Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shariat, S. F.
Right arrow Articles by Slawin, K. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shariat, S. F.
Right arrow Articles by Slawin, K. M.
Journal of Clinical Oncology, Vol 20, Issue 3 (February), 2002: 833-841
© 2002 American Society for Clinical Oncology

Association of Preoperative Plasma Levels of Insulin-Like Growth Factor I and Insulin-Like Growth Factor Binding Proteins-2 and -3 With Prostate Cancer Invasion, Progression, and Metastasis

By Shahrokh F. Shariat, Dolores J. Lamb, Michael W. Kattan, Cuong Nguyen, JaHong Kim, Josie Beck, Thomas M. Wheeler, Kevin M. Slawin

From the Baylor Prostate Center and Male Reproductive Medicine and Surgery, the Scott Department of Urology and Department of Molecular and Cellular Biology, Department of Pathology, Baylor College of Medicine, and The Methodist Hospital, Houston, TX; and the Department of Urology and Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Kevin Mark Slawin, MD, Scott Department of Urology, Baylor College of Medicine, 6560 Fannin St, Ste 2100, Houston, TX 77030; email: kslawin{at}www.urol.bcm.tmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: We tested the hypothesis that preoperative plasma levels of insulin-like growth factor (IGF) binding protein (BP)-2 or IGFBP-3 would predict cancer stage and prognosis in patients undergoing radical prostatectomy.

MATERIAL AND METHODS: Plasma levels of IGF-I, IGFBP-2, and IGFBP-3 were measured preoperatively in 120 consecutive patients who underwent radical prostatectomy for clinically localized disease, postoperatively in 51 of these patients, in 44 healthy men, in 19 patients with metastases to regional lymph nodes, and in 10 patients with bone metastases.

RESULTS: Plasma IGFBP-3 levels were lowest in patients with bone metastases (P <= .043). IGFBP-2 levels were elevated in prostate cancer patients compared with healthy subjects (P <= .006). However, within the group of prostatectomy patients, preoperative plasma IGFBP-2 levels were lower in patients with advanced disease (P <= .033), were inversely correlated with prostatic tumor volume (P = .037), and declined after prostate removal (P = .044). Lower preoperative IGFBP-2 and IGFBP-3 levels and biopsy Gleason score were independent predictors of biochemical progression (P = .043, P = .040, and P = .020, respectively). In patients with disease progression, preoperative plasma IGFBP-3 levels were lower in those with aggressive than in those with nonaggressive failure (P = .042).

CONCLUSION: Elevation of plasma IGFBP-2 levels in prostate cancer patients apparently is due to increased release directly from the prostate. For patients with clinically localized prostate cancer, preoperative plasma IGFBP-2 levels are inversely associated with biologically aggressive disease and disease progression. Preoperative plasma IGFBP-3 levels were decreased in patients with prostate cancer metastases and were an independent predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE INSULIN-LIKE growth factors (IGFs) and IGF binding proteins (IGFBPs) are involved in the regulation of growth, cellular proliferation and transformation, and apoptosis. The levels of free IGF-I and -II are modulated by IGFBPs, which comprise a super family of at least six proteins (IGFBP-1 to -6). Depending on the cellular context, IGFBPs not only regulate IGF action and bioavailability, but also directly mediate IGF-independent actions, including regulation of cell growth and induction of apoptosis.1-5 The local expression of IGFs and IGFBPs has been associated with tumor grade, pathologic stage, and disease progression for patients with breast,6,7 lung,8 colon cancer,9 and prostate cancer.10-13

The origin and the role of circulating levels of IGFs and IGFBPs with respect to prostate cancer development and progression remain unclear. Epidemiologic studies have found high circulating IGF-I and low IGFBP-3 levels to be associated with an increased risk of developing breast,14 endometrial,15 lung,16 colorectal cancer,17 and prostate cancer.18-20 However, other studies have consistently found no difference in IGF-I levels between men with prostate cancer and cancer-free controls.21-25 In addition, we have previously shown that systemic levels of IGF-I are not associated with metastasis, established markers of biologically aggressive disease, or disease progression in patients with clinically localized prostate cancer.21 Although these findings question the clinical utility of IGF-I in the diagnosis, staging, and management of patients with prostate cancer, the complex regulation of the IGF axis may have obscured its role when examining IGF-I without considering IGFBPs.

