Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases

Aim: To understand the role of hypoxia in cancer progression of primary colorectal cancer and colorectal liver metastases. To look at associations of hypoxia with more aggressive phenotypes. Methods: Archival tissue was retrieved from 55 patients and tissue micro arrays were constructed using tissue from the margin and the Centre of the tumour. Hypoxia markers Hif-1 alpha, Vegf, CA-9, VRL and Glut-1 were visualised using immunohistochemical detection and quantified using semi-quantitative analysis of the digitised images. Clinical details and outcome data were retrieved by case note review and collated with hypoxia markers data in a statistical database. Results: Significantly increased expression of all markers were found at the tumour margin compared to the tumour Centre, both in primary colorectal cancer (CRC) and liver metastases. Pushing margin CRC was associated with increased Vegf expression. Positive correlations were observed between Hif-1 alpha and Vegf (p < 0.001), and Hif-1 alpha and VHL (p < 0.001) in primary CRC, but no relationship was seen between Hif-1 alpha and either Glut-1 or CA-9. A significant trend to worse disease-free survival was also noted with increased margin expression of Hif-1 alpha (p < 0.001) and VHL (p = 0.02) in primary CRC, but not for any of the other markers. Conclusion: This study underlines the importance of the invasive margin in colorectal cancer biology. It is the area most responsive to hypoxic influences and its dependence on its ability to up-regulate Hif-1 alpha has a significant impact on disease-free survival. (C) 2009 Elsevier Ltd. All rights reserved.