Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases.
OBJECTIVE
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-1alpha, Vegf, CA-9, VHL 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-1alpha and Vegf (p<0.001), and Hif-1alpha and VHL (p<0.001) in primary CRC, but no relationship was seen between Hif-1alpha and either Glut-1 or CA-9. A significant trend to worse disease-free survival was also noted with increased margin expression of Hif-1alpha (p<0.001) and VHL (p=0.02) in primary CRC, but not for any of the other markers.


CONCLUSIONS
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-1alpha has a significant impact on disease-free survival.
Rajaganeshan
R
R
Academic Surgical Unit, St. James's University Hospital, Level 7 Clinical Sciences Building, Leeds, LS9 7TF, UK. ugmrr@leeds.ac.uk
Prasad
R
R
Guillou
P J
PJ
Scott
N
N
Poston
G
G
Jayne
D G
DG
D000328:Adult; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D018832:Molecular Chaperones; D010641:Phenotype; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D027342:Excitatory Amino Acid Transporter 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; C108825:VBP1 protein, human; D042461:Vascular Endothelial Growth Factor A; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases