Serum Levels of Vascular Endothelial Growth Factor (VEGF) and Endostatin in Renal Cell Carcinoma Patients Compared to a Control Group

european urology 51 (2007) 168–174

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Kidney Cancer

Serum Levels of Vascular Endothelial Growth Factor (VEGF) and Endostatin in Renal Cell Carcinoma Patients Compared to a Control Group Luigi Schips a,*, Orietta Dalpiaz a, Katja Lipsky a, Cord Langner b, Peter Rehak c, Peter Puerstner d, Karl Pummer a, Richard Zigeuner a a

Department of Urology, Medical University Graz, Graz, Austria Institute of Pathology, Medical University Graz, Graz, Austria c Institute of Biostatistics, Medical University Graz, Graz, Austria d Department of Obstetrics and Gynaecology, Medical University Graz, Graz, Austria b

Article info

Abstract

Article history: Accepted June 15, 2006 Published online ahead of print on July 5, 2006

Objectives: Renal cell carcinoma (RCC) is a vascularised neoplasm. The importance of the angiogenic process in its growth and metastatic spreading is widely recognised. We assessed serum levels of endogenous endostatin and vascular endothelial growth factor (VEGF) in RCC patients and healthy volunteers, and evaluated the factors’ prognostic role for patients’ survival, distinguishing histologic subtypes with respect to correlation with tumour stage, grade, and size. Methods: We considered 146 consecutive patients with RCC and 110 healthy volunteers. Serum samples from all subjects were analysed for endostatin and VEGF by using competitive enzyme immunoassays. RCC samples were compared with serum from the control group and with clinicopathologic factors and clinical outcome. Results: Mean age was 63 years (range: 37–85 years) in RCC patients and 62 years (range: 23–88 years) in the control group. VEGF levels (median: 3.6 ng/ml  6.97; range: 0–48.4 ng/mL) were significantly higher in RCC patients, compared with controls ( p = 0.001). Endostatin levels did not differ significantly between the two groups ( p = 0.9) without correlation between endostatin and VEGF levels ( p = 0.09). No significant difference was found in the endostatin levels among the histologic subtypes ( p = 0.973) and VEGF ( p = 0.232). The median follow-up was 27 months (range: 1–57 months). Conclusions: Serum VEGF levels are elevated in RCC patients, compared with controls, and do not correlate significantly with circulating endostatin levels. No difference in preoperative serum VEGF and endostatin levels among the different histologic subtypes was found. In multivariate analysis VEGF and endostatin failed to be prognostic; only tumour stage and grade remained independent predictors of survival.

Keywords: Renal cell carcinoma VEGF Endostatin Angiogenesis

# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Medical University Graz, Auenbruggerplatz 7, 8036 Graz, Austria. Tel. +43 316 385 2152; Fax: +43 316 385 3550. E-mail address: [email protected] (L. Schips). 0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2006.06.026

european urology 51 (2007) 168–174

1.

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 angiogenesisrelated 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 [9–11]. Furthermore, all

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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. 2.

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 institutional review board and informed consent from all patients were obtained. All RCC patients underwent radical nephrectomy. All specimens were systematically reevaluated by one pathologist (C.L.). Tumour staging was performed according to the TNM stage classification system (2002), tumour grade was based on Fuhrman grading [12], and histologic subtypes were assessed according to the World Health Organization guidelines [13]. After surgery all patients were followed up with clinical and radiologic examinations. Peripheral blood samples were obtained before surgery from a peripheral vein; after centrifugation the serum was stored at 70 8C degrees until analysis. We collected samples from 110 consecutive patients who had no history or evidence of any malignant disease and were treated at our department for nonmalignant urologic diseases. Serum endostatin and VEGF were determined with the use of competitive enzyme immunoassays (ACCUCYTE Human VEGF and ACCUCYTE Human Endostatin; Cytimmune Sciences Inc, Rockville, MD). For statistical analysis, data are presented as means and medians, including ranges and standard deviations (SD). Differences between the two groups were evaluated with the Wilcoxon test. The Spearman correlation test was used to evaluate correlations between serum VEGF and endostatin levels. Associations between clinicopathologic variables (pT stage, tumour grade) were assessed by the chi-square test. The Kruskal-Wallis tests for nonparametric variables were used to compare serum levels of VEGF and endostatin and histopathologic groups. The Mann-Whitney and linear regression model were used to compare values of VEGF and endostatin, and stage, histologic grade, and size of lesions. p values 0.05 were considered statistically significant.

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The survival time was measured from date of nephrectomy to date of death or date of last follow-up. Prognostic impact of either parameter was evaluated by the Kaplan-Meier method and the log-rank test. For multivariate testing, a Cox proportional hazards regression analysis was performed for parameters including serum VEGF level, serum endostatin level, age, gender, tumour size, tumour grade, and pT stage.

3.

Comparison of VEGF and endostatin measurements

Median VEGF serum levels were 3.6 ng/ml ( SD: 6.97; range: 0–48.4) in patients with RCC, compared with median levels of 1.6 ng/ml ( SD: 2.57; range: 0.1–22.4) in the control patients ( p = 0.0001). Endostatin levels did not differ significantly between the two groups: in RCC patients; median levels were 30.0 ng/ml ( SD: 19.02; range: 0–101.2), compared with 30.4 ng/ml ( SD: 15.28; range: 4.9–76.2) in the control group, respectively ( p = 0.9) (Table 2). Table 1 – Clinical and pathologic characteristics of RCC patients No. of RCC patients Age (yr) (range) Gender

146 63 (37–85) 86 male 60 female

Mean pathologic size of neoplasms (cm) (range)

5.3 (1–15.8)

Fuhrman grade (N) (%) 1 2 3 4

16 (11) 77 (53) 51 (35) 2 (1)

pT (N) (%) 1a 1b 2 3a 3b

51 (35) 24 (16) 10 (7) 28 (19) 33(23)

Histologic type (N) (%) Clear cell Papillary Chromophobe Unclassified

115 (79) 11 (8) type 1, 5 (3) type 2 6 (4) 9 (6)

RCC: renal cell carcinoma.

Serum levels

RCC patients

Control group

p value

VEGF (ng/ml  SD) Endostatin (ng/ml  SD)

3.6  6.97

1.6  2.57

0.0001

30.0  19.02

30.4  15.28

0.9

RCC: renal cell carcinoma; VEGF: vascular endothelial growth factor.

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. 3.1.

Table 2 – Serum VEGF and endostatin levels in the RCC and control groups

Within the RCC group, no associations between VEGF levels and stage, grade, or tumour size could be observed. No significant difference was found among the endostatin levels of the histologic subtypes ( p = 0.973) and VEGF ( p = 0.232) (Table 3, Figs. 1 and 2). 3.2.

Correlation between VEGF and endostatin levels

Median and standard deviation values of VEGF and endostatin are reported in Table 2. No correlation was found between endostatin and VEGF levels in the cancer patients ( p = 0.09; Spearman’s rho). Using linear regression analysis, we found no correlation between serum levels of VEGF or endostatin and pathologic stage, grade, or tumour size ( p = NS) (Table 4). 3.3. Impact of VEGF and endostatin measurements on survival

After a median follow-up of 27 months (range: 1–57 months), 113 patients were alive and free of disease, 15 were alive with metastatic RCC, and 18 died of carcinoma. In multivariate analysis only stage pT3 (relative risk [RR] = 5.3; 95% confidence interval [CI] = 1.8–15.6; p = 0.002) and Fuhrman grade 3–4 (RR = 12.5; 95% CI = 4.0–39.1; p < 0.0001) resulted in independent prognostic factors, whereas neither serum VEGF nor endostatin showed a prognostic significance in terms of survival.

Table 3 – Serum levels of VEGF or endostatin among histologic subtypes Histotype Clear cell carcinoma Papillary type 1 Papillary type 2 Chromophobe Granular p value*

VEGF (ng/ml  SD)

Endostatin (ng/ml  SD)

3.6  6.9 2.4  2.3 1.6  2.6 5.2  3.5 2.0  3.2 0.232

30.0  19.0 36.4  20.5 44.8  18.9 28.2  19.6 27.2  14.2 0.973

VEGF: vascular endothelial growth factor. Kruskal-Wallis test.

*

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Table 4 – Correlation between serum levels of VEGF or endostatin and pathologic stage, grade and tumour size using a linear regression model ( p value)

Stage Grade Size

VEGF

Endostatin

0.051 0.281 0.918

0.713 0.410 0.988

VEGF: vascular endothelial growth factor.

4.

Fig. 1 – Levels of VEGF in the different histologic subtypes.

Fig. 2 – Levels of endostatin in the different histologic subtypes.

