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Clinical Cancer Research Vol. 10, 1992-1999, March 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Association of Pre- and Postoperative Plasma Levels of Transforming Growth Factor ß1 and Interleukin 6 and Its Soluble Receptor with Prostate Cancer Progression

Shahrokh F. Shariat1,3, Michael W. Kattan4,5, Erica Traxel1, Ben Andrews1, Kuichun Zhu1, Thomas M. Wheeler1,2 and Kevin M. Slawin1

1 Baylor Prostate Center, Scott Department of Urology and 2 Department of Pathology, Baylor College of Medicine, and The Methodist Hospital, Houston, Texas; 3 Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; and Departments of 4 Urology and 5 Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: We have shown that preoperative plasma levels of transforming growth factor-ß1 (TGF-ß1), interleukin 6 (IL)-6, and its receptor (IL-6sR) are associated with prostate cancer progression and metastasis. The objectives of this study were to confirm these findings and to examine the association of changes in plasma levels of these markers after surgery with disease progression in a large consecutive cohort of patients.

Experimental Design: Plasma levels of TGF-ß1, IL-6, and IL-6sR were measured pre- and postoperatively (6–8 weeks after surgery) in 302 consecutive patients who underwent radical prostatectomy for clinically localized disease.

Results: Pre- and postoperative levels of TGF-ß1 were significantly elevated in patients with extraprostatic extension, seminal vesicle involvement, and metastases to lymph nodes. In contrast, preoperative levels of IL-6 and IL-6sR, but not postoperative levels, were significantly associated with tumor volume, prostatectomy Gleason sum, and metastases to lymph nodes. In a postoperative model that included pre- and postoperative TGF-ß1, IL-6, and IL-6sR and standard postoperative parameters, postoperative TGF-ß1 and prostatectomy Gleason sum were significant predictors of overall and aggressive disease progression. Although, for all patients, plasma levels of all three markers declined significantly after prostate removal, for patients that experienced disease progression, only IL-6 and IL-6sR levels decreased significantly.

Conclusions: For patients undergoing radical prostatectomy, preoperative plasma levels of TGF-ß1 and IL-6sR are associated with metastases to regional lymph nodes, presumed occult metastases at the time of primary treatment, and disease progression. After prostate removal, postoperative TGF-ß1 level increases in value over preoperative levels for the prediction of disease progression.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Several pre- and postoperative prostate cancer nomograms have been developed to predict prostate cancer stage and progression after attempted curative therapy. These predictive tools are primarily based on pretreatment prostate-specific antigen (PSA) level, along with clinical stage, biopsy Gleason sum, and in some cases percentage of cores positive (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) . However, recently there has been a dawning realization that pretreatment PSA levels may reflect primarily the presence of benign prostatic hyperplasia rather than prostate cancer. Stamey et al. (11, 12, 13) recently reported that for patients with a PSA level of <9 ng/ml, PSA poorly reflected the risk of progression after radical prostatectomy but was significantly correlated with the volume of the radical prostatectomy specimen, a direct reflection of the degree of benign prostatic hyperplasia present. We have also failed to detect an independent predictive value for preoperative PSA for disease progression in several studies that have included more modern patient cohorts with clinically localized prostate cancer undergoing radical prostatectomy who are more likely than ever to be diagnosed with a PSA level of <10 ng/ml (14 , 15) . Therefore, there is a clear need for novel markers that are specifically associated with biologically aggressive prostate cancer for improved prediction of disease stage and of outcome in patients diagnosed with clinically localized prostate cancer, especially in those patients diagnosed with lower PSA levels.

We and others (16, 17, 18, 19) have previously shown that plasma levels of transforming growth factor ß1 (TGF-ß1), interleukin (IL)-6, and IL-6 soluble form of receptor (IL-6sR) are markedly elevated in patients with distant prostate cancer metastases. However, plasma levels of TGF-ß1, IL-6, and IL-6sR levels were not different between prostate cancer patients and healthy subjects (16 , 17) . Remarkably, we recently demonstrated that in patients undergoing radical prostatectomy for clinically localized disease, preoperative plasma TGF-ß1, IL-6, and IL-6sR were associated with eventual prostate cancer progression, when adjusted for the effects of clinical stage, biopsy Gleason sum and preoperative PSA (16 , 17) . Furthermore, preoperative plasma levels of these markers were associated with features of aggressive disease progression, suggesting that this association was caused by the presence of occult micrometastases already present by the time of surgery. These initial studies prompted us to additionally evaluate the use of these markers for the management of patients with clinically localized prostate cancer as well as to investigate the underlying biological mechanisms responsible for these associations.

