Inflammatory Cytokines Pathways as Potential Therapeutic Targets for Gastric Cancer

Raquel      Mejias-Luque; Carme      de Bolos

Abstract

Gastric cancer is the fourth most common cancer and the second most common cause of cancer deaths worldwide. The 90% of gastric cancers are adenocarcinomas and two main types can be distinguished: diffuse and intestinal. The process preceding the diffuse-type carcinomas is not well known whereas the precursor stages of the intestinal-type are histologically well identified. The colonization of the gastric mucosa by Helicobacter pylori and the associated inflammatory response, induced by the presence of inflammatory cytokines, have been postulated as initiators of the neoplastic transformation. TNF-α, IL-1β, IL-6, and IFN-γ cytokines have been detected in H. pylori-infected stomachs, and can activate specific transcription factors that would regulate the expression of genes implicated in the transformation of the gastric mucosa. In vivo mouse models of gastric cancer have been recently developed to analyse the implication of the inflammatory cytokines in the regulation of specific genes involved in the gastric neoplastic transformation. The signalling pathways activated by proinflammatory cytokines represent new valid approaches for antitumor therapies, and the specific transcription factors activated are potential targets for inhibition. STAT3 and NF-kappaB that are hyperactivated in many human tumors, are implicated in the transcription of genes that promote oncogenesis and metastasis by the participation in cell proliferation, apoptosis, migration, angiogenesis and immune evasion processes. Different approaches such as peptidomimetics and small molecule inhibitors have been synthesised. Their potential antitumoral effects are being analysed in different tumor models and some data from pre-clinical assays are available. The association between inflammation and gastric cancer development makes this human tumor type a potential target for the use of these therapeutic approaches.

Keywords: Gastric cancer, Helicobacter pylori, inflammation, IFN-γ, IL-1, TNF-α, IL-6

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