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Clinical Cancer Research 14, 3362, June 1, 2008. doi: 10.1158/1078-0432.CCR-07-4707
© 2008 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

Preoperative Plasma Endoglin Levels Predict Biochemical Progression After Radical Prostatectomy

Robert S. Svatek1, Jose A. Karam1, Claus G. Roehrborn1, Pierre I. Karakiewicz2, Kevin M. Slawin3 and Shahrokh F. Shariat1,3

Authors' Affiliations: 1 Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; 2 Cancer Prognostics and Health Outcomes Unit, University of Montreal, Montreal, Quebec, Canada; and 3 Baylor Prostate Center, The Scott Department of Urology,Baylor College of Medicine, Houston, Texas

Requests for reprints: Shahrokh F. Shariat, Department of Urology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110. Phone: 469-363-8500; Fax: 214-648-8786; E-mail: Shahrokh.Shariat{at}UTSouthwestern.edu.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Purpose: Endoglin (CD105) is a transmembrane glycoprotein expressed by human vascular endothelial cells thought to play a pivotal role in endothelial cell proliferation. The aim of this study was to evaluate the association of preoperative plasma endoglin levels with established clinical and pathologic features of prostate cancer and disease progression after radical prostatectomy.

Experimental Design: Preoperative plasma endoglin levels were measured in 425 patients who underwent radical prostatectomy for clinically localized prostate cancer using a commercially available ELISA assay. Multivariate logistic regression was used to test the association of plasma endoglin levels with biochemical progression after radical prostatectomy.

Results: Median follow-up for patients alive at the time of analysis was 36.8 months (interquartile range, 44.1). Of 425 patients, 77 patients (18.1%) experienced biochemical progression after radical prostatectomy. Preoperative plasma endoglin levels were significantly elevated in patients with higher preoperative total serum prostate-specific antigen (P < 0.001) and adverse pathologic features. Preoperative plasma endoglin was an independent predictor of biochemical progression after surgery after adjusting for the effects of standard preoperative and postoperative features (P < 0.001 and P = 0.026, respectively).

Conclusions: Preoperative plasma endoglin levels are associated with established features of advanced prostate cancer. More importantly, higher preoperative plasma endoglin levels are independent predictors of an increased risk of biochemical progression in patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy.

Widespread screening with prostate-specific antigen (PSA) has resulted in early detection of prostate cancer for men in the United States. Today, the majority of patients diagnosed with prostate cancer are found to have clinically localized disease (1). As a result, most men are counseled to undergo treatment with curative intent, most often with radical prostatectomy or radiation therapy. Although these modalities provide durable cancer control for the majority of men with clinically localized prostate cancer, the disease course is variable and approximately one third of patients eventually fail treatment, as evidenced by a detectable and rising PSA (2, 3). Nomograms and multivariate Cox regression models use important clinical variables such as PSA and pathologic features of the prostatectomy specimen, to predict disease outcome in men treated for prostate cancer (4, 5). However, the biological variability of prostate cancer cannot be satisfactorily predicted by clinicopathologic criteria alone. Identification of new markers that can account for the biological variability of prostate cancer is needed to improve our ability to determine which patients are destined to fail primary localized treatment.

Endoglin, or CD105, is a transmembrane glycoprotein (6) that is typically expressed by human vascular endothelial cells (7). Functionally, it is a cell-surface coreceptor for transforming growth factor β1 and β3 (8) that modulates cellular responses to transforming growth factor β in the early steps of endothelial cell proliferation. Its critical role in angiogenesis has prompted investigators to evaluate the role of endoglin in cancer progression and metastasis of various malignancies such as breast and colon carcinoma (9, 10). In prostate cancer tissue, endoglin is preferentially found on new, immature blood vessels, and tissue immunohistochemical analysis supports an association between endoglin expression and disease progression (11). We have previously studied 425 patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy, and showed that preoperative endoglin levels were significantly associated with pelvic lymph node metastasis.(12) We have used here the same cohort of patients to more thoroughly analyze the association of endoglin with PSA recurrence and other pathologic features after radical prostatectomy.


   Materials and Methods
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Patient population. All studies were undertaken with the approval and oversight of the Institutional Review Board for the Protection of Human Subjects at both institutions. The study comprised 425 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma who had plasma samples available. Study period was from July 1994 through November 1997. The clinical stage was assigned by the operative surgeon according to the 1992 tumor-node-metastasis system. No patients received preoperative hormonal or radiation therapy and none had secondary cancers. Serum total PSA was measured by the Hybritech Tandem-R assay (Hybritech, Inc.). Staff pathologists from each institution, who were blinded to clinical outcome, examined all prostatectomy specimens. Evaluation of the radical prostatectomy specimen was done as previously described (13) in accordance with the guidelines of the College of American Pathologists (14).

Plasma endoglin measurements. Plasma samples were collected after a preoperative overnight fast on the morning of the day of surgery, at least 4 wk after transrectal guided needle biopsy of the prostate. Blood was collected into Vacutainer CPT 8-mL tubes containing 0.1 mL of Molar sodium citrate (Becton Dickinson Vacutainer Systems) and centrifuged at room temperature for 20 min at 1,500 g. The top layer corresponding to plasma was decanted using sterile transfer pipettes. The plasma was immediately frozen and stored at –80°C in polypropylene cryopreservation vials (Nalgene; Nalge Nunc). For quantitative measurements of endoglin levels, we used a commercially available quantitative immunoassay (R&D Systems). Every sample was run in duplicate, and the mean was calculated for data analysis. Differences between the two measurements were minimal (intra-assay precision coefficients of variation, 7.9% ± 5.0%).

Postoperative follow-up. Patients generally were scheduled to have a digital rectal examination and serum total PSA evaluation postoperatively every 3 mo for the first year, semiannually from the second through the fifth year, and annually thereafter. PSA progression was defined as a sustained elevation, on two or more occasions, of serum total PSA of >0.2 ng/mL and was assigned to the date of the first value of >0.2 ng/mL. Patients were categorized into those with features of aggressive disease progression and those without. Features of aggressive disease progression included positive metastatic work-up (positive bone or ProstaScint scan), PSA doubling times <10 mo, and/or failure to respond to local salvage radiation therapy as previously described (13).

Statistical analysis. Continuous variables are reported as medians and interquartile range (IQR). Differences in endoglin levels across categorical variables were assessed using the Mann-Whitney U test or the Kruskal-Wallis test. Spearman's rank correlation coefficient was used to compare ordinal and continuous variables. P values of the Spearman correlation were determined by Wilcoxon's rank sum test. The Kaplan-Meier method was used to calculate survival functions, and differences were assessed with the log-rank statistic. Univariate and multivariate survival analyses were done using the Cox proportional hazards regression model. The lowest category was used as the reference category when calculating the hazards ratios. Preoperative total PSA level had a skewed distribution and was therefore modeled with a log transformation. Preoperative endoglin level had a normal distribution. Preoperative total PSA and preoperative endoglin levels were used as continuous variables in the Cox regression models. Three patients did not have information regarding lymph node status, and eight patients did not have biopsy Gleason sum available. Therefore, 414 patients were available for Cox regression analyses. Statistical significance in this study was set at a P value of ≤0.050. All reported P values are two-sided. All analyses were done with SPSS version 13.0 (SPSS, Inc.).


   Results
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Association of preoperative plasma endoglin levels with clinical and pathologic characteristics of prostate cancer. Median patient age was 61.1 years (IQR, 10.9). Median preoperative serum total PSA was 5.7 ng/mL (IQR, 5.0) and median preoperative plasma endoglin level was 28.8 ng/mL (IQR, 18.7-37.5). Overall, 27.6% of the patients had a total PSA of <4 ng/mL, 56.3% had a total PSA between 4 and 9.99 ng/mL, and 16.1% had a total PSA of ≥10 ng/mL. The clinical and pathologic characteristics of the 425 consecutive prostatectomy patients and their association with preoperative plasma endoglin levels are shown in Tables 1 and 2 . Plasma endoglin levels were higher in patients with positive surgical margins (P = 0.029), higher pathologic Gleason sum (P = 0.037), and lymph node metastasis (P < 0.001). In addition, preoperative plasma endoglin level was weakly but positively correlated with preoperative serum total PSA (correlation coefficient, 0.296; P < 0.001) and number of positive biopsy cores (correlation coefficient, 0.105; P = 0.047).


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  		Table 1. Association of preoperative plasma endoglin levels with categorical clinical and pathologic features of 425 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer

 

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  		Table 2. Univariate analysis (Spearman's correlation) of preoperative plasma endoglin levels (ng/mL) with continuous clinical and pathologic variables of 414 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer

 
Association of preoperative plasma endoglin levels with PSA progression after radical prostatectomy. Of 425 patients, 77 patients (18.1%) experienced PSA progression after radical prostatectomy. Median follow-up for patients alive at the time of analysis was 36.8 months (IQR, 44.1). The overall PSA progression-free survival was 79.5% ± 2.3% (SE) at 3 years, 76.6% ± 2.6% ± at 5 years, and 71.7% ± 3.6% at 7 years. Patients with preoperative plasma endoglin levels in the 3rd tertile had a higher probability of PSA progression than those with endoglin levels in the first 2 tertiles (P = 0.014; Fig. 1 ).


Figure 1
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  		Fig. 1. Probabilities of PSA progression-free survival in 425 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized disease stratified by preoperative plasma endoglin tertiles.

 
Preoeprative and postoperative multivariate analyses are shown in Table 3 . In the preoperative analysis, which adjusted for the effects of clinical stage (P = 0.057), preoperative endoglin, preoperative total PSA, and biopsy Gleason sum predicted PSA progression after radical prostatectomy (P < 0.001). In a postoperative analysis, which adjusted for the effects of preoperative total PSA (P = 0.112), extraprostatic extension (P = 0.159), seminal vesicle invasion (P = 0.701), and lymph node metastasis (P = 0.411), preoperative endoglin (P = 0.026), pathologic Gleason sum (P = 0.002), and surgical margin status (P = 0.012) were all three associated with PSA progression after radical prostatectomy.


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  		Table 3. Preoperative and postoperative multivariate Cox regression analyses of clinical and pathologic features for the prediction of PSA progression in 414 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer

 
Association of preoperative plasma endoglin levels with aggressive disease progression after radical prostatectomy. Of the 77 patients with disease progression, 43 (55.8%) of patients were categorized as having features of aggressive disease progression. Features of aggressive progression included PSA doubling time of <10 months (n = 29; median, 6.5 months; range, 0.8-9.7), presence of lymph node metastasis at time of radical prostatectomy (n = 14), development of distant metastasis [positive bone scan or ProstaScint scan (Cytogen); n = 6], and/or failure of local salvage radiation therapy (n = 8). Preoperative plasma endoglin levels were higher (P = 0.040) in patients with features of aggressive disease progression (median, 41.4; IQR, 26.9) compared with patients with features nonaggressive disease progression (median, 33.1; IQR, 19.9).


   Discussion
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The identification of a marker that is able to model the biological potential of prostate cancer will be an invaluable addition to current predictive models for disease progression. To our knowledge, this is the first study to assess the association of blood levels of endoglin with clinical outcomes after radical prostatectomy for clinically localized prostate cancer. Using a commercially available assay, we found that preoperative plasma endoglin levels were associated with markers of advanced prostate cancer such as higher preoperative total PSA values and higher pathologic Gleason sum in a large cohort of consecutive patients treated with radical prostatectomy for clinically localized disease. More importantly, preoperative plasma endoglin level was an independent predictor of biochemical progression after surgery after controlling for the effects of standard preoperative and postoperative features.

Angiogenesis plays a pivotal role in the initiation and progression of solid malignancies (15). Tumor growth beyond 1 to 2 mm is dependent on the development of new blood vessels from existing endothelial cells (15, 16). Angiogenesis is regulated by a balance between proangiogenic and antiangiogenic factors and, in normal tissues, this balance results in a vasculature that is maintained in a steady state. Deregulated angiogenesis requires an increase in stimulating factors, a decrease in inhibiting factors, or both (17). Prostate tumor growth is dependent on angiogenesis, and prostate cancer growth is inhibited by antiangiogenic therapy (18, 19). Prostate cancer progression, prognosis, and survival are related to angiogenesis (20–25); angiogenesis and prostate cancer vascularization correlates with the development of metastatic disease (26).

