Chronic inflammation and the development of malignancy in the GI tract

Abstract

The role of immunologic factors in the development of gastrointestinal (GI) neoplasia, made evident from the high degree of association of chronic intestinal or gastric inflammation with the development of cancer, has attracted much attention because it promises new ways of treating disease. Here we develop the idea that immunologic factors influence the appearance of GI cancer on two levels: (i) a basic and initiating level during which the epithelial cell is induced to undergo pre-cancerous molecular changes that render it prone to further cancer progression; and (ii) a secondary level that builds on this vulnerability and drives the cell into frank malignancy. This secondary level is uniquely dependent on a single epithelial cell signaling pathway centered on STAT3, and it is this pathway upon which stimulation of mucosal cytokine production and microbiota effects converge.

Figure 1. 1^st Stage Oncogenic Events

The development of malignancy in the gastrointestinal epithelium as a result of chronic intestinal inflammation is usually a two stage process. The first stage is a “stealthy” and relatively prolonged process in which factors in the milieu created by chronic inflammation cause oncogenic “hits” i.e, molecular changes involving tumor suppressor genes or pro-oncogenic genes that result cells vulnerable to immunologic stimulation of signaling pathways that drive frank malignant changes. Inflammatory cytokines such as TNF-a induce down-stream factors such ROS to cause silent mutational changes in oncogenes such TP53 and Kras. These changes render the cell vulnerable to induction of frank neoplastic changes in the second stage of tumor development. The presence of the Apc genetic mutation or the administration of a genotoxic agent such as azoxymethane (AOM) “short-circuit” this initial phase and allow the rapid progress of oncogenesis by immunologic factors.

Figure 2. 2^nd Stage Oncogenic Events

Cytokine activation of the STAT3 signaling pathway is the gateway to the second phase of immunologically-mediated oncogenesis. A number of cytokines, most notably IL-6,IL-11 and IL-22 are induced by upstream pro-inflammatory factors and activate the STAT3 signaling pathway. Th17 responses, possibly induced by bacteria in the microbiome are important initiators of IL-6 and IL-22 production. However, there is recent evidence that such activation is favored by the presence of particular non-pathogenic members of the microbiome.