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Roles of Myofibroblasts in Prostaglandin E₂–Stimulated Intestinal Epithelial Proliferation and Angiogenesis

¹ Department of Surgery and Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana; ² Department of Surgery, University of Cincinnati, Cincinnati, Ohio; and ³ Department of Medicine, University of Texas Medical Branch, Galveston, Texas

Requests for reprints: Hongmiao Sheng, Department of Surgery, Indiana University, Indianapolis, IN 46202. Phone: 317-274-2630; E-mail: hsheng{at}iupui.edu.

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 PGE₂, play important roles in intestinal epithelial proliferation, differentiation, inflammation, and neoplasia through secreting growth factors and cytokines. Here, we show that PGE₂ 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 PGE₂. An epidermal growth factor–like growth factor, amphiregulin (AR), which was not expressed by untreated cells, was strongly induced by PGE₂. Expression of vascular endothelial growth factor A (VEGFA) was rapidly increased by PGE₂ exposure. Hepatocyte growth factor (HGF) was elevated in PGE₂-treated myofibroblasts at both mRNA and protein levels. Thus, PGE₂-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 PGE₂, 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 PGE₂-induced intestinal epithelial proliferation and angiogenesis, which play critical roles in intestinal homeostasis, inflammation, and neoplasia. (Cancer Res 2006; 66(2): 846-55)

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