Understanding the Role of Pro-inflammatory Cytokines in the Development of Gastric Cancer — ASN Events

Understanding the Role of Pro-inflammatory Cytokines in the Development of Gastric Cancer (#294)

Jun Ting Low 1 , Tracy Putoczki 1 , Andreas Strasser 1 , Lorraine A O'Reilly 1
  1. The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

NF-κB, in particular the RelA subunit, is an important transcriptional regulator of many genes involved in tumour-promoting inflammation, cell proliferation and survival, and has frequently been found to be aberrantly over-activated in infiltrating immune cells in gastritis and in gastric cancer (GC). Our laboratory has discovered that ageing NF-κB1-deficient (nfκb1-/-) mice develop GC in a manner that mimics the progression of human invasive intestinal-type GC. These mice develop chronic gastritis, gastric mucosal atrophy or dysplasia, with a high incidence of invasive gastric adenocarcinomas. We observed abnormally increased infiltration of F4/80-positive macrophages and CD45-positive leukocytes in the stomachs of young nfκb1-/- mice. Concurrent with the recruitment of inflammatory cells into the gastric mucosa, elevated levels of pro-inflammatory cytokines and chemokines were found in the serum of young nfκb1-/- mice, and also in established tumours of these mice. This implicates deregulated expression of pro-inflammatory cytokines in GC disease progression.

Inflammatory cells recruited into the gastric mucosa during chronic gastritis secrete pro-inflammatory cytokines and chemokines. Interestingly, loss of NF-κB1 has been found to exacerbate macrophage M1-driven inflammation, augmenting pro-inflammatory cytokine production. In order to characterise the role of abnormally elevated cytokines in the onset and progression of GC in nfκb1-/- mice, we generated compound mutant mice lacking both NF-κB1 and individual pro-inflammatory cytokines that have been linked to cancer development. The survival, histopathology, immune cell infiltration, cytokine and chemokine levels of these mice is being examined at multiple time points. We have also characterised the cell populations in the gastric mucosa and have quantified the levels of phosphorylated-Stat3 and phosphorylated-p65/NF-κB levels in gastric epithelial cells and infiltrating leukocytes of these compound mutant mice. Our results determine the roles these cytokines have in driving GC in the nfκb1-/- mice and highlight the therapeutic potential in targeting pro-inflammatory cytokines for the treatment of GC.