Various sources may contribute to the total level of these candidate markers found in the blood of patients with prostate cancer. In addition to direct release from either primary or metastatic tumor cells, the host may also produce these cytokines and receptors as a direct response to distant organ cancer invasion or through a more complex response to cancer metastasis. A better understanding of the biological mechanisms underlying the elevation of circulating levels of TGF-ß1, IL-6, and IL-6sR in patients with clinically evident and occult metastatic cancer would potentially lead to more effective clinical management as well as provide new target pathways for therapy in these patients. Therefore, to confirm the association of preoperative levels of TGF-ß1, IL-6, and IL-6sR with prostate cancer progression, to investigate the association of early postoperative plasma levels of these markers with disease progression, and to gain insight into the origin of circulating TGF-ß1, IL-6, and IL-6sR levels in prostate cancer patients, we studied pre- and postoperative levels of TGF-ß1, IL-6, and IL-6sR in a cohort of 302 consecutive patients who underwent radical prostatectomy for clinically localized disease.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population.
All studies were undertaken with the approval and institutional oversight of the Institutional Review Board for the Protection of Human Subjects at Baylor College of Medicine. All 511 patients admitted to The Methodist Hospital with the intent to treat their clinically localized prostate cancer (cT1c-3a, NX, and M0) with radical prostatectomy by surgeons of the Scott Department of Urology during the period from 11/7/94 through 12/96 were potential candidates for this analysis. The clinical stage was assigned by the operative surgeon according to the 1992 TNM system. After obtaining consent, pre- and postoperative plasma specimens were obtained for 357 of these men. Thirty-five men initially treated with hormonal therapy, 11 who were treated with definitive radiotherapy, and 2 who were treated with cryotherapy before surgery were excluded from the analysis. No disease follow-up information was available for seven men, and they were also excluded. This left 302 men for analysis. The mean patient age in this study was 61.8 ± 7.3 years (median, 62.6; range, 40–80 years). Serum prostate specific antigen was measured by the Hybritech Tandem-R assay (Hybritech, Inc., San Diego, CA).

TGF-ß1, IL-6, and IL-6sR Measurements.
Preoperative serum and plasma samples were collected at least 4 weeks after transrectal guided needle biopsy of the prostate, typically on the morning of the day of surgery after an overnight fast. Postoperative plasma samples were collected between 6 and 8 weeks after surgery. Specimen collection and measurement was described previously (16 , 17) . Briefly, blood was collected into Vacutainer CPT 8-ml tubes containing 0.1 ml of 1 M sodium citrate (Becton Dickinson, Franklin Lakes, NJ) and centrifuged at room temperature for 20 min at 1500 x g. The top layer corresponding to plasma was decanted using sterile transfer pipettes and immediately frozen and stored at -80°C in polypropylene cryopreservation vials (NalgeNunc, Rochester, NY). For quantitative measurements of TGF-ß1, IL-6, and IL-6sR levels, we used quantitative immunoassays (R&D Systems, Minneapolis, MN). We have previously found that TGF-ß1 levels were three to six times higher when measured in serum than when measured in plasma (16) . Because TGF-ß1 is present in platelet granules and is released upon platelet activation, the higher levels of TGF-ß1 in serum were likely due at least in part to release from damaged platelets, making the quantification of nonplatelet-derived TGF-ß1 less accurate. Therefore, as in our previous study, for TGF-ß1, before assessment, an additional centrifugation step of the plasma was performed at 10,000 x g for 10 min at room temperature for complete platelet removal. Every sample was run in duplicate, and the mean was used. Differences between the two measurements for TGF-ß1, IL-6, and IL-6sR were minimal (intra-assay precision coefficients of variation: 5.43 ± 2.01%, 4.37 ± 2.39, and 4.98 ± 3.24%, respectively).

