Inhibitory effects of prostaglandin E2on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinomaReport as inadecuate




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BMC Cancer

, 14:413

Cell and molecular biology

Abstract

BackgroundSeveral studies have described an increased cyclooxygenase-2 COX-2 expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis.

MethodsImmunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin αSMA. Pancreatic stellate cells PSC were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by H-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of H-thymidine in DNA. Cyclic AMP cAMP was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR.

ResultsImmunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β IL-1β, epidermal growth factor EGF, thrombin, and PGE2, but not by transforming growth factor-β1 TGFβ. Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase ERK. Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis.

ConclusionsThe present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors.

KeywordsPancreatic stellate cells Prostaglandin E2 Cyclic AMP DNA synthesis Collagen synthesis Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-413 contains supplementary material, which is available to authorized users.

Ewa Pomianowska, Dagny Sandnes contributed equally to this work.

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Author: Ewa Pomianowska - Dagny Sandnes - Krzysztof Grzyb - Aasa R Schjølberg - Monica Aasrum - Ingun H Tveteraas - Vegard Tjoms

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