and autoimmune diseases, their role in inflammation-associated tumourigenesis remains ill-defined. Here, we sought to elucidate the role for the inflammasome adaptor ASC, and downstream inflammasome effector cytokines IL-18 and IL-1b, in gastric cancer (GC).
Methods: Tumour formation was assessed in the gp130F/F spontaneous GC model crossed onto backgrounds deficient in genes encoding ASC (Pycard), Il18 or the IL-1 receptor (Il1r). Tumourigenesis was also assessed in reciprocal bone marrow chimeras between gp130F/F and gp130F/F:Asc-/- mice. In gastric tumours of mice, apoptosis was assessed by numerous techniques including immunohistochemistry (Caspase-8) and immunofluorescence (Caspase-3), and inflammation was quantified by flow cytometry and immunohistochemistry. The expression of ASC, IL-18 and IL-1b in human GC patient biopsies was assessed by quantitative real-time PCR and/or ELISA. In vitro assays investigated the ASC- and IL-18-regulated growth-responsiveness of human GC cells.
Results: ASC deficiency in gp130F/F mice suppressed gastric tumourigenesis by augmenting a Caspase-3/8-like apoptotic cell death cascade in the gastric epithelium, independent of hematopoietic-derived myeloid cells and mucosal inflammation. Suppressed tumourigenesis was associated with reduced levels of mature IL-18, but not IL-1b, in gastric tumours. A specific pro-tumourigenic role for IL-18 was confirmed by its genetic ablation in gp130F/F mice, and antibody-mediated inhibition of IL-18 suppressed the growth potential of human GC cells. We also demonstrate a significant positive correlation between elevated mature IL-18 protein and ASC mRNA levels in human GC tumours.
Conclusions: Collectively, these findings reveal the ASC/IL-18 axis as a new therapeutic target in GC.