Pathological Examination.
All prostatectomy specimens were examined pathologically at our institution by a single pathologist (T. M. W.) who was blinded to clinical outcome. The radical prostatectomy specimens were processed by whole-mount technique, and pathological parameters were evaluated in a manner described previously (20) . Total tumor volume was computed by computerized planimetry from the whole-mount sections for 255 of the 302 prostatectomy patients (21) .

Postoperative Follow-Up.
Patients generally were scheduled to have a digital rectal examination and serum PSA evaluation postoperatively every 3 months for the first year, semiannually from the second through the fifth year, and annually thereafter. Biochemical progression was defined as a sustained elevation, on two or more occasions, of PSA >0.2 ng/ml and was assigned to the date of the first value > 0.2 ng/ml. Pelvic lymph node dissections were performed on all men. Radical prostatectomy was aborted in 2 of the 6 patients who were found to have nodal metastases on frozen section analysis during the operation; these men are not excluded from the analysis. All patients with metastases to regional lymph nodes were categorized among those with progression from the day after surgery. Six patients (2%) received adjuvant radiation therapy before biochemical progression because of positive surgical margins. Three of them subsequently experienced PSA relapse and were considered to have disease progression from the date of the first value >0.2 ng/ml, whereas the other 3 were censored on the date of the last follow-up examination. Of 302 patients who underwent radical prostatectomy, 43 had progression of disease. A staging evaluation, including bone scan, Prostascint scan, and/or PSA doubling time calculation, was performed in 35 of the 37 patients experiencing biochemical progression before administration of salvage radiation or hormonal therapy. Postprogression serum PSA doubling time was calculated for patients who had biochemical progression, and at least three PSA measurements were performed after the date of progression using the formula: DT = log2 x T/[log(final PSA) - log(initial PSA)] (22) , where DT is the serum PSA doubling time, T is the time interval between the initial and final PSA level, final PSA is the preradiation PSA level, and initial PSA is the PSA level noted at the time of the postoperative biochemical progression. The natural logarithm was used in all logarithmic transformations. Nineteen (51%) of the 37 patients who had biochemical progression were treated at The Methodist Hospital with external beam radiation therapy limited to the prostatic fossa. Radiation was delivered with 15–20 MV photons, and the four-fields technique was used with customized field sizes. Total radiation therapy dose ranged from 60 to 66 Gy, delivered daily in fractions. A complete response to salvage radiation therapy was defined as the achievement and maintenance of an undetectable serum PSA level. Radiation therapy was considered to have failed if the postradiation serum PSA levels did not fall to and remain at an undetectable level (23 , 24) .

Statistical Analysis.
Differences in TGF-ß1, IL-6, and IL-6sR levels between clinical and pathological features were tested by the Mann Whitney U test. Spearman’s rank correlation coefficient was used to compare ordinal and continuous variables. Logistic regression was used for multivariate analysis of binary outcome variables. Multivariable survival analysis was performed with the Cox proportional hazard regression model. Preoperative PSA level had a skewed distribution and therefore was modeled with a log transformation. Clinical stage was evaluated as T1 versus T2 versus T3a. Biopsy and radical prostatectomy Gleason sum were evaluated as grades 2–6 versus 7–10. Differences in TGF-ß1, IL-6, and IL-6sR levels between pre- and postoperative samples were tested by Wilcoxon signed-rank test. Statistical significance in this study was set as P < 0.05. All reported Ps are two-sided. All analyses were performed with SPSS statistical package (SPSS version 10.0 for Windows).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Association of Pre- and Postoperative Plasma Levels of TGF-ß1, IL-6, and IL-6sR with Clinical and Pathological Characteristics.
Clinical and pathological characteristics of the 302 consecutive prostatectomy patients and association with pre- and postoperative plasma TGF-ß1, IL-6, and IL-6sR levels are shown in Table 1Citation . Preoperative and postoperative plasma TGF-ß1 levels were elevated in patients with extraprostatic extension (P = 0.028 and P < 0.001, respectively), seminal vesicle involvement (P = 0.029 and P = 0.023, respectively), and regional lymph node metastases (P < 0.001 and P < 0.001, respectively). Preoperative IL-6 and IL-6sR levels were elevated in patients with prostatectomy Gleason sum >= 7 (P = 0.014 and P = 0.034, respectively) and regional lymph node metastases (P = 0.005 and P < 0.001, respectively). The mean preoperative PSA was 8.9 ± 7.0 ng/ml (median, 7.1 ng/ml; range, 0.2–59.9 ng/ml). Pretreatment TGF-ß1, IL-6, and IL-6sR levels were positively correlated with preoperative PSA levels (P = 0.004, P < 0.001, and P = 0.011, respectively). Pretreatment IL-6 and IL-6sR levels were also positively correlated with prostatic tumor volume (P = 0.018 and P = 0.016, respectively). Postoperative IL-6 and IL-6sR levels were not associated with any of the clinical or pathological parameters.


