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

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Roles of Myofibroblasts in Prostaglandin E2–Stimulated Intestinal Epithelial Proliferation and Angiogenesis Research Article Roles of Myofibroblasts in Prostaglandin E2–Stimulated Intestinal Epithelial Proliferation and Angiogenesis Jinyi Shao,1 George G. Sheng,2 Randy C. Mifflin,3 Don W. Powell,3 and Hongmiao Sheng1 1Department of Surgery and Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana; 2Department of Surgery, University of Cincinnati, Cincinnati, Ohio; and 3Department of Medicine, University of Texas Medical Branch, Galveston, Texas Abstract advantage to intestinal neoplasms (6, 7). In contrast, genetic dis- Prostaglandins (PG) are produced throughout the gastroin- ruption of the cyclooxygenase-2 (COX-2) gene or the E-prostanoid testinal tract and are critical mediators for a complex array receptor 2 (EP2) results in a substantial reduction of polyps in of physiologic and pathophysiologic processes in the intestine. APC knockout mice (8, 9). Further evidence shows that PGE2 Intestinal myofibroblasts, which express cyclooxygenase promotes intestinal neoplasia through enhancing tumor angiogen- esis (9–11). Knockout of the EP2 receptor or inhibition of COX-2 (COX) and generate PGE2, play important roles in intestinal D716 epithelial proliferation, differentiation, inflammation, and enzyme results in a reduction of neoangiogenesis in APC neoplasia through secreting growth factors and cytokines. mouse tumors (9, 12). Understanding the precise mechanisms by Here, we show that PGE activated human intestinal sub- which PGE2 promotes intestinal epithelial growth and angiogenesis 2 remains a significant challenge. It has been shown that PGE epithelial myofibroblasts (18Co) through Gs protein–coupled 2 E-prostanoid receptors and the cyclic AMP/protein kinase A directly stimulates the proliferation of transformed intestinal pathway. 18Co cells and primary colonic myofibroblast iso- epithelial cells (6, 13, 14) and increases the expression of lates expressed a number of growth factors; several of them proangiogenic growth factors in colon cancer cells (15, 16). However, the effects of PGE2 on cell growth and angiogenesis were dramatically regulated by PGE2. An epidermal growth factor–like growth factor, amphiregulin (AR), which was not in vivo are considerably complex. Interactions between intestinal epithelial cells and stromal cells, which include fibroblasts, expressed by untreated cells, was strongly induced by PGE2. Expression of vascular endothelial growth factor A (VEGFA) myofibroblasts, endothelial cells, and other cell types, may dramatically influence the homeostasis and transformation of the was rapidly increased by PGE2 exposure. Hepatocyte growth factor (HGF) was elevated in PGE -treated myofibroblasts at intestinal epithelium (17). 2 A large body of studies has shown that intestinal subepithelial both mRNA and protein levels. Thus, PGE2-activated myo- fibroblasts promoted the proliferation and migration of in- myofibroblasts (ISEMF) play crucial roles in intestinal organo- testinal epithelial cells, which were attenuated by neutralizing genesis (18–21), proliferation, and differentiation of intestinal antibodies to AR and HGF, respectively. Moreover, in the epithelial cells (19), mucosal protection, and wound healing (22). ISEMFs are located in the lamina propria throughout the presence of PGE2, myofibroblasts strongly stimulated the mi- gration and tubular formation of vascular endothelial cells. gastrointestinal tract (23, 24) and act through the secretion of Neutralizing antibody to VEGFA inhibited the observed growth factors, cytokines, and chemokines. ISEMFs express and stimulation of migration. These results suggest that myofibro- produce a large number of growth factors, including hepatocyte blast-generated growth factors are important mediators for growth factor (HGF; ref. 25), insulin-like growth factor (26), PGE -induced intestinal epithelial proliferation and angio- basic fibroblast growth factor (bFGF; ref. 27), platelet-derived 2 growth factor (PDGF; ref. 28), transforming growth factor-h genesis, which play critical roles in intestinal homeostasis, h inflammation, and neoplasia. (Cancer Res 2006; 66(2): 846-55) (TGF- ; ref. 29), colony stimulating factor (30), nerve growth factor (30), and stem cell factor (31). Furthermore, immunohis- tochemical studies reveal that fibroblasts are the predominant Introduction cell type in the lamina propria of normal colon; however, in Prostaglandins (PG) are generated throughout the gastrointes- both hyperplastic and neoplastic polyps, interstitial fibroblasts are tinal tract and play critical roles in an array of physiologic and replaced by myofibroblasts, suggesting that myofibroblasts play pathophysiologic processes (1, 2). PGs exert a trophic