Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients

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Abstract

Solid tumours require neovascularisation for growth and metastasis. Vascular endothelial growth factor (VEGF) has been shown to be an important regulator of tumour angiogenesis. To examine the relevance of VEGF in the neoplastic transformation of human colon, we analysed protein expression in a total 30 polyps and 145 colorectal carcinomas by immunohistochemistry. All adenoma specimens, regardless of histological differentiation, and normal colonic mucosa did not express VEGF. Amongst 90 patients with non-metastatic colorectal cancer, VEGF expression was observed in 43 (48%) cases, whilst 29 of the 55 patients (53%) with metastases expressed the angiogenic factor. Both the proportion and intensity of VEGF expression were positively associated with the progression of colon carcinogenesis. Tumours with the highest VEGF expression tended to correlate with patients' survival, although VEGF expression did not emerge as an independent risk factor in a multivariate analysis. After exclusion of the patients with distant metastases, both univariate and multivariate analysis did not indicate any prognostic value for the tissues with the highest VEGF expression. Our results suggest that VEGF may play a role in the progression of colon cancer, although evaluation of this angiogenic phenotype did not provide additional prognostic information compared with that obtained from Dukes' staging of the tumours.

Introduction

Traditionally, the clinical outcome of colorectal cancer patients may be predicted by pathological staging, by either Dukes' staging or the UICC-TNM system. However, some of Dukes' stage A (approximately 10%) and Dukes' stage B patients (30–40%) will develop local recurrence or distant metastasis years after receiving standard surgical treatments. Therefore, it is important to find some other indicators that can predict for recurrence or the development of metastases so that we can screen for high-risk early-stage patients who may need preventive chemotherapy or other adjuvant therapy.

Angiogenesis, or the development of a vascularised stroma, is essential for tumours to grow beyond a minimal size 1, 2 and metastasise 3, 4, 5. Growth factors secreted by tumour cells regulate angiogenesis by acting via members of a family of endothelial-specific receptors. Although various factors may be capable of either positively or negatively regulating endothelial cell growth and neovascularisation, vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been shown to be definitely associated with angiogenesis 6, 7. VEGF is a 34–42 kDa multifunctional glycosylated dimeric protein with structure homology to platelet-derived growth factor [8] and is expressed in four isoforms derived by alternative mRNA splicing 9, 10, 11, i.e. VEGF206, VEGF189, VEGF165 and VEGF121. Of these, VEGF165 is known to be the most abundant isoform. VEGF may contribute to angiogenesis by stimulating endothelial cell mitogenesis and inducing microvessel permeability 12, 13. VEGF has been detected in a variety of human neoplasms 14, 15, 16, 17, 18, 19, 20, 21, 22. The expression of VEGF in colorectal cancer, either at the mRNA or protein level, is reported to be higher than that in normal colonic mucosa. In addition, VEGF levels are higher in metastatic cell lines and colorectal cancer tissues than in non-metastatic cells or tissues [23].

In contrast to the number of studies reporting an association between high microvessel density and a greater incidence of metastases and decreased survival 24, 25, 26, 27, 28, few studies on the role of VEGF expression in predicting the prognosis of the patients with cancers, especially colorectal cancers, have been published. Amongst those studies, some have indicated VEGF expression as an independent factor in predicting patient prognosis 29, 30, 31, whilst others reported no such association 32, 33, 34. This retrospective cohort study was performed to clarify the relationship between VEGF expression and the long-term survival of colorectal cancer patients.

Section snippets

Patients and tumour specimens

145 paraffin-embedded colorectal cancer specimens resected at the Department of Surgery, National Cheng Kung University Hospital from 1989 to 1993 were studied. These specimens belonged to consecutive patients collected from chronological hospital records both retrospectively and non-selectively. None of the patients had received chemotherapy or radiation therapy before surgery. 41 patients were recruited in 1989, 29 in 1990, 40 in 1991, 25 in 1992 and 10 in the first 3 months of 1993. There

Results

The demographic and tumour characteristics of the 145 patients are summarised in Table 1. Our series had a majority of locally advanced cases with 66% of patients with T4 tumours. In the 84 patients with Dukes' stage B tumours, 53 (63%) had T4 tumours; in the 35 patients of Dukes' stage C, 22 (66%) had T4 tumours. 38 (75%) of the 51 patients with sigmoid colon cancer, 42 (82%) of the 51 patients with proximal colon cancer, and 15 (35%) of the 43 patients with rectal cancer had T4 tumours.

Discussion

Angiogenesis, or the development of a vascularised stroma, is essential for tumours to grow beyond a minimal size 1, 2 and metastasise 3, 4. It has been demonstrated that increased vessel counts in solid tumours are associated with a higher risk of metastasis of various types of cancers 3, 25, 26, 27, including colon cancer [28]. In support of this hypothesis, expression of VEGF has been shown to correlate positively with microvessel count and metastasis [24]. This study was performed to

Acknowledgements

This study was supported by NCKUH-86-011 from National Cheng Kung University Hospital, Tainan, Taiwan.

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