We studied pre- and postoperative levels of IGFBP-2, the main IGFBP produced by prostate epithelial cells, and IGFBP-3, the main carrier protein for IGF-I in blood, in patients with clinically localized prostate cancer who underwent radical prostatectomy, in patients with metastases to regional lymph nodes, in patients with metastases to bone, and in healthy men. The availability of pre- and postoperative plasma specimens provided a unique opportunity to study the origin of circulating IGF-I and IGFBPs in prostate cancer patients and to determine the association of these factors with prostate cancer invasion, progression, and metastases.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL 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. We measured plasma IGF-I, IGFBP-2, and IGFBP-3 levels in 44 healthy patients without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 patients with bone scan–proven, metastatic prostate cancer. The patients with metastatic lymph node disease and patients with metastatic bone disease were not treated with either hormonal or radiation therapy before plasma collection. The healthy noncancer group was composed of three sets of consecutive patients who participated in the Baylor Prostate Center’s weekly prostate cancer screening program and who had no previous history of any cancer or chronic disease, a normal digital rectal examination, and a prostate-specific antigen (PSA) level of less than 2.0.0 ng/mL (a PSA range that has an estimated probability of prostate cancer detection of < 1% in the first 4 years after screening).26

In addition, we evaluated 120 consecutive patients who underwent radical prostatectomy for clinically localized prostatic adenocarcinoma (clinical stage T1 to T2) at The Methodist Hospital, Houston, TX, between December 1994 and November 1995 for whom plasma samples were available (preoperative, n = 120; postoperative, n = 51). No patient was treated preoperatively with either hormonal or radiation therapy, and none had secondary cancers. The clinical stage was assigned by the operative surgeon according to the 1992 tumor-node-metastasis system. The mean patient age in this study was 61.8 ± 7.2 years (median, 63.0; range, 40 to 76 years). Serum PSA was measured by the Hybritech Tandem-R assay (Hybritech, Inc, San Diego, CA).

IGF-I, IGFBP-2, and IGFBP-3 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. Blood was collected into Vacutainer CPT 8-mL tubes containing 0.1 mL of 1 mol/L of sodium citrate anticoagulant (Becton Dickinson, Franklin Lakes, NJ) and centrifuged at room temperature for 20 minutes at 1,500 x g. The top layer, corresponding to diluted plasma, was decanted using sterile transfer pipettes and immediately frozen and stored at -80°C in polypropylene cryopreservation vials (Nalge Nunc, Rochester, NY).21 For quantitative measurements of serum and plasma IGF-I and IGFBP-3 levels, we used the DSL-10-5600ACTIVE IGF-I enzyme-linked immunosorbent assay kit and the DSL-10-6600ACTIVE IGFBP-3 enzyme-linked immunosorbent assay kit, respectively (DSL, Webster, TX). For quantitative measurements of serum and plasma IGFBP-2 levels, we used the DSL-7100 IGFBP-2 Radioimmunoassay kit (DSL). Every sample was run in duplicate and the mean calculated for data analysis. Differences between the two measurements were minimal, as shown by the intra-assay precision coefficient of variation of only 4.73% ± 1.87% for IGF-I, 6.95% ± 3.86% for IGFBP-2, and 5.78% ± 4.07% for IGFBP-3.

Impact of Collection Formats on IGFBP-2 and IGFBP-3 Levels
As in our earlier study of IGF-I, we assessed the effect of different collection formats on IGFBP-2 and IGFBP-3 levels.21 Mean IGFBP-2 and IGFBP-3 levels measured in diluted citrate plasma from Vacutainer CPT tubes (359.3 ± 18.1 and 3,273 ± 256 ng/mL, respectively) were 26% and 28%, respectively, lower than those measured in Vacutainer K3EDTA plasma (487.9 ± 28.4 and 4,566 ± 376 ng/mL, respectively) and 37% and 39%, respectively, lower than those measured in serum (567.8 ± 31.0 and 5,401 ± 430 ng/mL, respectively). The lower IGFBP-2 and IGFBP-3 values obtained with the citrate plasma were attributable to dilution of the top plasma layer primarily by 1.0 mL of 0.1 mol/L of sodium citrate anticoagulant. Although absolute IGFBP-2 and IGFBP-3 levels measured in serum and in plasma using different collection formats were significantly different (P < .001), all three collection formats were highly correlated with each other (correlation coefficients, r [IGFBP-2] >= 0.70 and r [IGFBP-3] >= 0.72; P < .001). As in our previous study, we used plasma from Vacutainer CPT sodium citrate tubes for IGF-I, IGFBP-2, and IGFBP-3 measurements for our study.

Pathologic 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 pathologic parameters were evaluated as previously described.27 Total tumor volume was computed by computerized planimetry from the whole-mount sections from 60 of the 120 prostatectomy patients.28

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. In patients experiencing biochemical progression, a staging evaluation, including bone scan, ProstaScint scan (Cytogen, Princeton, NJ), and/or PSA doubling time calculation was performed in 11 of the 15 patients before the administration of salvage radiation or hormonal therapy. Biochemical progression was defined as a sustained elevation, on two or more occasions, of PSA more than 0.2 ng/mL and was assigned to the date of the first value more than 0.2 ng/mL. Two patients (1.7%) had lymph node-positive disease at the time of radical prostatectomy, and surgery was halted before prostate removal. These patients were categorized among those with progression from the day after surgery. Two patients (1.7%) received adjuvant radiation therapy before biochemical progression because of positive surgical margins. One of them subsequently experienced PSA relapse and was considered to have disease progression from the date of the first value more than 0.2 ng/mL, whereas the second was censored on the date of the last follow-up examination. Of 120 patients who underwent radical prostatectomy, 19 had progression of disease. PSA relapse was the sole indication of progression in 16 patients, whereas three had clinical as well as biochemical evidence of progression. 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 = log(2) x T/[log(final PSA) - log(initial PSA)],29 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 recurrence. The natural logarithm was used in all logarithmic transformations. Eight (53%) of the patients who had progression were treated at the Methodist Hospital with external-beam radiation therapy limited to the prostatic fossa. Radiation was delivered with 15- to 20-MV photons, and the four-fields technique was used (anteroposterior/posteroanterior and opposing laterals) 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.

Statistical Analysis
Differences in plasma IGFBP-2 and IGFBP-3 levels across collection formats were assessed using analysis of variance. Multiple comparisons were conducted using the Fisher’s least significant difference, when the overall test was significant at the 5% level. Differences in IGF-I, IGFBP-2, and IGFBP-3 levels between clinical and pathologic features were tested by the independent sample t 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. The Kaplan-Meier method was used to calculate survival functions, and differences were assessed with the log-rank statistic. Multivariate survival analysis was performed with the Cox proportional hazards regression model. Preoperative PSA level had a skewed distribution and therefore was modeled with a log transformation. Preoperative IGFBP-2 levels and postoperative IGF-I levels had a skewed distribution and therefore were modeled with a 1/X transformation. Clinical stage was evaluated as T1 versus T2. Biopsy and radical prostatectomy Gleason score were evaluated as grade 2 to 6 versus grade 7 to 10. Differences in IGF-I, IGFBP-2, and IGFBP-3 levels between pre- and postoperative samples were tested by the paired sample test. Statistical significance in this study was set as P < .05. All reported P values are two-sided. All analyses were performed with SPSS statistical package (Version 10.0 for Windows; SPSS, Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical and Pathologic Characteristics as a Function of IGF-I, IGFBP-2, and IGFBP-3
Clinical and pathologic characteristics of 120 prostatectomy patients and association with preoperative plasma levels of IGF-I, IGFBP-2, and IGFBP-3 are shown in Table 1. The mean preoperative PSA was 9.5 ± 6.3 ng/mL (median, 8.2; range, 2.1 to 49.0 ng/mL). Seventy-five patients (63%) had PSA levels between 4 and 10 ng/mL, and 36 (30%) had PSA levels of 10 ng/mL and beyond. There was no association between IGF-I or IGFBP-3 and any of the clinical and pathologic features. Preoperative IGFBP-2 levels were lower in patients with biopsy Gleason score >= 7 (P = .026), extracapsular extension (P = .014), seminal vesicle involvement (P = .033), or pathologic Gleason score >= 7 (P = .019). On univariate analysis, pretreatment IGF-I levels were correlated with pretreatment IGFBP-3 levels (P < .001), and pretreatment IGFBP-2 levels were inversely correlated with prostatic tumor volume (P = .037).


View this table:
[in this window]
[in a new window]
  		Table 1.  Preoperative Plasma IGF-I, IGFBP-2, and IGFBP-3 Levels
 
