Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma

BMC Cancer

Ewa Pomianowska²  Dagny Sandnes³  Krzysztof Grzyb¹  Aasa R Schjølberg⁴  Monica Aasrum³  Ingun H Tveteraas³  Vegard Tjomsland²  Thoralf Christoffersen³  Ivar P Gladhaug² 

[1] Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway

[2] Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway

[3] Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway

[4] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

关键词: Collagen synthesis;    DNA synthesis;    Cyclic AMP;    Prostaglandin E₂;    Pancreatic stellate cells;   

Others  :  1125395
DOI  :  10.1186/1471-2407-14-413

 received in 2013-05-03, accepted in 2014-05-20,  发布年份 2014

【 摘 要 】

Background

Several 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.

Methods

Immunohistochemistry 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 [³H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [³H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR.

Results

Immunohistochemistry 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.

Conclusions

The 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.

【 授权许可】

   
2014 Pomianowska et al.; licensee BioMed Central Ltd.

【 图 表 】

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