Cyclooxygenase-2 (COX-2) is selectively over-expressed in colorectal tumours. The mechanism of COX-2 induction in these tumours is not fully understood, although evidence suggests a possible link between nuclear factor (NF)-κB and COX-2. We hypothesised an association between COX-2 expression and NF-κB-p65, NF-κB-p50 and IκB-kinase-α (IKKα) in both epithelial and stromal cells in human colorectal cancer.
Using immunohistochemistry, we measured COX-2, NF-κB-p65, NF-κB-p65 nuclear localisation sequence (NLS), NF-κB-p50, NF-κB-p50 NLS and IKKα protein expression in matched colorectal biopsy samples comprising both non-tumour and adjacent tumour tissue from 32 patients with colorectal cancer.
We have shown that stromal cells of malignant and surrounding normal colorectal tissue express COX-2. In all cell types of malignant tissue, and in vascular endothelial cells (VECs) of neighbouring normal tissue, COX-2 expression was strongly associated with NF-κB-p65 expression (Pearson's correlation, P=0.019 for macrophages, P=0.001 for VECs, P=0.002 for fibroblasts (malignant tissue), and P=0.011 for VECs (non-malignant tissue)) but not NF-κB-p50 or IKKα.
These data suggest that in these cells COX-2 induction may be mediated through activation of the canonical NF-κB pathway. Finally, the lack of association between COX-2, NF-κB-p65 or IKKα in stromal cells with the clinical severity of colorectal cancer as determined by Duke's stage, suggests that COX-2, NF-κB-p65 and IKKα expression are possibly early post-initiation events, which could be involved in tumour progression.