Final Pathologic Stage and Progression as a Function of IGFBP-2 and IGFBP-3 and Other Parameters
In a multivariate logistic regression analysis, higher preoperative plasma IGFBP-2 levels (P = .001) but lower preoperative serum PSA levels (P = .034) and biopsy Gleason score (P = .005) were significant predictors of organ-confined disease. Overall, only 16% of patients (19 of 120) had cancer progression, with a median postoperative follow-up period of 57.5 months (range, 1.16 to 63.7 months). The overall PSA progression-free survival rate was 90.7% ± 2.7% (SE) at 3 years and 84.0% ± 3.5% (SE) at 5 years. Using the log-rank test, we found that patients with preoperative plasma IGFBP-2 or IGFBP-3 levels below the median (437.4 ng/mL and 3,239 ng/mL, respectively) had a significantly increased probability of PSA progression (P = .042 and P = .038; Figs 1 and 2). However, there was no significant difference in PSA progression-free survival between patients stratified by the median level of IGF-I (151 ng/mL; P = .489). On univariate Cox proportional hazards regression analysis (Table 2), lower preoperative plasma IGFBP-2 and IGFBP-3 levels, as well as a biopsy Gleason score >=7, were associated with the risk of PSA progression (P = .016, P = .031, P = .005, respectively). In preoperative multivariate models that included preoperative PSA level, clinical stage, and biopsy Gleason score, lower preoperative plasma IGFBP-2 (P values<=0.049) and lower preoperative IGFBP-3 (P <= .044), but not preoperative IGF-I (P >= .239), were independent predictors of disease progression along with biopsy Gleason sum >= 7 (P <= .028). In a model that included all IGFs (IGF-I, IGFBP-2, and IGFBP-3), IGFBP-2, IGFBP-3, and biopsy Gleason score were independent predictors of disease progression after surgery (P = .043, P = .040, and P = .020, respectively; Table 2).



View larger version (21K):
[in this window]
[in a new window]
  		Fig 1. Kaplan-Meier estimates of PSA progression-free probability for the 120 patients with clinically localized prostate cancer treated with radical prostatectomy stratified into groups above or below the median IGFBP-2 level of 437.4 ng/mL

 

View this table:
[in this window]
[in a new window]
  		Table 2.  Univariate and Multivariate Cox Regression Analysis of Clinical Features for the Prediction of PSA Progression
 


View larger version (21K):
[in this window]
[in a new window]
  		Fig 2. Kaplan-Meier estimates of PSA progression-free probability for the 120 patients with clinically localized prostate cancer treated with radical prostatectomy stratified into groups above or below the median IGFBP-3 level of 3,239 ng/mL.

 
Characteristics of Patients With Disease Progression
Of the 19 radical prostatectomy patients whose disease progressed, two patients had lymph node–positive disease at the time of radical prostatectomy. Seven patients were categorized as having nonaggressive failure because their PSA doubling times were >= 10 months (n = 5; median, 20 months; range, 12 to 215 months) and/or because they achieved a complete response to local salvage radiation therapy (n = 2). Eight patients were categorized as having aggressive failure because of the results of a metastatic work-up (positive bone or ProstaScint scan; n = 3), because their PSA doubling times were less than 10 months (n = 7; median, 7 months; range, 2 to 7 months), and/or because they failed to respond to local radiation therapy (n = 4). Preoperative plasma IGFBP-3 levels were lower in patients with aggressive failure (median, 2,042 ng/mL; range 1,244 to 2,785 ng/mL) than those with nonaggressive failure (median, 2,981; range, 1,885 to 3,695; P = .042). However, neither preoperative plasma IGF-I levels nor IGFBP-2 levels were different between these two groups of patients (P = .69 and P = .189, respectively).

IGF-I, IGFBP-2, and IGFBP-3 in Healthy Men and Patients With Prostate Cancer Metastases
Plasma IGF-I, IGFBP-2, and IGFBP-3 levels in the 19 patients with prostate cancer metastatic to regional lymph nodes, in the 10 patients with prostate cancer metastatic to bones, in the cohort of 120 prostatectomy patients, and in the 44 healthy screening patients are shown in Table 1. IGF-I levels did not differ between the groups (P >= .413). Plasma IGFBP-2 levels in prostate cancer patients were higher than those in the healthy subjects (P <= .006). Moreover, prostate cancer patients with adverse clinical and pathologic features had consistently higher IGFBP-2 levels than healthy men. However, IGFBP-2 levels were not different between prostatectomy patients, patients with lymph node metastases, or patients with bone metastases (P > .413). Plasma IGFBP-3 levels in patients with bone metastases were lower than those in patients with metastases to regional lymph nodes (P = .017), which in turn were lower than those in prostatectomy patients and in healthy subjects (P <= .043). IGFBP-3 levels in the prostatectomy patients were, however, not different from those in healthy subjects (P = .575).

Differences in Pre- Versus Postprostatectomy IGF-I, IGFBP-2, and IGFBP-3 Levels
We measured plasma IGF-I, IGFBP-2, and IGFBP-3 levels in 51 patients before and after radical prostatectomy. Postoperative IGFBP-2 levels were lower than preoperative levels (P = .037). In contrast, preoperative IGF-I and IGFBP-3 levels were not different from those in postoperative samples (P = .074 and P = .054, respectively).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found that, in concordance with previous reports regarding a variety of cancers30-41 as well as prostate cancer,42-44 IGFBP-2 levels were significantly more elevated in patients with clinically localized and metastatic prostate cancer than in healthy subjects. In addition, we found that these higher circulating levels of IGFBP-2 probably were prostatic in origin, because they fell significantly after the prostate was removed. Surprisingly, for patients with clinically localized prostate cancer, preoperative IGFBP-2 levels were significantly decreased in those who had features of biologically aggressive disease, such as high tumor grade, extraprostatic extension, and seminal vesicle involvement. Furthermore, lower preoperative IGFBP-2 and biopsy Gleason score were independent predictors of biochemical progression after surgery.

