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

Abstract

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)

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

“…Chemokine CXCL1 (growth-regulated oncogene-␣) can be induced by PGE 2 in colon cancer cells, which then promotes neoangiogenesis in intestinal neoplasia via a paracrine pathway (37). Amphiregulin, hepatocyte growth factor, and VEGF are induced by PGE 2 in intestinal subepithelial myofibroblasts, which stimulate the growth of intestinal epithelial cells and promote angiogenesis through a paracrine mechanism (38). In the present study, we added the proinflammatory cytokine IL-1␣ to the list of growth factors/cytokines, which are induced by PGE 2 and mediate PGE 2 proneoplastic actions through autocrine or paracrine mechanisms.…”

TNF-α potentiates lysophosphatidic acid-induced COX-2 expression via PKD in human colonic myofibroblasts

“…These cells share many of the structural and functional characteristics of in situ colonic subepithelial myofibroblasts, including a reversible stellate morphology, ␣-smooth actin expression, and the presence of multiple cell surface receptors (51). 18Co cells provide a model to elucidate physiological and pathophysiological functions of intestinal subepithelial myofibroblasts and, accordingly, have been used extensively to study colonic myofibroblast function in a variety of settings (22,33,42). 18Co cells were maintained at 37°C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) in a humidified atmosphere containing 10% CO 2 and 90% air.…”

Role of eicosanoids on intestinal epithelial homeostasis

“…Eicosanoids derived from both stromal and epithelial cells may stimulate stromal cells to release growth factors, which, in turn, provide a pro-proliferative and pro-neoplastic environment for the intestinal epithelium. Shao et al [28] found that exogenous PGE 2 induced the expression and secretion of several pro-proliferative and pro-angiogenic growth factors such as amphiregulin, vascular endothelial growth factors, hepatocyte growth factor and neuregulins by intestinal subepithelial myofibroblasts, which may mediate intestinal epithelial growth and transformation. Finally, we must consider that activated macrophages also produce eicosanoids [29] that are present near the epithelial progenitor niche [30].…”