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In 1998, Kinzlker and Vogelstein proposed a hypothesis that expanded the limited data available from known specific genetic defects into a general mechanistic process underlying malignant transformation of the gastrointestinal tract.1 In this model, classic tumour suppressor genes such as APC function as “gatekeepers”, preventing, in the case ofAPC, the translocation of β-catenin to the nucleus where it complexes with Tcf- 4 and induces, inter alia, expression of c-myc, with ensuing increased cell proliferation and selection. Secondly, DNA repair proteins such asMLH1 and MSH2 act as “caretakers” of the genome, correcting mismatches in potentially important genes and thus preventing their inappropriate expression. Finally, in a series of diseases as disparate as inherited polyposis syndromes such as juvenile polyposis syndrome (JPS), and acquired conditions such as ulcerative colitis, changes in the stromal component of the lesions—the clonal stromal component of the hamartomas of JPS and the inflammatory infiltrate in ulcerative colitis—result in an altered terrain for epithelial cell growth which increases cancer susceptibility (the “landscaper” hypothesis or effect). In this model, it is envisaged that mutations in the stroma of the hamartomas in some way modulate epithelial cell proliferation through epithelial:mesenchymal interactions or epithelial damage (fig 1) while the cocktail of cytokines secreted by the inflammatory infiltrate have similar effects on the colonic epithelium in ulcerative colitis. The detailed molecular processes underlying this epithelial:mesenchymal “cross talk” remain to be elucidated although several examples have now been demonstrated. For example, large fold gastritis is a premalignant gastric condition that involves Helicobacter pylori colonisation causing an increase in cytokine (interleukin 1β) production by the inflammatory infiltrate. This in turn stimulates hepatocyte growth factor production and release by mesenchymal cells, resulting in increased epithelial proliferation due to the released hepatocyte growth factor binding toc-met receptors …