Circulating IGFBP-2 exhibits a complex relationship with prostate cancer development and progression. Local IGFBP-2 expression, like that of PSA, is markedly higher in prostate tissue than in most other tissues, and in seminal fluid, levels of both IGFBP-2 and PSA are higher than those of any other body fluid.45 Moreover, blood levels of both IGFBP-2 and PSA fall significantly after prostate removal. However, in men with clinically localized prostate cancer, IGFBP-2 levels, unlike PSA levels, were inversely associated with prostatic tumor volume and with features of advanced disease, while still remaining higher than in men without prostate cancer. In the absence of a clear understanding of the biologic activity of prostatic IGFBP-2, one hypothesis that would explain this phenomena is that as with PSA,46,47 cellular expression of IGFBP-2 is reduced in higher grade and presumably more aggressive prostate cancer. In contrast to PSA, which is elevated in the circulation of patients with advanced prostate cancer by virtue of an increase in leakage from the prostate, prostatic release of IGFBP-2 into the circulation may be less affected by changes in tissue architecture associated with prostate cancer. This would allow circulating levels of IGFBP-2 to more closely reflect prostate tissue levels. Another hypothesis would be that IGFBP-2 is increasingly proteolytically degraded in advanced prostate cancer, either locally before release into the blood stream or in the blood stream itself. Alternatively IGFBP-2 local sequestration might be increased in more advanced cancer, serving as a storage pool for the augmented local levels of IGF-I and IGF-II. On proteolysis IGFBP-2 might release its ligands into the pericellular environment, enhancing local tumor growth and progression. IGFBP-2 could also directly stimulate prostate cancer cell growth by an IGF-independent mechanism.3,5 Alternatively, there may be changes in the degradation rate of IGFBP-2 with advancing disease.

In the current study, plasma IGFBP-3 levels were lowest in patients with bony metastases. They were lower in patients with metastases to regional lymph nodes than in patients with nonmetastatic prostate cancer or in healthy subjects. Circulating IGFBP-3 levels previously have been shown to be lower in patients with metastatic prostate cancer than in healthy controls42 but not to be different between patients with clinically localized prostate cancer and healthy controls.43 IGFBP-3 levels were not associated with any clinical or pathologic features of patients undergoing radical prostatectomy for clinically localized disease. Although prediction of final pathologic features is important, nomograms incorporating biomarkers that can predict disease progression in patients undergoing radical prostatectomy would provide a more useful adjunct for the management of patients with prostate cancer.48

We found that preoperative plasma IGFBP-3 level was an independent predictor of prostate cancer progression in patients undergoing radical prostatectomy, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy. In support of this hypothesis, preoperative IGFBP-3 levels were significantly lower in patients with aggressive prostate cancer recurrence, based on a PSA doubling times of less than 10 months,49 the failure to respond to salvage local radiation therapy, or a positive metastatic work up, than in patients with nonaggressive failure. IGFBP-3 levels were significantly lower in patients who experienced aggressive disease progression than in patients with nonaggressive failure.

In prostate cancer, IGFBP-3 has been shown to exhibit a protective effect by inducing apoptosis in a dose-dependent manner through binding to its own putative receptor, in addition to blocking IGF interactions with its receptor.1,50 Local expression of IGFBP-3 has been shown to be lower in patients with prostate cancer10,11,51 and to be inversely associated with tumor stage and grade.11,12 In bone, IGFs are the most abundant class of stromal growth factors.52,53 IGFBP-3 has been associated with bone status and turnover.54 Bone-derived IGFBP-3 has been shown to inhibit the osteoblastic activity of IGFs.55,56 Doherty et al57 recently suggested that IGFBP-3 is directly involved in generating osteoblastic bony metastases through PSA-dependent proteolysis within bone matrix. In support of these findings, Smith et al58 reported that local IGFBP-3 levels were lower in PSA-expressing prostate cancer bone metastases than in breast cancer bone metastases that did not express PSA. Therefore, clinically evident or occult bone metastases might directly or indirectly decrease bone-derived contribution to circulating IGFBP-3 levels.