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  		Table 1 Association of pre- and postoperative plasma levels of transforming growth factor (TGF)-ß1, interleukin-6 (IL) and IL-6 soluble form of receptor (IL-6sR) with categorical, clinical, pathologic, and continuous parameters of 302 consecutive patients who underwent radical prostatectomy for clinically localized disease

 
In univariable logistic regression analyses, preoperative TGF-ß1 levels predicted organ confined disease (P = 0.017; hazard ratio, 0.902; 95% CI 0.828–0.982) but preoperative IL-6 and IL-6sR did not (P = 0.118 and P = 0.079, respectively). In a preoperative multivariable model, clinical stage (P = 0.035) and biopsy Gleason sum (P < 0.001) were the only predictors of organ confined disease, when adjusted for the effects of preoperative PSA (P = 0.087), preoperative TGF-ß1 (P = 0.112), preoperative IL-6 (P = 0.639), and preoperative IL-6sR (P = 0.725).

Association of Pre- and Postoperative Plasma Levels of TGF-ß1, IL-6, and IL-6sR with Prostate Cancer Progression.
Overall, only 14% of patients (43 of 302) had cancer progression with a median postoperative follow-up of 50.7 months (range, 1.2–73.5 months). The overall PSA progression-free survival was 88.8 ± 1.5% (SE, SE) at 3 years and 85.1 ± 1.9% (SE) at 5 years. On univariable Cox proportional hazards regression analyses (Table 2)Citation , pre- and postoperative TGF-ß1 (P < 0.001), preoperative IL-6 (P < 0.001), preoperative IL-6sR (P < 0.001), preoperative PSA (P < 0.001), biopsy and prostatectomy Gleason sum (P < 0.001 and P < 0.001, respectively), extraprostatic extension (P < 0.001), seminal vesicle involvement (P < 0.001), and surgical margin status (P < 0.001) were associated with cancer progression, but postoperative IL-6 (P = 0.162), postoperative IL-6sR (P = 0.079), and clinical stage (P = 0.103) were not.


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  		Table 2 Multivariable Cox regression analysis models of postoperative features for the prediction of prostate cancer progression of 302 patients treated with radical prostatectomy for clinically localized disease

 
In a preoperative multivariable model, preoperative TGF-ß1 (P = 0.010; hazard ratio, 1.710; 95% CI 1.078–2.470), IL-6sR (P = 0.038; hazard ratio, 1.515; 95% CI 1.011–2.061), and biopsy Gleason sum (P < 0.001; hazard ratio, 2.896; 95% CI 1.630–5.145) were associated with cancer progression when adjusted for the effects of preoperative PSA (P = 0.058), preoperative IL-6 (P = 0.062), and clinical stage (P = 0.837).

