Vascular endothelial growth factor and interleukin-8 are associated with poor prognosis in epithelial ovarian cancer patients

https://doi.org/10.1016/j.clinbiochem.2004.01.014Get rights and content

Abstract

Background: Ovarian cancer represents an important problem in gynecologic oncology. A growing tumor induces the host endothelial cells to proliferate and supply the requisite vascular support allowing tumor development. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) have been demonstrated to induce angiogenesis in epithelial tumors in vivo.

Patients and methods: This study included 24 tumors from patients with epithelial ovarian cancer in different stages, in addition to 20 tissue samples of benign ovarian lesions as a control group. VEGF has been measured in the cytosolic fractions using enzyme immunoassay and confirmed by Western blot analysis. Tissue IL-8 mRNA was assessed using reverse transcriptase polymerase chain reaction and immunohistochemistry for its protein.

Results: VEGF mean rank was significantly higher in ovarian cancer tumors compared to benign lesions (P < 0.001). Moreover, it was increased with advanced stages (P < 0.05) and in patients with poor survival (P < 0.05). Eight samples were positive for IL-8 mRNA, seven of them were in malignant group, with highest frequency in stages III and IV of the disease (6/12, 50%). IL-8 correlated with poor survival of the patients (P < 0.05). Log rank of Kaplan–Meier survival analysis was significant for FIGO stage, VEGF, and IL-8 (P < 0.05).

Conclusion: These results indicate that VEGF and IL-8 are related to the malignant transformation process and can be considered as indicators of poor prognosis in epithelial ovarian cancer patients.

Introduction

The identification of prognostic factors that attempt to predict which patients are at high risk for poor outcome is one major advance in the management of ovarian carcinoma. Despite advances in chemotherapy, ovarian carcinoma remains the leading cause of death from gynecologic malignancy with mortality rates decreasing only marginally over the past few decades [1].

Tumor angiogenesis is a process necessary for solid tumor growth through establishment of the adequate blood supply for propagation of tumor cells and metastasis [2]. Among the tumor angiogenic factors, the main factors induced from tumor cells are basic fibroblast growth factor (basic FGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) [3].

Vascular endothelial growth factor (VEGF) is a disulfide-linked 34–45 kDa homodimeric glycoprotein expressed by a wide variety of solid tumors. It was reported first to have the ability to increase microvascular permeability [4]. Later, its capacity to act as a selective endothelial mitogen in addition to its ability to induce angiogenesis in vivo has been demonstrated [5]. Four subtypes of VEGF have been identified: VEGF206, 206 amino acids; VEGF189, deletion of exon 6′, 189 amino acids; VEGF165, deletion of exon 6, 6′, 165 amino acids; and VEGF121, deletion of exons 6, 6′, and 7, 121 amino acids. The smaller species are secreted and soluble, while the larger ones are secreted but remain bound to the cell and/or extracellular matrix, due to the addition in larger forms of basic sequences that bind more tightly to heparin and other polyanions [6].

Ovarian cancer has been proposed to be “a cytokine-propelled disease” based on the numerous cytokine receptors that are expressed in these tumors [7]. Interleukin-8 (IL-8) is a small (8 kDa) chemotactic cytokine mainly attracting and activating neutrophilic granulocytes, but it is also implicated in angiogenic events [8]. Local expression of IL-8 has been reported in several human tumor types, such as colorectal, breast, and prostate carcinomas [9], [10], [11].

The aim of the current investigation is to examine the clinical significance and the predictive value of VEGF overexpression as well as the frequency of IL-8 expression in epithelial ovarian cancer patients to acquire more information about possible role of these angiogenic factors in the biology of ovarian tumors.

Section snippets

Subjects and methods

This study was conducted in the period from March 1999 to April 2002. The clinical specimens were obtained from the Obstetrics and Gynecology Department, Ain Shams University Hospitals. The laboratory work was carried out at the Oncology Diagnostic Unit (ODU), Medical Biochemistry Department, Ain Shams Faculty of Medicine.

Results

Vascular endothelial growth factor and IL-8 expression were assessed in benign and malignant ovarian tumors. The benign group included 20 patients (mean age, 37.1 ± 12.2; range, 20–60 years); the malignant group included 24 epithelial ovarian cancer patients (mean age, 43.5 ± 15.9; range, 21–65 years). Of the malignant group, 10 tumors were papillary serous adenocarcinoma, 7 were mucinous, and 7 were endometrioid tumors. All patients have been followed up for a total follow-up period of 36

Discussion

Newly developed capillary network formation from the original vessel is known as neovascularization. Generally, the turnover of capillary endothelial cells is extremely slow in, the order of months or years, physiologic neovascularization, whereas the turnover in the ovary and the endometrium is rapidly altered along with the ovarian cycle. In malignant transformation, the turnover becomes rapid, which could contribute to the acceleration of tumor growth [21].

In this study, it was demonstrated

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