Although the major significance of IGF-I seems to be restricted to cancer development during subclinical disease stages, the IGF binding proteins seem to play a more direct role in prostate cancer progression. Specifically, IGFBP-2 levels seem to be inversely associated with the progression from early to more advanced stages of prostate cancer, and IGFBP-3 seems to be inversely associated with the establishment and progression of prostate cancer metastases. The mechanisms for these associations remain to be elucidated.


   ACKNOWLEDGMENTS
 
Supported in part by grants from the Frost Foundation Ltd, Santa Fe, NM, and from the Austrian Science Fund, Vienna, Austria.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Rajah R, Valentinis B, Cohen P: Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. J Biol Chem 272: 12181-12188, 1997[Abstract/Free Full Text]

2. Hoeflich A, Fettscher O, Lahm H, et al: Overexpression of insulin-like growth factor-binding protein-2 results in increased tumorigenic potential in Y-1 adrenocortical tumor cells. Cancer Res 60: 834-838, 2000[Abstract/Free Full Text]

3. Chatterjee S, Dai B, Owlia A, et al: Novel strategy for growth inhibition of human prostatic cancer cells: Endogeneous IGFBP-2 suppression. Programs and abstracts of the 81st Annual Meeting of the Endocrine Society, San Diego, CA, June 12-15, 1999 (abstr 169)

4. Chatterjee S, Singh P: Anti-IGFBP-2 suppresses prostate tumor growth in nude mice. Programs and abstracts of the 82nd Annual Meeting of the Endocrine Society, Toronto, Canada, June 21-24, 2000 (abstr A975)

5. Moore M, Liu B, Wetterau L, et al: IGFBP-2 stimulates prostate cancer cell growth by an IGF-independent mechanism involving interactions with novel protein partners. Programs and abstracts of the 82nd Annual Meeting of the Endocrine Society, Toronto, Canada, June 21-24, 2000 (abstr A927)

6. Toropainen E, Lipponen P, Syrjanen K: Expression of insulin-like growth factor I (IGF-I) in female breast cancer as related to established prognostic factors and long-term prognosis. Eur J Cancer 9: 1443-1448, 1995[CrossRef]

7. Yee D, Sharma J, Hilsenbeck SG: Prognostic significance of insulin-like growth factor-binding protein expression in axillary lymph node-negative breast cancer. J Natl Cancer Inst 86: 1785-1789, 1994[Abstract/Free Full Text]

8. Takanami I, Imamuma T, Hashizume T, et al: Insulin-like growth factor-II as a prognostic factor in pulmonary adenocarcinoma. J Surg Oncol 61: 205-208, 1996[CrossRef][Medline]

9. Kawamoto K, Onodera H, Kondo S, et al: Expression of insulin-like growth factor-2 can predict the prognosis of human colorectal cancer patients: Correlation with tumor progression, proliferative activity and survival. Oncology 55: 242-248, 1998[CrossRef][Medline]

10. Thrasher JB, Tennant MK, Twomey PA, et al: Immunohistochemical localization of insulin-like growth factor binding proteins 2 and 3 in prostate tissue: Clinical correlations. J Urol 155: 999-1003, 1996[CrossRef][Medline]

11. Tennant MK, Thrasher JB, Twomey PA, et al: Insulin-like growth factor-binding protein-2 and -3 expression in benign human prostate epithelium, prostate intraepithelial neoplasia, and adenocarcinoma of the prostate. J Clin Endocrinol Metab 81: 411-420, 1996[Abstract]

12. Figueroa JA, De Raad S, Tadlock L, et al: Differential expression of insulin-like growth factor binding proteins in high versus low Gleason score prostate cancer. J Urol 159: 1379-1383, 1998[CrossRef][Medline]

13. Mita K, Nakahara M, Usui T: Expression of the insulin-like growth factor system and cancer progression in hormone-treated prostate cancer patients. Int J Urol 7: 321-329, 2000[CrossRef][Medline]

14. Hankinson SE, Willett WC, Colditz GA, et al: Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351: 1393-1396, 1998[CrossRef][Medline]

15. Ayabe T, Tsutsumi O, Sakai H, et al: Increased circulating levels of insulin-like growth factor-I and decreased circulating levels of insulin-like growth factor binding protein-1 in postmenopausal women with endometrial cancer. Endocr J 44: 419-424, 1997[Medline]

16. Yu H, Spitz MR, Mistry J, et al: Plasma levels of insulin-like growth factor-I and lung cancer risk: A case-control analysis. J Natl Cancer Inst 91: 151-156, 1999[Abstract/Free Full Text]

17. Ma J, Pollak MN, Giovannucci E, et al: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91: 620-625, 1999[Abstract/Free Full Text]

