Prostaglandins (PG) are produced throughout the gastrointestinal tract and are critical mediators for a complex array of physiologic and pathophysiologic processes in the intestine. Intestinal myofibroblasts, which express cyclooxygenase (COX) and generate PGE 2 , play important roles in intestinal epithelial proliferation, differentiation, inflammation, and neoplasia through secreting growth factors and cytokines. Here, we show that PGE 2 activated human intestinal subepithelial myofibroblasts (18Co) through Gs protein-coupled E-prostanoid receptors and the cyclic AMP/protein kinase A pathway. 18Co cells and primary colonic myofibroblast isolates expressed a number of growth factors; several of them were dramatically regulated by PGE 2 . An epidermal growth factor-like growth factor, amphiregulin (AR), which was not expressed by untreated cells, was strongly induced by PGE 2 . Expression of vascular endothelial growth factor A (VEGFA) was rapidly increased by PGE 2 exposure. Hepatocyte growth factor (HGF) was elevated in PGE 2 -treated myofibroblasts at both mRNA and protein levels. Thus, PGE 2 -activated myofibroblasts promoted the proliferation and migration of intestinal epithelial cells, which were attenuated by neutralizing antibodies to AR and HGF, respectively. Moreover, in the presence of PGE 2 , myofibroblasts strongly stimulated the migration and tubular formation of vascular endothelial cells. Neutralizing antibody to VEGFA inhibited the observed stimulation of migration. These results suggest that myofibroblast-generated growth factors are important mediators for PGE 2 -induced intestinal epithelial proliferation and angiogenesis, which play critical roles in intestinal homeostasis, inflammation, and neoplasia. (Cancer Res 2006; 66(2): 846-55)

Sheng G, Guo J, Warner BW. Epidermal growth factor receptor signaling modulates apoptosis via p38␣ MAPK-dependent activation of Bax in intestinal epithelial cells.

The retinoblastoma protein Rb is critical for the regulation of mammalian cell cycle entry. Hypophosphorylated Rb is considered to be the active form and directs G 1 arrest, while hyperphosphorylated Rb permits the transition from G 1 to S phase for cell proliferation. Upon stimulation by various growth factors, Rb appears to be phosphorylated by a cascade of phosphorylation events mediated mainly by kinases associated with cyclins D and E. Here we report that in prototype small intestine crypt stem cells (RIEC-6), stimulation with either epidermal growth factor or fetal bovine serum results in an unexpected rapid and sustained

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