Pre- and postoperative TGF-ß1, IL-6, and IL-6sR were analyzed in separate postoperative multivariable Cox proportional hazards regression analyses that also included extracapsular extension, seminal vesicle involvement, surgical margin status, pathological Gleason sum, and preoperative PSA. In the first model that included preoperative levels of the candidate markers, preoperative TGF-ß1 (P < 0.001) and IL-6sR (P = 0.045) along with prostatectomy Gleason sum (P < 0.001), seminal vesicle involvement (P = 0.020), and surgical margin status (P = 0.009) were associated with cancer progression. In the second model that included postoperative levels of the candidate markers, only postoperative TGF-ß1 (P < 0.001) and prostatectomy Gleason sum (P < 0.001) were associated with disease progression. In the third model that included pre- and postoperative levels of TGF-ß1, IL-6, and IL-6sR, only postoperative TGF-ß1 (P = 0.013) and prostatectomy Gleason sum (P = 0.005) were associated with prostate cancer progression.

Association of Pre- and Postoperative Plasma Levels of TGF-ß1, IL-6, and IL-6sR with Features of Aggressive Prostate Cancer Progression.
Nineteen patients were categorized as having features of nonaggressive prostate cancer progression because their PSA doubling times were >=10 months (n = 18; median, 23 months; range, 12–224 months) and/or because they achieved a complete response to local salvage radiation therapy (n = 5). Twenty-four patients were categorized as having features of aggressive cancer progression because of positive lymph nodes found at the time of radical prostatectomy (n = 6), of a positive metastatic work-up (bone or Prostascint scan; n = 4) because their PSA doubling times were <10 months (n = 23; median, 7 months; range, 1–9 months), and/or because they failed to respond to local radiation therapy (n = 14). Pre- and postoperative TGF-ß1 levels (P < 0.001 and P < 0.001, respectively), pre-operative IL-6 levels (P < 0.001), and preoperative IL-6sR levels (P < 0.001) were higher in patients with features of aggressive failure than in those with features of nonaggressive failure. In contrast, postoperative levels of IL-6 and IL-6sR were not different between patients with features of aggressive failure and those with features of nonaggressive failure (P = 0.062 and P = 0.075, respectively). In a preoperative multivariable Cox proportional hazards regression analysis, preoperative plasma TGF-ß1 (P < 0.001; hazard ratio, 1.298; 95% CI 1.093–1.716), preoperative IL-6sR (P = 0.021; hazard ratio, 1.312; 95% CI 1.099–1.837), and biopsy Gleason sum (P = 0.010; hazard ratio, 3.112; 95% CI 1.122–8.534) were associated with aggressive prostate cancer progression when adjusted for the effects preoperative IL-6 (P = 0.058), preoperative PSA (P = 0.086), and clinical stage (P = 0.432).

Pre- and postoperative TGF-ß1, IL-6, and IL-6sR were analyzed in separate postoperative multivariable Cox proportional hazards regression analyses that also included extracapsular extension, seminal vesicle involvement, surgical margin status, pathological Gleason sum, and preoperative PSA (Table 3)Citation . In the first model that included preoperative levels of the candidate markers, preoperative TGF-ß1 (P = 0.013) and IL-6sR (P = 0.042) along with prostatectomy Gleason sum (P = 0.009) and seminal vesicle involvement (P = 0.027) were associated with aggressive cancer progression. In the second model that included postoperative levels of the candidate markers, only postoperative TGF-ß1 (P = 0.012), seminal vesicle involvement (P = 0.044), and prostatectomy Gleason sum (P = 0.021) were associated with aggressive disease progression. In the third model that included pre- and postoperative levels of the candidate markers, only postoperative TGF-ß1 (P = 0.043), prostatectomy Gleason sum (P = 0.037), and seminal vesicle involvement (P = 0.049) were associated with aggressive prostate cancer progression.


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  		Table 3 Multivariable Cox regression analysis models of postoperative features for the prediction of features of aggressive prostate cancer progression

 
Pre- versus Postprostatectomy TGF-ß1, IL-6, and IL-6sR Levels.
Overall, postoperative TGF-ß1, IL-6, and IL-6sR levels were all lower than preoperative levels (P = 0.029, P <= 0.001, and P < 0.001, respectively; Table 4Citation ). In the subgroup of patients who experienced disease progression, postoperative IL-6 and IL-6sR levels were both lower than preoperative IL-6 and IL-6sR levels (P < 0.001 and P < 0.001, respectively). However, postoperative TGF-ß1 levels were not different from preoperative TGF-ß1 levels (P = 0.074). In the subgroup of patients who did not experience cancer progression, preoperative levels of TGF-ß1, IL-6, and IL-6sR declined after surgery P < 0.001, P = 0.042, and P = 0.034, respectively).