effect on critical roles in colorectal neoplasia (32). small intestinal mucosa and stimulate intestinal epithelial cell 18Co cells were derived from human colonic mucosa and exhibit proliferation (3). Short-term administration of PGE2 causes many properties of intestinal subepithelial myofibroblasts (33). significant stimulation of DNA synthesis; prolonged PGE2 treat- Expression of COX-1 is constitutive in 18Co cells, whereas COX-2 ment markedly increases the weight and DNA content of the can be induced by a variety of stimuli (34). Interleukin-1-activated intestinal mucosa (4). PGE2 and prostacyclin stimulate intestinal 18Co cells produce a significant amount of PGE2 (35). Given the epithelial cell migration and therefore promote intestinal restitu- critical functions of both ISEMF and PGE2 in the intestine, we tion (5). Moreover, PGE2 exerts growth-stimulatory effects on hypothesized that PGE2 may induce the production of certain intestinal tumors, and administration of PGE2 provides a growth growth factors by ISEMF, which, in turn, stimulate the growth and transformation of intestinal epithelium. In the present study, we show that PGE2 exposure increased the expression and secretion of amphiregulin (AR), HGF, and vascular endothelial growth factor Requests for reprints: Hongmiao Sheng, Department of Surgery, Indiana (VEGF) in 18Co cells and as well as in primary human colonic University, Indianapolis, IN 46202. Phone: 317-274-2630; E-mail: [email protected]. I2006 American Association for Cancer Research. myofibroblasts. PGE2-activated 18Co cells stimulated the prolifer- doi:10.1158/0008-5472.CAN-05-2606 ation and migration of intestinal epithelial cells. Conditioned Cancer Res 2006; 66: (2). January 15, 2006 846 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2006 American Association for Cancer Research. PGE2 Activation of Myofibroblasts media from PGE2-activated 18Co cells promoted the migration and RNA extraction and Northern blot analysis. Extraction of total cellular tubular formation of vascular endothelial cells. Thus, our study RNA was carried out as previously described (39). RNA samples were separated on formaldehyde-agarose gels and blotted onto nitrocellulose suggests that myofibroblasts may play critical roles in PGE2- induced intestinal growth and transformation. membranes. Blots were hybridized with cDNA probes labeled with [a-32P]dCTP by random primer extension (Stratagene, La Jolla, CA). After hybridization and washes, the blots were subjected to autoradiography. Materials and Methods Reverse transcription-PCR. Expression of EP receptors in 18Co cells Cell culture and reagents. 18Co cells were purchased from American was determined using reverse transcription-PCR (RT-PCR) as described Type Culture Collection (Manassas, VA) and grown in MEM supplemented previously (14). Human HGF and VEGF primer pairs were purchased from with 10% fetal bovine serum (FBS) and nonessential amino acids. 18Co cells R&D Systems. RT-PCR was carried out using ProStar RT-PCR system used for this study were passages 12 to 14. Primary colonic myofibroblast (Stratagene) according to the manufacturer’s instructions. (CMF, passages 4-10) cultures were established from histologically normal ELISA. Levels of human HGF, AR, and VEGF proteins in cell culture margins of surgically resected colonic tissue using the outgrowth method media were quantified using ELISA kits (R&D Systems). Cells were seeded in described by Mahida et al. (36, 37). The myofibroblast phenotype was 24-well plate, and serum was deprived for 24 hours before PGE2 treatment. verified by immunohistochemistry and flow cytometry. All are positive for Culture media were collected and stored at À80jC until assays. a-SMA, myosin heavy chain, and vimentin but are negative for cytokeratin Transient transfection and luciferase assay. Assays to determine (epithelial cell marker), desmin (smooth muscle cell marker), factor VIII transcriptional activity were described previously (39). Briefly, 18Co cells (endothelial cell marker), CD45 (bone marrow–derived hematopoetic cell were transfected with 0.5 Ag of AR reporter plasmid (À850 to À87) or VEGF marker), CD83 and ILT3 (dendritic cells), lysozyme and MAC 387 (both for reporter plasmid (À2279 to +54) along with 0.1 Ag of the pRL-SV plasmid, macrophages), and other markers of dendritic cells, B cells, or endothelia. containing the Renilla luciferase gene (Promega, Madison WI), using the Rat intestinal epithelial (RIE) cells were a generous gift from Dr. Susan FuGENE 6 procedure (Roche, Indianapolis, IN) as described in the Kirkland (University of London) and grown in DMEM with 10% FBS. Human manufacturer’s protocol. Transfected cells were lysed at indicated times umbilical vein endothelial cells (HUVEC) were purchased from Cascade for luciferase assay. Firefly and Renilla
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