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

Oncogene volume 21, pages 7175–7186 (2002)Cite this article

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-β type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-β1) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1–2 μM) 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.

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Acknowledgements

We acknowledge the kind assistance of the Molecular Medicine Unit Confocal Imaging Group with the immunofluorescence experiments and the expert assistance of Dr S Shnyder (University of Bradford, UK) with the caecal xenograft experiments. This work was funded by the MRC (UK), Yorkshire Cancer Research and the West Riding Medical Research Trust. MA Hull holds an MRC (UK) Clinician Scientist Fellowship.

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  1. Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK

    Stanley CW Ko, Keith S Chapple, Gillian Hawcroft, P Louise Coletta, Alexander F Markham & Mark A Hull

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Correspondence to Mark A Hull.

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Ko, S., Chapple, K., Hawcroft, G. et al. Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells. Oncogene 21, 7175–7186 (2002). https://doi.org/10.1038/sj.onc.1205869

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