Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer.
OBJECTIVE
Recent studies have shown that cyclooxygenase (COX)-2 and its products, prostaglandins (PGs), may be involved in colorectal carcinogenesis. The aim of this study was to determine whether COX-2 expression and PGE(2) production correlate with microvessel density, vascular endothelial growth factor (VEGF) expression, and tumor metastasis in human colorectal cancer.


METHODS
Tumor samples and adjacent normal mucosa were obtained from 31 surgical specimens. Immunohistochemical expression of COX-2, VEGF, and CD31 was analyzed on paraffin-embedded tissue sections. COX-2 and COX-1 proteins were determined by Western blot analysis. COX-2 and VEGF messenger RNA expressions were evaluated using Northern blot analysis. PGE(2) production was determined by specific radioimmunoassay.


RESULTS
The immunohistochemical expressions of both COX-2 and VEGF were significantly correlated with microvessel density (P = 0.02 and P = 0.002, respectively). A significant correlation was found between COX-2 and VEGF expression (P = 0.004). Western analysis confirmed the up-regulation of COX-2 protein expression. COX-2 and VEGF genes were overexpressed in tumor specimens as compared with normal mucosa. PGE(2) levels were significantly higher in metastatic tumors than in nonmetastatic ones (P = 0.03).


CONCLUSIONS
COX-2 is related to tumor angiogenesis in colorectal cancer. It is likely that VEGF is one of the most important mediators of the COX-2 angiogenic pathway.
Cianchi
F
F
Department of General Surgery, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. cianchif@mail.unifi.it
Cortesini
C
C
Bechi
P
P
Fantappiè
O
O
Messerini
L
L
Vannacci
A
A
Sardi
I
I
Baroni
G
G
Boddi
V
V
Mazzanti
R
R
Masini
E
E
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone