The progression of intestinal-type gastric cancer (IGC) is slow and mostly asymptomatic. As a result, the disease is often diagnosed at late stages when there are limited treatment options and a poor prognostic outcome. Chronic inflammation caused by persistent colonization with the gram-negative bacterium H. pylori is a known contributor to the onset and progression of IGC, with eradication of the infection attributed to a reduced incidence. In light of these observations, new treatment strategies are focused on controlling the inflammatory tumour microenvironment, and in turn the growth of malignant lesions.
Chronic inflammation is caused in part by the over-production of a number of pro-inflammatory cytokines including Interleukin (IL)-22, a member of the IL-10 family of cytokines. IL-22 signals through a heterodimeric receptor complex to activate the signal transducer and activator of transcription (STAT)-3, a potent inducer of genes involved in tumour cell survival, proliferation, and formation of blood vessels which facilitate tumour growth and metastasis. Recent studies highlight a role for IL-22 in chronic inflammatory conditions, including colorectal cancer. However, its role in gastric tumourigenesis has not previously been investigated. We examined the expression of IL-22, and other pro-inflammatory cytokines in human IGC biopsies and their correlation with the level of STAT3 activation. Our expression data, and mining of publically available datasets, suggest that IL-22 is among the prominent cytokines expressed at high levels in tumour tissue.
In order to determine the relative contribution of individual cytokines to IGC, we utilized the gp130Y757F mouse model. Our results show that ablation of a number of pro-inflammatory cytokines (IL-1, IL-6, IL-10, IL-12, IL-17, IL-18 and IL-23) do not impact significantly on tumour progression. However, loss of either IL-11 or IL-22 alleviated tumour burden. Our results suggest a hierarchy in cytokine signalling and identify IL-22 as an emerging therapeutic target for IGC.