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  		Table 4 Pre- versus postoperative TGF-ß1,a IL-6, and IL-6sR levels in 302 patients treated with radical prostatectomy for clinically localized disease

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We confirmed our previously reported observations that preoperative plasma levels of TGF-ß1, IL-6, and IL-6sR are associated with established features of aggressive primary prostate cancer, with clinically evident and occult metastases present at the time of primary treatment, and with eventual disease progression (16 , 17) . Although all three of these markers were associated with frank metastatic disease to lymph nodes, we identified definite distinctions in the associations of these markers with other clinical and pathological parameters of the local tumor. For example, preoperative plasma levels of TGF-ß1 were associated with features of locally invasive disease, e.g., extraprostatic extension and seminal vesicle invasion but not the histological grade of disease. On the other hand, preoperative plasma levels of IL-6 and IL-6sR were associated with pathological grade of disease (i.e., Gleason sum) but not extraprostatic extension or seminal vesicle invasion. Furthermore, preoperative levels of IL-6 and IL-6sR were positively correlated with local tumor volume, whereas TGF-ß1 levels were not.

Not surprisingly, therefore, plasma levels of all three markers decreased significantly after prostate removal when evaluated in all patients. This remained true for patients who did not experience cancer progression. Interestingly, although the decrease in TGF-ß1 levels was greater in patients who did not experience cancer progression compared with all patients (33 versus 18%), the decrease in IL-6 and IL-6sR was proportionally less marked (18 versus 21 and 17 versus 22%, respectively). In contrast, in patients who experienced disease progression, the fall in postoperative IL-6 and IL-6sR levels after prostate removal was significant (30 and 27%, respectively), whereas postoperative TGF-ß1 levels fell only minimally (9%) and were not significantly different from preoperative TGF-ß1 levels. These findings are similar to findings reported for other surgically treated malignancies with TGF-ß1 decreasing only in patients apparently cured after definitive surgery and remaining elevated in patients found to have lymph node or distant metastases and/or residual disease after surgery (25, 26, 27) . In addition, in concordance with our findings, Tsushima et al. (27) found that in patients undergoing colon resection for colorectal cancer, both the pre- and postoperative TGF-ß1 level were associated with development of liver metastases when controlling for the effects of age, pre- and postoperative carcinoembryonic antigen level, gender, and clinical tumor grade and stage. On the other hand, circulating levels of IL-6 have been reported to significantly decrease after surgery, regardless of whether cure was surgically achieved (28) .

Taken together, these data suggest that in patients with cancer, blood levels of IL-6 and IL-6sR are produced primarily by tumor cells in the primary prostate cancer. Furthermore, circulating levels of IL-6 and its soluble receptor appear to be only associated with the potential of prostate cancer to metastasize but not with the metastases themselves. In contrast, it appears that circulating levels of TGF-ß1 are more closely associated with the metastatic process, either due to direct release from foci of metastatic tumor or to the host’s response to cancer invasion and dissemination. The increased predictive value of postoperative TGF-ß1 levels seen in postoperative multivariable analysis for the prediction of prostate cancer progression in our cohort of patients supports this concept. Although, in a standard postoperative model that included preoperative levels of the three candidate markers, both preoperative IL-6sR and TGF-ß1 were associated with prostate cancer progression, when only postoperative levels of three candidate markers were included in the model, postoperative TGF-ß1 was the sole candidate marker to be associated with cancer progression. Furthermore, when both pre- and postoperative levels of all three candidate markers were included in the same standard model, again only postoperative TGF-ß1 level remained associated with prostate cancer progression, once again demonstrating the loss of predictive value of IL-6 and IL-6sR after removal of the primary tumor, but the improvement of predictive value of postoperative levels of TGF-ß1 over the preoperative levels for prediction prostate cancer progression.

