No abstract

No abstract

Upregulation of cyclooxygenase-2 (COX-2) and prostaglandin-dependent vascularisation in small adenomatous polyps is an essential part of colon carcinogenesis. To study the underlying cellular mechanisms, LT97 and Caco2 human colorectal tumour cells not expressing endogenous COX-2 were exposed to 1 mM prostaglandin E 2 (PGE 2 ) in their medium. At 30 min after addition, expression of c-fos was stimulated 5-fold and 1.3-fold, respectively, depending on the activation of both extracellular signal-regulated kinase and p38. The amount of c-jun in nuclear extracts was increased 20% in LT97 cells. Expression of COX-2 was upregulated 1.7-fold in LT97 cells and 1.5-fold in Caco2 2 h after prostaglandin (PG) addition by a p38-mediated pathway. The known PGE 2 target gene vascular endothelial growth factor (VEGF) was not modulated. Effects of sustained PGE 2 production were studied in VACO235 cells that have high endogenous COX-2 and in LT97 cells infected with an adenovirus expressing COX-2. Prostaglandin E 2 secretion into the medium was 1 -2 nM and 250 pM, respectively. Expression of both VEGF and c-fos was high in VACO235 cells. In LT97 cells, COX-2 upregulated c-fos expression and c-jun content in nuclear extracts 1.7-and 1.2-fold, respectively, in a PG-dependent way. This shows that exogenous PGE 2 as well as COX-2 overexpression affect signalling and gene expression in a way that enhances tumour progression. British Journal of Cancer (2006) Upregulation of cyclooxygenase-2 (COX-2) expression in early adenomas is an essential prerequisite of colorectal carcinogenesis. It causes elevated levels of prostaglandins (PGs) in the tissue and PG-dependent neovascularisation (Eberhart et al, 1994). Adenomatous polyps regress under therapy with non-steroidal anti-inflammatory drugs whose main cellular target is COX-2 (DuBois et al, 1996). Mice carrying a hereditary mutation in the APC gene (min-mice or transgenic DAPC-mice; (de Wind et al, 1998) develop a multitude of intestinal polyps in a COX-2 and prostaglandin E 2 (PGE 2 )-receptor-dependent way (Sonoshita et al, 2001;Seno et al, 2002;Sunayama et al, 2002). Immunohistochemical analysis of tissue sections shows that much of the COX-2 is located in connective tissue but not in the epithelial compartment of the polyps. In the pathology of human colorectal cancer, COX-2 plays a similar role and has become the main target of chemoprevention in high-risk patients (DuBois et al, 1996;Gupta and Dubois, 2001). As in the mouse models, COX-2 is mainly located in the connective tissue of human adenomatous polyps.This raises the question whether PGs produced in the microenvironment (fibroblasts, endothelial cells or macrophages) can in turn affect early premalignant cells and trigger expression of tumour-associated genes. To answer these questions we have established the human colonic adenoma cell line LT97 from microadenomas of a polyposis patient that do not yet express COX-2 or produce PGE 2 (Richter et al, 2001). Tumour-promoting bile acids have been shown to induce expression of ...

No abstract

No abstract