Heterogeneous Expression of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Within Colorectal Tumors: Correlation with Tumor Angiogenesis

Background: Recent studies have shown that the cyclooxygenase (COX) and the inducible nitric oxide synthase (iNOS) pathways are involved in the development of tumor angiogenesis in human cancers.

Aims: To investigate whether a different pattern of COX-2 and iNOS expression/activity exists within different areas of colorectal tumors and to analyze the relationship between these two enzymes and tumor angiogenesis.

Methods: Microvessel density (MVD) and COX-2, iNOS, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein expression were evaluated at both the invasive front (IF) and the tumor center (TC) in 46 human colorectal cancer specimens. We also investigated the concentration of PGE2 and NO at the same sites.

Results: COX-2 and iNOS protein expression and activity were significantly higher within the IF than the TC of the tumor specimens. Similarly, MVD and VEGF/VEGFR-2 expression significantly increased from the TC to the IF. Only COX-2 expression was significantly correlated with MVD and VEGF/VEGFR-2 expression at both the TC and the IF.

Conclusion: Our study shows a heterogeneous expression of COX-2 and iNOS in colorectal cancer. The up-regulation of COX-2 at the IF parallels an increase in vessel density and VEGF/VEGFR-2 expression, thus supporting the hypothesis that the tumor periphery is the most aggressive portion of a colorectal tumor.