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 patients was found. Feldman et al. [8] reported high preoperative endostatin levels in 66 patients with RCC. Furthermore, the levels of both VEGF and endostatin increased significantly after nephrectomy with a significantly poorer prognosis when the levels increased more than 2-fold after surgery. They demonstrated a moderate correlation between serum endostatin and VEGF levels, suggesting that a correlation between both factors may be associated with the elaboration of proteases that cleave endostatin from collagen XVIII in the peritumoural environment. It is also possible that elevated endostatin levels represent a direct response to elevated VEGF levels [14]. In our study no correlation between endostatin and VEGF levels in the RCC patients was found. Our results are in agreement with data published by others authors. Wechsel et al. [15] did not find a correlation between levels of the angiogenesis factors b-FGF, VEGF, angiogenin, and the tumour vascular density in RCC. Furthermore, they could demonstrate no survival benefit for RCC patients with normal serum levels of b-FGF, VEGF, and angiogenin over those with elevated serum angiogenic factor levels. Angiogenesis seems to represent an essential factor for development and progression of RCC, but until now the determination of systemic angiogenic factors might not have led to adequate data concerning prognosis in RCC. In an analysis of serum VEGF in 53 patients with RCC, Edgren et al. [16] could not indicate a correlation between serum VEGF levels, tumour stage, and patient survival. Recently Beecken et al. [17] demonstrated that

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serum angiogenetic activity of 28 patients with RCC did not differ significantly from that of healthy controls. Furthermore, no correlation of the serum angiogenic activity and tumour stage and grade has been found. In contrast, Jacobsen et al. [18] and Sato et al. [19] found significantly higher levels of VEGF in serum of RCC patients, compared with control patients, and reported that serum VEGF levels were significantly correlated with tumour stage, grade, and survival. However VEGF did not remain as an independent prognostic factor in multivariate analysis, confirming the results of this study. The local activation of tumour angiogenesis might not lead to an increase in serum angiogenic activity in RCC, as it seems to be the case in other neoplasms. The lack of systemic detection of tissue activation of angiogenesis could be explained by different mechanisms, such as small amounts of proangiogenic factors making sufficient systemic detection impossible or a coexpression of enzymatic activity, leading to the formation of a systemically active angiogenesis inhibitor that abrogates the systemic angiogenic activity. Another possible mechanism could be that the activation of angiogenesis in RCC is based on vulnerable factors that lose their activity on freezing. However, studies with a larger cohort might show different results. Furthermore, conflicting results could be explained by the different laboratory detection tests of serum angiogenetic factors. Laboratory methods have different technologies, qualifications, specificities, and sensitivities. Table 5 reports the main series for assessing the expression of angiogenetic factors in renal cancer, including information on measurements and type of test used. Another bias could exist in assessing angiogenetic levels in plasma or serum samples. By definition, plasma is the virtually cellfree supernatant obtained after centrifugation of the whole blood. Serum resembles plasma in composition but lacks the coagulation factors; this difference may result in significant variability and/or misclassification. Therefore, interpretation of the results is complex and, in our opinion, clinical value and costeffectiveness have to be assessed. In all reported

studies serum samples and enzymatic immunoassay have been used for analysis; this approach is essential in comparing results. Patients with histologically different tumours, and thus a different spectrum of clinical behaviour, can show a wide variation in clinical outcome [20]. The impact of various genetic, biologic, and histologic factors is particularly important in establishing a diagnostic and staging system in renal cancer. The current histopathologic classification system does not predict the biologic behaviour of RCC sufficiently to establish the best therapeutic strategy. On the basis of histologic features, conventional clear cell carcinoma is highly vascularized; increased serum levels of VEGF and endostatin have been demonstrated. In contrast, papillary carcinoma and chromophobe appears hypoavascular, pointing to a possible difference in terms of the angiogenic process and thus angiogenic factors expression. In the present study no difference in preoperative serum VEGF and endostatin levels among the different histologic subtypes was found. This finding could depend on the limited incidence of the neoplasm subtypes, which limits disproportionately the knowledge about the underlying molecular basis for development and progression of the subtypes. In this study 79% of patients had a clear cell carcinoma, and 11%, 4%, and 6% had a papillary, chromophobe, and unclassified histologic type, respectively. A fine equilibrium exists between physiologic proangiogenic and antiangiogenic factors, and the complexity of gene expression implicates a real difficulty in the understanding of the histogenesis of renal tumours, which until now has been defined only by surgical approach [21]. Thus, the search for potential serum markers could be effective for preoperative diagnosis, prognostic evaluation, and therapeutic strategies. New rationally designed therapies with smart drugs that target pathways involved in signal transduction and angiogenesis have been developed, and recently antiangiogenic drugs are being investigated with promising results, as reported in a recent review [22]. This study shows the important role of angiogenic factors in tumour angiogenesis, confirming

