To date, there have been few studies on COX‐2 expression in human ampullary cancer tissues. In our series the great majority of ampullary carcinomas (97.5%) showed expression of COX‐2 protein, suggesting an important role in ampullary cancer.
Recent studies have shown that COX‐2 is involved in several potential mechanisms of cancer development and progression. COX‐2 inhibits apoptosis by activation of an apoptosis repressor gene, bcl‐222,23
; confers invasive ability on tumour cells in vitro by activating metalloproteinase, which is the prerequisite for tumour invasion24
; and stimulates tumour angiogenesis through the modulation of production of variable angiogenic factors.16,22
Tumour angiogenesis is controlled by a balance of angiogenic and angiostatic regulators involved in multiple pathways that result in endothelial proliferation, differentiation, and organisation into a functional network of vascular channels.25,26
Moreover, tumour angiogenesis, as quantitated by measurement of MVD, has been shown to be a significant negative prognostic factor in several cancers.27,28,29
Among the many reported angiogenic factors, VEGF—a key factor for induction of tumour angiogenesis—is increased in various human tumours.20,30
In the present study, a positive statistical correlation was found between VEGF and MVD in ampullary carcinoma (p<0.0001). The median value of MVD was lower in VEGF negative than in VEGF positive tumours (p
0.02). These data are consistent with other reports that found a strong positive correlation between VEGF expression and MVD in various human tumours.31,32
We believe that our study has shown for the first time that there is a relation between VEGF expression and MVD in human ampullary carcinoma. Furthermore, on the basis of the median MVD value, a significant statistical difference was found between VEGF grade 1 and grade 2 tumours (p
0.001) and between VEGF grade 2 and grade 3 tumours (p
0.012). These results show the direct relation between MVD and VEGF as any augmentation of VEGF expression is associated with a significant increase in MVD.
Tsujii et al16
used an endothelial cell/colon carcinoma co‐culture model to explore the role of COX in tumour related angiogenesis. They showed that COX‐2 overexpression stimulates endothelial motility and tube formation by the increased production of proangiogenic factors such as VEGF. These effects can be blocked by NS‐398, a selective inhibitor of COX‐2. One hypothesis is the stimulation of tumour angiogenesis by the products of COX‐2 activity, especially PGE2. PGE2 has been reported to be capable of stimulating VEGF production in various cell types,33,34,35
and to enhance angiogenesis in pancreatic carcinoma.36
To investigate the angiogenic pathway involved in COX‐2 activity in ampullary cancer, we evaluated VEGF expression and found that it was correlated with COX‐2 immunoreactivity (p
0.001). To the best of our knowledge, this is the first time a relation has been shown between COX‐2 activity and VEGF expression in human ampullary carcinoma.
Take home messages
- COX‐2 is highly expressed in ampullary carcinomas, suggesting involvement of the COX‐2 pathway in ampullary tumour associated angiogenesis.
- This provides a rationale for targeting COX‐2 in the treatment of ampullary cancer.
These data are in accordance with previous in vitro studies in which hypoxia—a common event in tumour biology resulting from exponential cellular proliferation37
—upregulates COX‐2 expression, which increases PGE2 levels; PGE2 induces translocation of HIF‐1α into the nucleus, inducing VEGF transcription.18
COX‐2‐induced prostaglandins contribute to tumour growth by promoting the formation of new blood vessels that sustain tumour cell viability and growth.38
Moreover, recent data indicate that COX‐2 inhibitors are powerful anti‐angiogenic agents in vivo.16
In our series, we failed to demonstrate a correlation between COX‐2 expression and tumour MVD (p
0.053). COX‐2 expression and MVD were not directly correlated, so any augmentation of COX‐2 expression associated with increase in MVD probably results from its strong relation to VEGF expression.
Our immunohistochemical findings cannot show a direct cause–effect link between COX‐2 overexpression and tumour angiogenesis through VEGF activity. However, our results suggest an involvement of the COX‐2 pathway in ampullary tumour associated angiogenesis and provide the rationale for clinical studies aimed at examining the efficacy of COX‐2 inhibitors for the treatment or prevention of ampullary carcinoma.