INTRODUCTION: Gastric cancer (GC) is the fourth most prevalent, and the third most common cause of cancer-related death worldwide. The disease is generally asymptomatic, and consequently is often diagnosed at an advanced stage when metastasis is present, and limited treatment options are available. Chronic inflammation is recognized as an integral component in the development and progression of GC, and is associated with increased infiltration of immune cells into the tumor microenvironment. The production of pro-inflammatory cytokines by these cells may contribute to tumor progression through activation of pathways promoting tumor cell survival and proliferation. Previous work from our lab has shown that therapeutic inhibition of the inflammatory cytokine interleukin (IL)-11 is effective in ameliorating disease progression in gastrointestinal cancer, however, it is unclear what role other pro-inflammatory cytokines, such as IL-18, might have in disease progression.
METHODS: To characterize the role of different pro-inflammatory cytokines in GC, we first analyzed microarray and qRT-PCR data of from human GC specimens and adjacent non-tumor tissue. Following the generation of a candidate list of cytokines deregulated in human GC, the role of individual cytokines in disease progression was examined using a validated mouse model of intestinal-type GC, referred to as gp130Y757F, by crossing into cytokine knock-out strains and monitoring tumor burden and the expression of genes and proteins classically associated with tumorigenesis.
RESULTS: We found that the expression pro-inflammatory cytokines including IL-1β and IL-18 were significantly elevated in the tumors of human GC patients compared to non-tumor tissue. In gp130Y757F mice, genetic ablation of IL-18, but not of IL-1β significantly reduced gastric tumor burden, which was associated with a reduction in the number of intratumoral macrophages, but not lymphocytes. This observation correlated with decreased expression of pro-inflammatory (Ifng, Tgfb1), antimicrobial (Reg3b, Reg3g), and tissue remodeling (Mmp9) genes, and a reduction in apoptosis in the gastric lesions in these mice.
CONCLUSION: Our results demonstrate that IL-18 has an important role in GC disease progression, and may serve as a potential therapeutic target.
Citation Format: Paul Nguyen, Rita Busuttil, Lisa Mielke, Gabrielle Belz, Alex Boussioutas, Matthias Ernst, Tracy Putoczki. IL-18 is associated with the onset and progression of gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1443.