Table 5 – Main series reporting VEGF and endostatin measurements Study Feldman (14) Edgren (16) Beecken (17) Jacobsen (18) Sato (19) Prsent study

nr RCC/controls

Laboratory test

Sample

Sensibility (%)

Specificity (%)

15/18 53 28/28 164 40/40 146/110

Competitive EIA EIA ELISA Quantitative EIA Sandwich ELISA Competitive EIA

Serum Serum Serum Serum Serum Serum

n.a. n.a. n.a. n.a. 80 n.a.

n.a. n.a. n.a. n.a. 72.5 n.a.

EIA: enzymatic immunoassay, ELISA: enzyme-linked immunosorbent assay, RCC: renal cell carcinoma.

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the data reported in literature. Their potential prognostic value is still debated and needs to be investigated in prospective clinical trials. Tumour stage and nuclear grade are currently the most powerful independent predictors of cancer-specific survival [23,24], but improved prediction is needed. Attempts to find better prognostic criteria remain under investigation. Individual studies of VEGF expression, Ki-67 LI, CD44 LI, and microvascular invasion provided significant survival information [10,25,26]. In our study the angiogenic factors failed to be independent predictors of cancer-specific survival probability, and, at a median follow-up of 27 months, only stage and grade remained independent prognostic variables. Furthermore, we would suggest the potential role of serum markers in predicting response to antiangiogenic drugs and in monitoring treatment. In the future, the 2-fold higher VEGF levels in RCC patients, compared with controls, may serve as a basis for evaluating VEGF as a marker after treatment of RCC.

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Editorial Comment Vincenzo Ficarra, Department of Urology, University of Verona, Italy [email protected] Angiogenesis plays an essential role in tumor growth and metastatization. In clear cell renal cell carcinoma (RCC), hypoxia as well as mutations of von Hippel-Lindau (VHL) gene can induce the expression of the genes involving in angiogenesis through the hypoxia-inducible factor 1a (HIF-1a) pathway. Moreover, some vascular endothelial growth factors (VEGFs) are present at high concentration within clear cell RCC. Specifically, VEGF-A is a glycoprotein involved in tumor neoangiogenesis, while VEFG-C and -D are supposed to play a role in tumor metastatization [1]. In the present issue of European Urology, Schips et al. assessed the prognostic role of serum levels of VEGF in a cohort of patients with non-metastatic RCC. Although the VEGF values were higher compared to those of an age-matched healthy control group, serum VEGF turned out to be unrelated to pathological stage, nuclear grades, and pathological size of the tumors. Moreover, VEGF was not proven to be an independent predictor of cancer-specific survival, regardless of tumor stage and grade. The data from the study enriches the previously available literature, which was controversial. Studies performed in patients with metastatic [2] and non-metastatic [3] RCC had previously failed to show the prognostic value of VEGF. Moreover, although Jacobsen et al. demonstrated correlations between VEGF levels and other pathological variables such as stage and grade, an independent predictive role was not proven [4].

Some drugs with anti-angiogenetic action are currently under investigation for the second-line treatment of the patients with metastatic RCC. Results from phase II studies are encouraging, allowing to hypothesize further protocols for adjuvant treatment of the patients with high risk cancers [1]. In this context, the paper from Schips et al. pointed out that, to date, the levels of VEGF cannot be used to select the patients with the worst prognosis who should undergo therapies with anti-angiogenetic drugs. Specifically, pathological stage, nuclear grade, pathological tumor size, and the presence of coagulative necrosis are the most powerful predictors of cancer-specific survival in patients with clear cell RCC. Those variables and the prognostic algorithms which include them should be still used to select patients for further clinical trials.

References [1] Patard JJ, Rioux-Leclerq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49:633–43. [2] Edgren M, Lennernas B, Larsson A, Kalkner KM. Angiogenic factors: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) are not necessarily elevated in patients with advanced renal cell carcinoma. Anticancer Res 2001;21:1423–9. [3] Beecken WD, Bentas W, Glienke W, et al. Serum angiogenic activity: diagnostic relevance in renal cell carcinoma. Eur Urol 2002;42:364–9. [4] Jacobsen J, Rasmuson T, Grankvist K, Ljungberg B. Vascular endothelial growth factor as prognostic factor in renal cell carcinoma. J Urol 2000;163:343–7.