The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment.
It is widely accepted that alterations to cyclooxygenase-2 (COX-2) expression and the abundance of its enzymatic product prostaglandin E(2) (PGE(2)) have key roles in influencing the development of colorectal cancer. Deregulation of the COX-2/PGE(2) 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/PGE(2) 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 beta-catenin function that fine-tune signalling networks to meet the ever-changing demands of a tumour.
Greenhough
Alexander
A
Department of Cellular and Molecular Medicine, Cancer Research UK Colorectal Tumour Biology Group, University of Bristol, University Walk, Clifton, Bristol, UK.
Smartt
Helena J M
HJ
Moore
Amy E
AE
Roberts
Heather R
HR
Williams
Ann C
AC
Paraskeva
Christos
C
Kaidi
Abderrahmane
A
D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D027361:Organic Anion Transporters; D018078:Receptors, Prostaglandin E; C503526:SLCO2A1 protein, human; D051176:beta Catenin; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; D015232:Dinoprostone