Investigating COX isoform dependency in intestinal tumourigenesis


Session type:


Noha-Ehssan Mohamed1,Rachel Ridgway1,Owen Sansom1
1Cancer Research UK Beatson Institute, Glasgow, UK



Inflammation is known to play important roles in sporadic colorectal cancer as well as in colitis-associated cancer. Cyclooxygenase-2 (COX-2), the inducible COX isoform responsible for prostaglandin production, is highly expressed in colorectal adenomas and adenocarcinomas. Targeting COX-2 using non-selective (e.g. aspirin) as well as selective (e.g. celecoxib) COX-2 inhibitors reduces the incidence of colorectal carcinoma and prevents adenoma recurrence. Recently, it has been shown that COX-1 expression is elevated in response to COX-2 deletion in melanoma cell lines and in fibroblasts, resulting in production of prostaglandins. Whether a similar compensation happens in intestinal tumours is not known.


To fully investigate COX isoform dependency, a genetically-engineered mouse (GEM) with a knockout of Ptgs2 (gene coding for COX-2) was crossed to the small intestinal adenoma ApcMin/+ mouse, to investigate tumour initiation and progression. To investigate possible compensation by COX-1, another GEM where Ptgs1 (gene coding for COX-1) is knocked into the Ptgs2 locus, characterized by a full loss of COX-2 protein and overexpression of COX-1 protein (the COX-1KI/KI mouse), was used. The COX-1KI/KI mouse was crossed to the ApcMin/+ mouse.


In the ApcMin/+ adenoma mouse, COX-2 knock out delayed tumour initiation, prolonged survival, and decreased intestinal tumour formation. Similarly, in the ApcMin/+ COX-1K1/KI mouse, tumour initiation in the small intestine (SI) was delayed as reflected by a decrease in the total number of tumours developed as well as the size of the tumours in SI collected from 120 days old mice. Survival benefit was evident upon ageing ApcMin/+ COX-1KI/KI mice, and this was associated with a decrease in SI tumour numbers. These tumours were characterized by being less proliferative and highly infiltrated by T-cells.


COX-2 is the isoform controlling intestinal tumour initiation and progression. COX-1 does not compensate for COX-2 in intestinal tumourigenesis.