Cyclooxygenase-2 Activation Mediates the Proangiogenic Effect of Nitric Oxide in Colorectal Cancer

Abstract

Purpose: Up-regulation of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes has been reported in colorectal cancer. We aimed at evaluating the possible interaction between the nitric oxide and COX-2 pathways, and its effect on promoting tumor angiogenesis.Experimental Design: Expression of iNOS, COX-2, vascular endothelial growth factor (VEGF), and CD31 was analyzed in tumor samples and corresponding normal mucosa obtained from 46 surgical specimens. We also evaluated iNOS activity, prostaglandin E 2 (PGE 2 ), cyclic GMP and cyclic AMP production in the same specimens. Nitrite/nitrate levels, and PGE 2 and VEGF production were assessed in HCT116 and HT29 colon cancer cell lines after induction and selective inhibition of the two enzyme pathways.Results: A significant correlation was found between iNOS and COX-2 immunohistochemical expression. PGE 2 production significantly correlated with iNOS activity and cGMP levels. A significant correlation was also found among PGE 2 production, microvessel density, and VEGF expression. Coinduction of both iNOS and COX-2 activities occurred after lipopolysaccharide (LPS) and epidermal growth factor (EGF) treatment in HCT116 and HT29 cells. Inhibition of iNOS by 1400W significantly reduced both LPS-and EGF-induced PGE 2 production. Treatment with LPS, EGF, and arachidonic acid significantly increased VEGF production in the iNOS-negative/COX-2-positive HT29 cells. This effect was completely reversed by treatment with the selective COX-2 inhibitor celecoxib.Conclusions: Our data showed a prominent role of nitric oxide in stimulating COX-2 activity in colorectal cancer. This interaction is likely to produce a cooperative effect in promoting angiogenesis through PGE 2 -mediated increase in VEGF production.

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

“…The absorbance of the organic phase was read spectrophotometrically at 532 nm wavelength over a standard curve of 1,1,3,3-tetramethoxypropane. The values are expressed as ng/mg of proteins, the latter determined as previously described [32].…”

Cyclooxygenase-2 and Inflammation Mediators Have a Crucial Role in Reflux-Related Esophageal Histological Changes and Barrett’s Esophagus

“…Prostaglandin E 2 (PgE 2 ) and Vascular Endothelial Growth Factor (VEGF) Production Supernatants (100 lL each) were utilized for PGE 2 and VEGF determination using competitive enzyme immunoassay kits (Cayman Chemical Co, Ann Arbor, MI, USA) according to methods previously described (Cianchi et al [8]). Celecoxib, 1 lmol/L, was added 30 min before adding EGF or DCA at 1 lM concentration.…”

“…COX-1 is considered a housekeeping gene and is constitutively expressed in most normal tissues, whereas COX-2 is an inducible enzyme, which can be rapidly induced by cytokines, inflammatory mediators, growth factors and tumour promoters and is related to human inflammatory diseases and carcinogenesis in different tissues [1][2][3][4][5]. A large body of evidence suggests that induction of COX-2 plays a pivotal role in cancer development by promoting cell proliferation, decreasing apoptosis rate, stimulating angiogenesis and increasing invasive and metastatic potential of the primary tumour [6][7][8][9]. A role of COX-2 in carcinogenesis is also indirectly supported by a wealth of epidemiological data which have shown an association of the long-term use of non steroidal anti-inflammatory drugs (NSAIDs) with a decreased incidence of colorectal, gastric and oesophageal cancers [10].…”

Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer

“…Studies with aberrant data (over a 10-fold difference than those reported in other papers) were also excluded. Based on these criteria, 12 studies were excluded from our collection (Liu et al, 1999;Haggstrom et al, 2000;Bhujwalla et al, 2001;Feldman et al, 2001;George et al, 2001;Huss et al, 2001;Kelavkar et al, 2001;Calvo et al, 2002;Mabjeesh et al, 2003;Cianchi et al, 2004;Singh et al, 2004;May et al, 2005) (Supplementary Table S6). …”