Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature

Abstract

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n ¼ 957) for RFS and 18 for OS (n ¼ 2383) and for VEGF in 17 studies, including nine studies for RFS (n ¼ 1064) and 10 for OS (n ¼ 1301). High MVD significantly predicted poor RFS (RR ¼ 2.32 95% CI: 1.39 -3.90; Po0.001) and OS (RR ¼ 1.44; 95% CI: 1.08 -1.92; P ¼ 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR ¼ 2.84; 95% CI: 1.95 -4.16) and OS (RR ¼ 1.65; 95% CI: 1.27 -2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.

Prognostic Value of Carcinoembryonic Antigen and Vascular Endothelial Growth Factor Tumor Tissue Content in Colorectal Cancer

“…Previous studies demonstrated that colon cancer patients with high level of tissue VEGF expression had an unfavorable outcome compared to patients with VEGF-negative tumors [5, 9, 21, 22], but none of them has evaluated the prognostic value of VEGF in association with CEA tumor tissue content. In our analysis, positive VEGF/CEA patients displayed the worst prognosis both in terms of RFS and OS with 5-year survival rates similar to those of Dukes’ stage C + D patients (48 vs. 46% and 65 vs. 65%, respectively).…”

Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer

“…Recently, a meta-analysis of all published studies showed that high MVD predicted poor survival in patients with CRCs. However, the overall link between MVD and survival was rather weak, with a global risk ratio of 1.44 for overall survival [9]. Considering methodological differences among these studies including the variety of endothelial markers with difference in sensitivity (factor VIII, CD31 and CD34), the different cut off values and microvessel counting techniques as well as the difference of patient selection (such as tumour size, stage), the authors of the meta-analysis suggested that future studies on assessment the prognostic significance of angiogenesis should be carried out in a large series of patients with stratification of tumour stage, using specific antibody (CD31 or CD34), standard microvessel counting technique and multivariate regression survival analysis.…”

Molecular Analysis of Vascular Endothelial Growth Factor (VEGF) Receptors in EUS-guided Samples Obtained from Patients with Pancreatic Adenocarcinoma*

“…Most of these evaluate the expression of VEGF using postoperative samples and mice models, or the level of VEGF in blood or bile. Several methods were employed for the assessment of VEGF expression in the tumours: most often immunohistochemistry (IHC), but also RT-PCR or Northern Blot [12]. Circulating VEGF may be related to the tumour, but it is also produced by platelets, granulocytes, monocytes; in addition, its assessment may be technically difficult [13].…”