Endoglin plays a key role in angiogenesis. For example, when endoglin was knocked-out in mice, the mice developed multiple vascular and cardiac defects culminating in their deaths in early embryonic life (27). Mutations in the endoglin gene are associated with hereditary hemorrhagic telangiectasia type 1, a disease characterized by arteriovenous malformations and bleeding in humans. Additional reports clearly identify endoglin as a critical factor in endothelial cell proliferation (28–31). On the other hand, the functional significance of endoglin in prostate cancer cells is less clear. Liu and colleagues (32) observed loss of endoglin expression in prostate cancer cell lines, and suppression of endoglin expression in a panel of prostate cancer cell lines led to increased motility and invasiveness. In contrast to their findings, Sharma and colleagues (33) showed lower levels of endoglin in less metastatic Dunning rat prostate cell line clone variants compared with a more metastatic clone.

Endoglin levels have been shown to be elevated in the serum of patients with angiogenic tumors (9, 10, 34). Immunohistochemical analyses have shown increased endoglin expression in a variety of malignancies such as esophagus (35), lung (36), breast (37, 38), ovary (39), endometrium (39), and prostate cancer (11). In addition, endoglin expression has been shown to be an independent predictor of outcome in endometrial and ovarian cancers (39, 40). Plasma endoglin levels have been observed to be higher in patients who had metastases (10), suggesting elevated plasma endoglin levels could be a surrogate marker for tumor angiogenesis and, thereby, help identify early metastases during follow-up (9, 10).

A number of patients in our cohort were found to have aggressive disease progression characterized by rapid posttreatment PSA doubling time, lymph node metastasis at the time of prostatectomy, or the development of clinical metastasis at time of biochemical progression. Presumably, many of these patients suffered from occult metastatic disease at the time of radical prostatectomy, and the benefit they acquired from surgery was uncertain. A biomarker that is elevated in the face of microscopic metastatic disease would undoubtedly assist in the care of such patients. We speculate that an elevated endoglin level in a patient undergoing radical prostatectomy may be a marker of occult metastasis as we found preoperative plasma levels to be significantly higher in patients experiencing aggressive disease progression compared with those with nonaggressive disease progression. This finding is not surprising, given the persuasive data supporting endoglin as a marker of angiogenesis.

Larger, prospective studies will be needed to validate endoglin as an indicator of aggressive disease and occult metastasis in patients anticipating therapy for presumed organ-confined prostate cancer. Studies with longer follow-up time will be important to confirm these findings and to address additional end-points such as time to metastasis and death from disease. The evaluation of endothelial and prostate tissue levels of endoglin in patients treated with radical prostatectomy will be important to help elucidate the biological role of this marker. In addition, the ability of plasma endoglin to monitor disease in patients with biochemical recurrence or metastatic disease could also be tested.

In conclusion, preoperative plasma endoglin is associated with biochemical progression after radical prostatectomy as well as established features of biologically aggressive prostate cancer such as positive surgical margin status and higher pathologic Gleason sum. Use of preoperative plasma endoglin could help identify patients at risk for disease progression, allowing selection of patients for a more aggressive treatment approach, neo-adjuvant or adjuvant therapy, or enrollment into clinical trials. Most importantly, endoglin may be extremely valuable as a surrogate marker for occult metastatic disease in patients with presumed organ-confined disease. Further investigation is needed to validate endoglin as a useful plasma marker in men with prostate cancer and to elucidate the mechanistic role of this marker in the development of prostate cancer progression.


   Disclosure of Potential Conflicts of Interest
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References
 
No potential conflicts of interest were disclosed.


   Footnotes
 
Grant support: Partially support by NIH K30-RR022269-08 (Clinical Research Curriculum Award: "Training Curriculum in Patient Oriented Research"; J.A. Karam).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: R.S. Svatek and J.A. Karam contributed equally.

Some of the information in Table 1 was submitted for a different manuscript.

Received 11/ 8/07; revised 2/ 8/08; accepted 2/11/08.


   References
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 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
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