Inflammatory bowel diseases are associated with an increased risk of early-onset colorectal cancer, resulting in great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways active in both inflammation and cancer, which may thus be targets of therapy or chemoprevention. The ErbB4 tyrosine kinase, a member of the epidermal growth factor-related ErbB growth factor receptor family, is expressed at elevated levels in colitis and in a subset of human colorectal cancers. This receptor is thus a candidate participant in colitis-associated tumorigenesis. We recently demonstrated that ErbB4 expression and activity are induced by tumor necrosis factor, and that ErbB4 in turn promotes colon epithelial cell survival in the presence of pro-inflammatory cytokines. Preliminary data developed for this application further show that ErbB4 promotes colon epithelial cell transformation in both in vitro and in vivo models. Furthermore, ErbB4-induced cell survival and transformation are associated with increased mRNA stability and protein levels for the prostaglandin synthase cyclooxygenase-2 (COX-2). Thus, this application proposes to test the hypothesis that ErbB4 promotes colon epithelial cell survival and transformation in the inflammatory milieu through a COX-2-dependent mechanism. Planned experiments will use coordinated in vitro (signal transduction analysis, apoptosis &and colony formation assays) and in vivo (nude mouse xenograft tumor formation assays) approaches to (1) Identify signaling pathways involved in ErbB4-induced COX-2 expression, and (2) investigate cooperation between ErbB4 and COX-2 in colon epithelial cell survival and transformation.
Patients with inflammatory bowel diseases are at elevated risk for the development of colorectal cancer, but the exact molecular mechanisms underlying this increased risk are poorly understood. The proposed studies will advance our mechanistic understanding of cellular signaling in inflammation and carcinogenesis, with implications for the development of novel clinical therapies targeting ErbB4 and COX-2.
|Frey, Mark R; Brent Polk, D (2014) ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res 75:127-32|
|McElroy, Steven J; Castle, Shannon L; Bernard, Jessica K et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol 184:2768-78|
|Williams, Jonathan M; Duckworth, Carrie A; Watson, Alastair J M et al. (2013) A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Dis Model Mech 6:1388-99|