The angiogenic switch occurs at the adenoma stage of the adenoma carcinoma sequence in colorectal cancer.
OBJECTIVE
The aim of this study was to examine the relationship between tissue factor (TF), vascular endothelial growth factor (VEGF) and the onset of angiogenesis in the adenoma-carcinoma sequence (ACS), the stepwise process encompassing colorectal cancer (CRC) disease progression.


METHODS
210 surgical specimens comprising the ACS were immunohistochemically stained for endothelial cells (CD31), VEGF and TF. Angiogenesis quantified using Chalkley grid analysis (microvascular density; MVD), and VEGF/TF expression were semiquantitatively graded and correlated with standard prognostic indicators including 5 year follow-up. VEGF and TF were measured by ELISA in tumour specimens and normal mucosa from an additional 90 CRC patients.


RESULTS
There was a significant increase in MVD across the ACS (p < 0.0005) with significant correlations with Dukes' stage (p = 0.01) and lymph node involvement (p = 0.02). The greatest increase in MVD was related to the onset of dysplasia, with an associated significant increase in VEGF expression (p < 0.0005). There was a significant relationship between VEGF and TF expression in the initial phase of the ACS (k = 0.44, p < 0.005), although no correlation between VEGF or TF, and MVD, tumour size, Dukes' classification, lymph node involvement or survival was found.


CONCLUSIONS
These findings are the first to suggest that the angiogenic switch occurs at the onset of dysplasia in the ACS, and provide further evidence of the close association between VEGF and TF in the early stages of CRC development.
Staton
Carolyn A
CA
Academic Unit of Surgical Oncology, University of Sheffield Medical School, Sheffield S10 2RX, UK.
Chetwood
Andrew S A
AS
Cameron
Iain C
IC
Cross
Simon S
SS
Brown
Nicola J
NJ
Reed
Malcolm W R
MW
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism; D000236:Adenoma / Q000098:blood supply* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D016019:Survival Analysis; D013925:Thromboplastin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin