Activated VEGFR2/KDR pathway in tumour cells and tumour associated vessels of colorectal cancer.
BACKGROUND
Vascular endothelial cell growth factor (VEGF) acts by phosphorylating specific tyrosine kinase receptors on endothelial cell membrane promoting angiogenesis. The study of the activation status of VEGF receptors in human malignancies has recently become feasible by means of specific monoclonal antibodies recognising the phosphorylated form of these receptors.


METHODS
In the current study, we investigate the expression of the phosphorylated VEGFR2/KDR receptor in normal colon and colorectal adenocarcinomas in parallel with histopathological parameters, prognosis and the expression of the 'hypoxia inducible factor' HIF1alpha.


RESULTS
pVEGFR2/KDR was weakly expressed in the normal colon, but it was expressed strongly in the cytoplasm and nuclei of cancer cells and in the tumour associated vasculature, mainly at the invading tumour edge. pVEGFR2/KDR expression in cancer cells was significantly associated with a tumour diameter > 6 cm (P = 0.04), poor histological differentiation (P = 0.004) and with high CEF1alpha expression (P = 0.05). High pVEGFR2/KDR expressing vascular density was significantly related with a high VEGF and HIF1alpha expression in cancer cells (P = 0.02 and 0.03, respectively). This was also related significantly to high pVEGFR2/KDR expression in cancer cells. In multivariate analysis, the most significant predictors for death were lympho-vascular invasion (P < 0.001) followed by VEGF (P = 0.014), node status (P = 0.015), standard vascular density (P = 0.022) and necrosis (P = 0.032).


CONCLUSIONS
pVEGFR2 receptors are largely expressed in colon cancer cells and intratumoural vasculature. As VEGF targeting agents enter the clinical practice, the role of monoclonal antibodies recognising the phosphorylated form of VEGF receptors as predictors of response to targeted therapies should be sought in clinicopathological trials.
Giatromanolaki
A
A
Tumor and Angiogenesis Research Group, Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
Koukourakis
M I
MI
Sivridis
E
E
Chlouverakis
G
G
Vourvouhaki
E
E
Turley
H
H
Harris
A L
AL
Gatter
K C
KC
D000230:Adenocarcinoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2