Kidney CancerSerum Levels of Vascular Endothelial Growth Factor (VEGF) and Endostatin in Renal Cell Carcinoma Patients Compared to a Control Group
Introduction
Renal cell carcinoma (RCC) is a heterogeneous disease with different genetic, biochemical, and morphologic features, accounting for about 3% of all solid tumours [1]. Clear cell carcinoma represents the most common histologic subtype, with a frequency of up to 80% of adult renal masses [2]. It is a highly vascularised neoplasm, showing a fine vascular network around tumour cells, and is characterised by an unpredictable pattern of metastasis [3]. Papillary and chromophobe tumours usually present a hypovascular pattern and show indolent behaviour, presenting a limited risk of progression and mortality [4].
Angiogenesis and the expression of angiogenesis-related genes produced by several neoplasms appear to mediate neoplastic growth and metastatic potential of several solid neoplasms. Tumours stimulate angiogenesis either by the upregulation of angiogenesis stimulators (e.g., VEGF, basic fibroblast growth factor [b-FGF]) or the downregulation of endogenous angiogenesis inhibitors (e.g., endostatin, thrombospondin-1, and angiostatin). The importance of the angiogenic process in RCC growth and development of metastasis is widely recognized [5], even if all studies are restricted to the clear cell type and show conflicting results. VEGF, also known as vascular permeability factor (VPF), is a dimeric glycoprotein and a member of the platelet-derived growth factor (PDGF) superfamily of growth factors. It has a critical importance in both normal and tumour-associated angiogenesis through increased microvascular permeability to plasma proteins, induction of endothelial cell division and migration, and promotion of endothelial cell survival through protection from apoptosis [6]. VEGF expression results from inactivation of the von Hippel-Lindau (VHL) tumour-suppressor gene, which is observed in the majority of RCC cases, thus identifying VEGF as a critical component of tumour angiogenesis. On the other hand, endostatin, a 20 kDa, C-terminal fragment of collagen XVIII, is an endogenous inhibitor of angiogenesis; it was first isolated from a murine hemangioendothelioma cell line and was found to have potent antitumour activities in mice [7]. Recently Feldman et al. [8] demonstrated the presence of endogenous endostatin in the circulation of healthy humans and elevated circulating endostatin levels in patients with RCC.
Although several studies demonstrated that the tumour tissue of RCC liberates angiogenic factors into the systemic blood flow and the physiologic relevance of angiogenic factors in tumoural angiogenesis is well accepted, their potential prognostic value is still under debate [9], [10], [11]. Furthermore, all studies were restricted to the clear cell type and show conflicting results.
The aims of our study were to compare the serum levels of VEGF and endostatin in RCC patients and in healthy volunteers to correlate the measurements to each other and to the usual clinical and pathologic parameters in RCC, and to test the respective prognostic values of the two measurements in uni- and multivariate analyses. Furthermore, we investigated the clinical relevance of VEGF and endostatin levels in distinguishing histologic subtypes with respect to correlation with tumour stage and grade, and size of neoplasms.
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Materials and methods
The study included 146 consecutive patients with RCC and 110 patients with nonmalignat urologic disease (controls) who were treated between October 1997 and June 2004. Preoperative evaluation included physical examination, blood count and serum chemistry, chest radiography, abdominal ultrasound, and computed tomographic (CT) scan of the kidneys. When intravenous contrast agents were contraindicated or caval invasion was suspected, magnetic resonance imaging was performed.
Approval by our
Results
Of the 146 RCC patients, 86 were men and 60 women with a mean age of 63 years (range: 37–85 years). There were 90 men and 20 women with a mean age of 62 years (range: 23–88 years) in the control group. Characteristics of RCC patients and tumour characteristics are reported in Table 1. No significant differences in age and gender were observed between the two groups of patients.
Discussion
In the last few years, several investigators evaluated the angiogenic process in renal cancer, and numerous serum markers or immunohistochemical tissue features have been proposed to predict prognosis of RCC. However, reported data on angiogenesis factors, such as VEGF or endostatin, show contradictory results. In the present study, patients with RCC present a significantly higher level of VEGF in serum than do control patients. No difference in endostatin levels between control and RCC
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Cited by (43)
Biomarkers of Renal Cancer
2017, Biomarkers of Kidney DiseaseBrain Metastasis from Renal Carcinoma: Locoregional and Systemic Treatments
2015, Brain Metastases from Primary Tumors: Epidemiology, Biology, and TherapyVascular endothelial growth factor as a biomarker for endostatin gene therapy
2013, Biomedicine and PharmacotherapyCitation Excerpt :Tumor growth is dependent on angiogenesis, which is controlled by proangiogenic and antiangiogenic molecules. VEGF is a central regulator of tumor angiogenesis and is highly expressed in many types of tumors, including RCC [27–31]. Thus, both angiogenesis and VEGF have been confirmed as targets of anticancer therapeutics [32].
Basic research in kidney cancer
2011, European UrologyCitation Excerpt :A third study suggested that large changes in serum VEGF, sVEGFR-2, and sVEGFR-3 levels corresponded with tumour response [62], and a fourth study found a correlation between fold increase of serum VEGF and clinical benefit [63]. In view of the contradictory results with VEGF and VEGFR [64,65], these markers might be more suitable as predictive than as diagnostic markers. Other markers related to tumour biology such as MMP-7, CD95, bFGF, hepcidin-25, interleukin (IL)-10, or IL-6 showed promising results as possible biomarkers for RCC [66–70].
Prognostic factors and predictive models in renal cell carcinoma: A contemporary review
2011, European UrologyCitation Excerpt :For example, in 302 mRCC patients, baseline serum VEGF levels predicted progression-free survival (HR: 1.19; p < 0.001) and overall survival (HR: 1.39; p < 0.001) after treatment [140]. However, serum VEGF failed to achieve independent predictor status in other studies [138–141]. This may be due to analytical problems in some of the studies.
Identification of Stanniocalcin 2 as Prognostic Marker in Renal Cell Carcinoma
2009, European UrologyCitation Excerpt :In order to allow for an individualized therapy, there is a clear need for novel prognostic biomarkers to ensure adequate risk stratification and to help with the choice of therapy options [4]. However, studies evaluating the expression of angiogenetic growth factors such as vascular endothelial growth factor (VEGF) in the serum of patients with RCC have produced conflicting results [5]. Several microarray-based expression studies have been conducted to characterize the molecular mechanisms of RCC development and to provide targets for further biomarker validation.