We confirmed the findings of our previous study showing that preoperative IL-6sR but not preoperative IL-6 was an independent predictor of cancer progression when modeled together in a standard preoperative multivariable analysis (17) . IL-6 acts through a hexametric cytokine receptor complex composed of an IL-6-specific receptor subunit and a signal transducer, gp130, that is also used by other cytokine receptors (29) . The binding of IL-6 to gp130 activates the Janus kinase/STAT3 signal transduction cascade in which STAT factors translocate to the nucleus where they activate the transcription of target genes that play a critical role in cell survival, the G1-S-phase cell cycle transition, cell movement, and cell differentiation (30 , 31) . Although Hobisch et al. (32) have shown by immunohistochemistry that both IL-6 and IL-6 receptor are overexpressed in clinically localized prostate cancer, Giri et al. (33) have recently demonstrated that in many prostate cancer cases there was either increased IL-6 or IL-6 receptor expression, suggesting two independent modes of inducing increased activation of the downstream signal transduction cascade. In addition, IL-6sR, which arises by proteolytic cleavage (34) or alternate splicing (35) of the cell surface IL-6 receptor, in addition to acting synergistically with IL-6 has been shown to be a potent regulator of IL-6 response in cells lacking IL-6 cell surface receptor expression (36 , 37) . For example, the presence of IL-6sR has been shown to be necessary for IL-6 to activate Stat signaling cascade in prostatic intraepithelial neoplasia cells lacking membrane-bound IL-6 receptor (38) . The stronger predictive value of preoperative IL-6sR over that of IL-6 for prostate cancer progression supports the role of IL-6sR as an agonistic regulator of IL-6 functions and suggests an underlying biological mechanism for its superiority to IL-6 for prognostic purposes in patients with prostate cancer.

Interestingly, the surgical margin status was associated with overall but not aggressive prostate cancer progression. Features of aggressive prostate cancer progression included either a positive metastatic work up or surrogate end points suggestive of the presence of metastasis or rapid progression to clinical metastatic disease [i.e., PSA doubling times of <10 months (24 , 39 , 40) and the failure to respond to salvage local radiation therapy (23 , 24) ]. The other predictors of overall progression (seminal vesicle involvement, pathological Gleason sum, preoperative IL-6sR and TGF-ß1) retained their predictive value for aggressive prostate cancer progression. These data support the notion that while seminal vesicle involvement, pathological Gleason sum, preoperative IL-6sR, and TGF-ß1 levels are associated with either established or occult metastatic disease or the propensity to develop metastases; positive surgical margins are associated with local recurrence that is typically nonaggressive. In concordance with these findings, Epstein et al. (41) reported that the surgical margin status is a strong predictor of local recurrence after radical prostatectomy. These data support the concept that positive surgical margins correlated with residual local tumor in the surgical bed and are the result of incomplete resection of the prostate by the surgeon.

In conclusion, our findings support the inclusion of preoperative levels of TGF-ß1 and IL-6sR to the standard preoperative nomogram for prediction of recurrence after radical prostatectomy. The generalizability of our findings to other cancers suggests that our observations and recommendations may be widely applicable to a variety of other cancers and cancer therapy modalities (i.e., radio- or chemotherapy). Furthermore, we have found that early postoperative TGF-ß1 is a strong predictor of prostate cancer progression and is an excellent candidate marker for inclusion in other standard predictive models for progression after primary therapy for prostate cancer.


   FOOTNOTES
 
Grant support: S. Shariat is supported by the Austrian Program for Advanced Research and Technology.

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.

Requests for reprints: Kevin M. Slawin, Professor, Duncan Chair in Prostate Diseases, Scott Department of Urology, Baylor College of Medicine, Director, The Baylor Prostate Center, 6560 Fannin Street, Suite 2100, Houston, TX 77030. Phone: (713) 798-8670; Fax: (713) 798-8030; E-mail: kslawin{at}www.urol.bcm.tmc.edu

Received 5/13/03; revised 12/ 5/03; accepted 12/12/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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