NF-κB is an important transcriptional regulator of genes involved in tumour-promoting inflammation, cell proliferation and neoplastic cell survival. Our laboratory has shown that NF-κB1-deficient (nfkb1-/-) mice develop intestinal-type gastric cancer (IGC), which histopathologically resembles the human disease. Interestingly, a human NFKB1 polymorphism is associated with gastric cancer risk.1 This observation suggests that NF-κB1 is a gastric cancer tumour suppressor.
In order to understand how the loss of nfkb1 alters epithelial cell behavior, gastric organoids were derived from nfkb1-/- mice. We observed that gastric organoids derived from nfkb1-/- mice had similar growth and budding frequency to that of wt-derived gastric organoids, suggesting that the survival and proliferative capacity of nfkb1-/- gastric stem cells is comparable to that of wt gastric stem cells at steady state conditions. We are currently focusing on screening potential therapeutic combinations in this organoid system.
Elevated levels of the pro-inflammatory cytokines IL-6, IL-11 and IL-22 are expressed in the gastric tumours of nfkb1-/- mice, which correspond with elevated phosphorylated STAT1 and STAT3 levels. In order to understand the role of these cytokines in IGC development, nfkb1-/- mice were crossed to mice lacking functional alleles for IL-6, IL-11Ra, or IL-22 and the compound mutant mice were assessed.
Histopathological analysis of the gastric epithelium, indicated that nfkb1-/;il-6-/- mice had significantly reduced gastritis at 6-12 months of age compared to nfkb1-/- mice, which was associated with a decrease in myeloid and B cell populations. In contrast, the genetic loss of IL-11 or IL-22 signalling did not alter the gastritis in nfkb1-/- mice, rather, loss of IL-22 significantly increased the gastric myeloid and lymphoid infiltration in nfkb1-/- mice. These results suggest that inhibition of individual cytokines alone may not be of therapeutic benefit to patients carrying the NFKB1 polymorphism.
Interestingly, inhibition of IL6 and IL11 signaling resulted in a decrease in the phosphorylation of STAT1 in the gastric antrum of nfkb1-/- mice at 12 months of age. Current investigations are focused on determining whether loss of each of these cytokines coupled to immunomodulatory therapies would be therapeutically beneficial.