18. Chan JM, Stampfer MJ, Giovannucci E, et al: Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study. Science 279: 563-566, 1998[Abstract/Free Full Text]

19. Wolk A, Mantzoros CS, Andersson SO, et al: Insulin-like growth factor 1 and prostate cancer risk: A population-based, case-control study. J Natl Cancer Inst 90: 911-915, 1998[Abstract/Free Full Text]

20. Stattin P, Bylund A, Rinaldi S, et al: Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: A prospective study. J Natl Cancer Inst 92: 1910-1917, 2000[Abstract/Free Full Text]

21. Shariat SF, Bergamaschi F, Adler HL, et al: Correlation of preoperative plasma IGF-I levels with pathologic parameters and progression in patients undergoing radical prostatectomy. Urology 56: 423-429, 2000[CrossRef][Medline]

22. Cutting CW, Hunt C, Nisbet JA, et al: Serum insulin-like growth factor-1 is not a useful marker of prostate cancer. BJU Int 83: 996-999, 1999[CrossRef][Medline]

23. Finne P, Auvinen A, Koistinen H, et al: Insulin-like growth factor I is not a useful marker of prostate cancer in men with elevated levels of prostate-specific antigen. J Clin Endocrinol Metab 85: 2744-2747, 2000[Abstract/Free Full Text]

24. Kurek R, Tunn UW, Eckart O, et al: The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer. BJU Int 85: 125-129, 2000[CrossRef][Medline]

25. Baffa R, Reiss K, El-Gabry EA, et al: Low serum insulin-like growth factor 1 (IGF-1): A significant association with prostate cancer. Tech Urol 6: 236-239, 2000[Medline]

26. Smith DS, Catalona WJ, Herschman JD: Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 276: 1309-1315, 1996[Abstract]

27. Wheeler TM, Lebovitz RM: Fresh tissue harvest for research from prostatectomy specimens. Prostate 25: 274-279, 1994[Medline]

28. Greene DR, Wheeler TM, Egawa S, et al: A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate. J Urol 146: 1069-1076, 1991[Medline]

29. Schmid HP, McNeal JE, Stamey TA: Observations on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 71: 2031-2040, 1993[CrossRef][Medline]

30. Reeve JG, Payne JA, Bleehen NM: Production of immunoreactive insulin-like growth factor-I (IGF-I) and IGF-I binding proteins by human lung tumours. Br J Cancer 61: 727-731, 1990[Medline]

31. Kanety H, Kattan M, Goldberg I, et al: Increased insulin-like growth factor binding protein-2 (IGFBP-2) gene expression and protein production lead to high IGFBP-2 content in malignant ovarian cyst fluid. Br J Cancer 73: 1069-1073, 1996[Medline]

32. Zumkeller W, Saaf M, Rahn T: Insulin-like growth factor (IGF)-I. -II and IGF-binding proteins in the cyst fluid of a patient with astrocytoma. Childs Nerv Syst 9: 100-103, 1993[CrossRef][Medline]

33. Zumkeller W, Schwander J, Mitchell CD, et al: Insulin-like growth factor (IGF)-I, -II and IGF binding protein-2 (IGFBP-2) in the plasma of children with Wilms’ tumour. Eur J Cancer 14: 1973-1977, 1993[CrossRef]

34. Boulle N, Logie A, Gicquel C, et al: Increased levels of insulin-like growth factor II (IGF-II) and IGF-binding protein-2 are associated with malignancy in sporadic adrenocortical tumors. J Clin Endocrinol Metab 83: 1713-1720, 1998[Abstract/Free Full Text]

35. Renehan AG, Jones J, Potten CS, et al: Elevated serum insulin-like growth factor (IGF)-II and IGF binding protein-2 in patients with colorectal cancer. Br J Cancer 83: 1344-1350, 2000[CrossRef][Medline]

36. el Atiq F, Garrouste F, Remacle-Bonnet M, et al: Alterations in serum levels of insulin-like growth factors and insulin-like growth-factor-binding proteins in patients with colorectal cancer. Int J Cancer 57: 491-497, 1994[Medline]

37. Karasik A, Menczer J, Pariente C, et al: Insulin-like growth factor-I (IGF-I) and IGF-binding protein-2 are increased in cyst fluids of epithelial ovarian cancer. J Clin Endocrinol Metab 78: 271-276, 1994[Abstract]

38. Flyvbjerg A, Mogensen O, Mogensen B, et al: Elevated serum insulin-like growth factor-binding protein 2 (IGFBP-2) and decreased IGFBP-3 in epithelial ovarian cancer: Correlation with cancer antigen 125 and tumor-associated trypsin inhibitor. J Clin Endocrinol Metab 82: 2308-2313, 1997[Abstract/Free Full Text]

