Carcinogenesis Advance Access published online on January 9, 2009
Carcinogenesis, 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
1 Cancer Research UK Colorectal Tumour Biology Group, Department of Cellular and Molecular Medicine, University of Bristol, University Walk, Clifton, Bristol, BS8 1TD, United Kingdom
2 The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom
* To whom correspondence should be addressed. E-mail: 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 cyclooxygenase-prostaglandin pathway emerging as important regulators of tumorigenesis; namely, the prostanoid (EP) receptors, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter (PGT). 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 (HIF-1), and dynamic switches in β-catenin function that fine-tune signalling networks to meet the ever-changing demands of a tumour.
Received September 8, 2008; revised December 4, 2008; accepted January 4, 2009.
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