Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells.

Abstract

In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cell-cell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-beta type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-beta(1)) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1-2 microM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce anti-neoplastic effects in vitro and in vivo.

• Authors: Stanley C W Ko, Keith S Chapple, Gillian Hawcroft, P Louise Coletta, Alexander F Markham, Mark A Hull
• Journal: Oncogene (Oncogene) Vol. 21 Issue 47 Pg. 7175-86 (Oct 17 2002) ISSN: 0950-9232 [Print] England
• PMID: 12370807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• Isoenzymes
• Pyrazoles
• Sulfonamides
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone

Topics

• Animals
• Cell Transformation, Neoplastic
• Cells, Cultured
• Cyclooxygenase 2
• Dinoprostone (physiology)
• Epithelial Cells (metabolism)
• Intestines (cytology)
• Isoenzymes (metabolism)
• Macrophage Activation
• Macrophages (metabolism)
• Mice
• Paracrine Communication
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Pyrazoles (pharmacology)
• Rats
• Sulfonamides (pharmacology)