Myofibroblasts are an influential stromal subpopulation that interact with neighboring cells in a paracrine fashion to regulate a number of important cellular processes, including intestinal epithelial proliferation and differentiation along the crypt-villous axis, mucosal repair, and fibrosis . They also participate in immune and inflammatory responses and have been implicated in the pathophysiology of inflammatory bowel disease (IBD) and colitis-associated cancer [2, 3].
Myofibroblasts are a target of inflammatory mediator signaling and, in particular, TNF-α, a 17-kDa pro-inflammatory cytokine that has been implicated in the pathogenesis of colitis-associated cancer [4, 5]. TNF-α is found in high concentrations in the lamina propria of patients with ulcerative colitis , which is where myofibroblasts reside, and is known to regulate the signaling pathways that govern their function [7, 8]. TNF-α binds to its receptors, TNF-α receptor 1 (TNFR1) and TNF-α receptor 2 (TNFR2), triggering the formation of a multiprotein complex (TRADD, RIP, TRAF-2) that culminates in the activation of MAP kinases and the transcription factor NFκB [reviewed in ]. However, alternative cross talk mechanisms exist between TNF-α and other pro-inflammatory mediators, including multiple G protein-coupled receptor (GPCR)-mediated agonists [7, 8], that not only sustain the chronic inflammation associated with IBD, but also trigger a counter-regulatory response intended to promote mucosal healing. Chronic inflammation leads to the upregulation of cyclo-oxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2, which is encoded by the PTGS2 gene in humans. COX-2, the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs) and thromboxanes, is one example of a cytoprotective response to mucosal injury that, when dysregulated, may promote epithelial transformation to an invasive phenotype and the development of cancer [8, 10]. It is increasingly recognized that the stromal compartment is the major reservoir of COX-2 in the GI tract [11, 12]. Therefore, the regulation of COX-2 expression in the colonic myofibroblast may be highly relevant to the pathogenesis of inflammation-associated cancer in the gut.
We recently reported that TNF-α dramatically upregulates epidermal growth factor receptor (EGFR) expression on the cell surface of colonic myofibroblasts , though the functional significance of this upregulated expression is not fully known. Here, we demonstrate, for the first time, that enhanced EGFR expression induced by TNF-α facilitates GPCR-mediated EGFR transactivation in colonic myofibroblasts, providing an important mechanism for stromal COX-2 over-expression that may predispose to the development of colitis-associated cancer.