The role of hypoxia in recurrence following resection of Dukes' B colorectal cancer.
OBJECTIVE
Tumour hypoxia has been shown to be a predictor of early distant relapse in node-negative breast and cervical cancer. The purpose of the present study was to determine the role of hypoxia in predicting patients who are at high risk of disease recurrence in Dukes B colorectal cancers.


METHODS
Archival tissue was retrieved from 52 patients who had undergone surgical resection for primary colorectal cancer. Tissue micro-arrays were constructed using tissue from the margin and the centre of the tumour. Hypoxia markers hypoxia-inducible factor (Hif)-1 alpha, vascular endothelial growth factor (VEGF), carbonic anhydrase (CA)-9 and glucose transporter (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
Primary colorectal cancers with a high Hif-1 alpha expression tended to have a significantly worse disease-free survival (log rank p < 0.001) and overall survival (log rank p = 0.012). VEGF was also a significant predictor of disease recurrence in primary colorectal cancers (p = 0.015). Significant correlations were also noted between Hif-1 alpha and VEGF (Pearson's p = 0.009). Glut-1 and CA-9 did not show a similar pattern with no differences in the expression pattern and no correlation observed with any of the markers. Multivariate analysis of prognostic factors showed vascular invasion (p < 0.001) and Hif-1 alpha at the tumour margin (p < 0.001) to be independent predictors for the development of liver metastases.


CONCLUSIONS
These results suggest an important role for Hif-1 alpha and VEGF in colorectal cancer progression, with both markers biological mechanisms directly interlinked through the hypoxic pathway. Identification of high-risk patients using the above factors will improve treatment strategies in node-negative disease and help improve patient outcome.
Rajaganeshan
R
R
Academic Surgical Unit, St James's University Hospital, Level 8, Clinical Sciences Building, Leeds LS9 7TF, UK. ugmrr@leeds.ac.uk
Prasad
R
R
Guillou
P J
PJ
Poston
G
G
Scott
N
N
Jayne
D G
DG
D014408:Biomarkers, Tumor / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D003082:Colectomy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000601:surgery; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D014408:Biomarkers, Tumor; D027342:Excitatory Amino Acid Transporter 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D002256:Carbonic Anhydrases