Carcinogenesis Advance Access originally published online on January 9, 2009
Carcinogenesis 2009 30(3):377-386; doi:10.1093/carcin/bgp014
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The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment
Cancer Research UK Colorectal Tumour Biology Group, Department of Cellular and Molecular Medicine, University of Bristol, University Walk, Clifton, Bristol BS8 1TD, UK
1 The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
* To whom correspondence should be addressed. Tel: +44 117 331 2072; Fax: +44 117 928 7896; Email: c.paraskeva{at}bristol.ac.uk
It is widely accepted that alterations to cyclooxygenase-2 (COX-2) expression and the abundance of its enzymatic product prostaglandin E2 (PGE2) have key roles in influencing the development of colorectal cancer. Deregulation of the COX-2/PGE2 pathway appears to affect colorectal tumorigenesis via a number of distinct mechanisms: promoting tumour maintenance and progression, encouraging metastatic spread, and perhaps even participating in tumour initiation. Here, we review the role of COX-2/PGE2 signalling in colorectal tumorigenesis and highlight its ability to influence the hallmarks of cancer—attributes defined by Hanahan and Weinberg as being requisite for tumorigenesis. In addition, we consider components of the COX–prostaglandin pathway emerging as important regulators of tumorigenesis; namely, the prostanoid (EP) receptors, 15-hydroxyprostaglandin dehydrogenase and the prostaglandin transporter. Finally, based on recent findings, we propose a model for the cellular adaptation to the hypoxic tumour microenvironment that encompasses the interplay between COX-2, hypoxia-inducible factor 1 and dynamic switches in β-catenin function that fine-tune signalling networks to meet the ever-changing demands of a tumour.
Abbreviations: APC, adenomatous polyposis coli; COX, cyclooxygenase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated protein kinase; GSK3β, glycogen synthase kinase-3 beta; HIF-1, hypoxia-inducible factor-1; MAPK, mitogen-activated protein kinase; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2; PGES, prostaglandin E synthase; PGF2
, prostaglandin F2; PGT, prostaglandin transporter; PI3K, phosphatidylinositol-3-OH kinase; PPAR, peroxisome proliferator-activated receptor; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; TCF, T-cell factor; TGFβ, transforming growth factor-beta; VEGF, vascular endothelial growth factor
Received September 8, 2008; revised December 4, 2008; accepted January 4, 2009.
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