Augmented gp130‐mediated cytokine signalling accompanies human gastric cancer progression

Abstract

H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity-associated CagA protein disrupts intracellular SHP-2 signalling pathways including those used by the IL-6 family cytokines, IL-6 and IL-11. Imbalanced IL-6 family cytokine signalling in the gp130(757FF) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori-dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro-inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL-6, IL-11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori-dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL-6 expression was increased after H. pylori infection and both IL-6 and IL-11 were strongly up-regulated in the gastric cancer biopsies. This suggests a mechanism by which IL-11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL-11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori-dependent gastritis that is likely driven in an IL-6-dependent fashion. IL-11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL-11 as a potent inducer of proliferation in the human gastric cancer setting.

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

“…In gastric cancer, the expression of molecules associated with this pathway has been related to a worse prognostic, to a VEGF over expression (Gong et al, 2005), and to a shorter survival post-surgery (Yakata et al, 2007). In addition, the activation of STAT3 and ERK 1/2 is increased in stomach samples of patients infected with H. pylori, and these increases are likely Intestinal gastric cancer markers related to inflammation R Mejías-Luque et al driven in an IL-6-dependent manner, whereas IL-11 is upregulated in gastric adenocarcinoma regulating epithelial cell turnover (Jackson et al, 2007). The inflammatory cells infiltrating human colorectal tumors have been recently characterized in a large cohort of samples, and in these tumors the type, density, and location of the immune cells have a prognostic value superior to the histopathological methods currently used to stage colorectal cancer (Galon et al, 2006).…”

A Double-Edged Sword: Roles of Helicobacter Pylori in Gastric Carcinoma

“…IL-10 inhibits the FasL-induced apoptosis in GECs though without significant effect on the transcription of Fas (Guo et al, 2006). IL-11 activates the STAT3 like IL-6 and concomitantly increases proliferation of GECs (Jackson et al, 2007). Some other molecules including cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nitric oxide (NO), inducible NO synthase (iNOS), monocyte chemoattractant protein 1 (MCP1), and hepatocyte growth factor (HGF) and c-MET also relate to GC-associated inflammatory responses (Zhuang X et al, 2001;Futagami et al, 2008;Snider & Cardelli, 2009;Cho et al, 2010).…”

STAT3 as a prognostic marker in human gastric cancer

“…9 Numerous in vitro studies have shown that STAT3 promotes proliferation and invasion of gastric cancer cells, 10,11 and upregulates expression of potent angiogenic factors.…”

“…In contrast to the rodent model, moderate alcohol consumption in humans is reported to increase serum adiponectin levels. [9][10][11] However, the overall importance of adiponectin in heavy drinkers and in patients with severe ALD has not yet been evaluated.…”

“…This is further underscored by several previous reports which have also shown increased STAT3 or activated STAT3 expression in gastric adenocarcinomas. 10,[17][18][19] An important issue here is the careful specification of the protein being measured, and also the use of complementary and more quantitative methods than immunohistochemistry, such as western blotting. Because STAT3 is activated after phosphorylation by JAK kinases, and the expression of total STAT3 protein changes relatively little with oncogenic progression, the best and most sensitive measure of STAT3 is the ratio of activated to total STAT3 (western blotting) or phosphorylated STAT3 (immunohistochemistry).…”