Cancer Letters

Cancer Letters

Volume 208, Issue 2, 28 May 2004, Pages 227-234
Cancer Letters

Correlation of p53 and bcl-2 expression with vascular endothelial growth factor (VEGF), microvessel density (MVD) and clinico-pathological features in colon cancer

https://doi.org/10.1016/j.canlet.2003.11.032Get rights and content

Abstract

This study was designed to elucidate the possible relationship between tumour related genes and angiogenesis in colon cancer. The protein expression of p53, bcl-2, Von Willebrand factor and vascular endothelial growth factor (VEGF) were analysed by immunohistochemistry in 57 paraffin-embedded colon cancer. The results showed that microvessel density (MVD) was lower in VEGF negative tumours than in VEGF positive ones (P<0.0001). MVD and VEGF in p53 negative tumours were significantly lower than in p53 positive tumours (respectively, P=0.003 and P<0.0001). Moreover, positive correlations were recorded between VEGF expression and MVD, and bcl-2 expression (respectively, P<0.0001 and P=0.009). Our data confirm the central role of VEGF in angiogenesis and suggest direct correlations among p53, bcl-2 and VEGF expression in colon cancer.

Introduction

Tumour growth and progression are closely dependent on an imbalance between cellular proliferation and death. The growth of solid tumours beyond a certain critical mass and the development of tumour metastases have been shown to be related to the establishment of a vasculature that provides continuous exposure to blood flow [1].

Some molecular factors related to cell cycle (e.g. proto-oncogenes and tumour suppressor genes) [2], [3], [4], and markers of metastatic propensity (e.g. tumour angiogenesis) [5], [6], [7] have been shown to be involved in the development and progression of colon cancer, one of the most common causes of cancer mortality in women and men. The biological mechanisms underlying their involvement have not yet been completely clarified, but several positive regulators of tumour angiogenesis have been identified. Vascular endothelial growth factor (VEGF) is a well-characterised angiogenic factor and is known to play a crucial role in neovascularisation. Some factors involved in the regulation of VEGF have been identified. The best characterised factor is hypoxia which has been shown to increase transcription of the gene and to stabilise its mRNA product [8], [9].

Recent, experimental results have shown that some tumour suppressor genes are involved in the regulation of angiogenesis [10], and interesting data have been reported on the genetic inactivation of p53 in cancer cells: loss of wt-p53 function contributes to activation of the angiogenic switch in tumours [11].

Moreover bcl-2 overexpression may enhance the synthesis of the hypoxia-stimulated VEGF protein in colon cancer. Recent in vitro studies have demonstrated that bcl-2 overexpression induces an increase of VEGF protein secretion when cells are cultured in hypoxic conditions [12].

Since hypoxia is characteristic of solid tumours, this microenvironmental stress may provide a common signal that induces a prolonged increase in angiogenic gene expression during tumourigenesis [13]. Thus, if tumour hypoxia primes cells for increased VEGF expression, bcl-2 overexpression would provide the necessary signal to increase or maintain this state of angiogenic growth factor production [12].

In this study, we aimed to determine whether p53 and bcl-2 expression correlate with VEGF expression and vessel counts in 57 paraffin-embedded surgical specimens of human colon cancer.

Section snippets

Clinical material

Surgical specimens of colon carcinomas (n=57), from patients with primary colon carcinoma, excluding those with multiple or metachronous cancer, diagnosed from January 1998 to August 2000, were randomly selected from the archives of the Service of Pathology at Campus Bio-Medico, Rome, Italy.

The patients' ages ranged from 33 to 90 years (average, 67); 40 were male and 17 were female. No patient had received chemotherapy or radiation therapy before surgery.

The pathologic features were classified

Correlations between immunohistochemical and pathological parameters and patients' characteristics

No statistically significant correlations were identified between ICH parameters (p53, bcl-2, MVD and VEGF) and patients' characteristics (age, sex and primary tumour site). Moreover, there were no correlations between pathological parameters (T,N,M and grading) and patients' characteristics. Finally, no statistically significant correlations were found between histologic grade of tumours and ICH parameters (data not showed).

Correlations between stage of disease and angiogenesis

MVD was lower in VEGF negative than in VEGF positive tumours (Fig. 1A

Discussion

The role of angiogenesis in the development and progression of human cancers has been widely studied [1], although a more complete knowledge of this phenomenon is obviously required. Since angiogenesis is associated with a higher risk of metastases in various types of cancer [20], [21], [22], we are interested in understanding the genetic regulation of the angiogenetic process. VEGF is a well-characterised angiogenic factor and is known to play a crucial role in tumour angiogenesis [23], [24].

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