39. Wex H, Vorwerk P, Mohnike K, et al: Elevated serum levels of IGFBP-2 found in children suffering from acute leukaemia is accompanied by the occurrence of IGFBP-2 mRNA in the tumour clone. Br J Cancer 78: 515-520, 1998[Medline]

40. Muller HL, Oh Y, Lehrnbecher T, et al: Insulin-like growth factor-binding protein-2 concentrations in cerebrospinal fluid and serum of children with malignant solid tumors or acute leukemia. J Clin Endocrinol Metab 79: 428-434, 1994[Abstract]

41. Mohnike KL, Kluba U, Mittler U, et al: Serum levels of insulin-like growth factor-I, -II and insulin-like growth factor binding proteins -2 and -3 in children with acute lymphoblastic leukaemia. Eur J Pediatr 155: 81-86, 1996[Medline]

42. Kanety H, Madjar Y, Dagan Y, et al: Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: Correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 77: 229-233, 1993[Abstract]

43. Cohen P, Peehl DM, Stamey TA, et al: Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients. J Clin Endocrinol Metab 76: 1031-1035, 1993[Abstract]

44. Ho PJ, Baxter RC: Insulin-like growth factor-binding protein-2 in patients with prostate carcinoma and benign prostatic hyperplasia. Clin Endocrinol (Oxf) 46: 145-154, 1997[CrossRef][Medline]

45. Schwander J, Mary JL: The RIA for IGFBP-2 in man: A meager catch? Growth Regul 3: 104-108, 1993[Medline]

46. Aihara M, Lebovitz RM, Wheeler TM, et al: Prostate specific antigen and Gleason grade: An immunohistochemical study of prostate cancer. J Urol 151: 1558-1564, 1994[Medline]

47. Darson MF, Pacelli A, Roche P, et al: Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: A novel prostate cancer marker. Urology 49: 857-862, 1997[CrossRef][Medline]

48. Kattan MW, Stapleton AM, Wheeler TM, et al: Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate carcinoma. Cancer 79: 528-537, 1997[CrossRef][Medline]

49. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281: 1591-1597, 1999[Abstract/Free Full Text]

50. Nickerson T, Huynh H, Pollak M: Insulin-like growth factor binding protein-3 induces apoptosis in MCF7 breast cancer cells. Biochem Biophys Res Commun 237: 690-693, 1997[CrossRef][Medline]

51. Hampel OZ, Kattan MW, Yang G, et al: Quantitative immunohistochemical analysis of insulin-like growth factor binding protein-3 in human prostatic adenocarcinoma: A prognostic study. J Urol 159: 2220-2225, 1998[CrossRef][Medline]

52. Mohan S, Baylink DJ: Bone growth factors. Clin Orthop 30-48, 1991

53. Rosen CJ, Donahue LR, Hunter SJ: Insulin-like growth factors and bone: The osteoporosis connection. Proc Soc Exp Biol Med 206: 83-102, 1994[Abstract]

54. Bing-You RG, Denis MC, Rosen CJ: Low bone mineral density in adults with previous hypothalamic-pituitary tumors: Correlations with serum growth hormone responses to GH-releasing hormone, insulin-like growth factor I, and IGF binding protein 3. Calcif Tissue Int 52: 183-187, 1993[CrossRef][Medline]

55. Mohan S, Bautista CM, Wergedal J, et al: Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: A potential local regulator of IGF action. Proc Natl Acad Sci U S A 86: 8338-8342, 1989[Abstract/Free Full Text]

56. Schmid C, Rutishauser J, Schlapfer I, et al: Intact but not truncated insulin-like growth factor binding protein-3 (IGFBP-3) blocks IGF I-induced stimulation of osteoblasts: Control of IGF signaling to bone cells by IGFBP-3-specific proteolysis? Biochem Biophys Res Commun 179: 579-585, 1991[CrossRef][Medline]

57. Doherty A, Smith G, Banks L, et al: Correlation of the osteoblastic phenotype with prostate-specific antigen expression in metastatic prostate cancer: Implications for paracrine growth. J Pathol 188: 278-281, 1999[CrossRef][Medline]

58. Smith GL, Doherty AP, Mitchell H, et al: Inverse relation between prostate-specific antigen and insulin-like growth factor-binding protein 3 in bone metastases and serum of patients with prostate cancer. Lancet 354: 2053-2054, 1999

Submitted June 18, 2001; accepted October 11, 2001.




This article has been cited by other articles:


Home page
 aacredbookHome page
B. A Teicher, J. M Yingling, and J. M McPherson
TGF{beta} Blockade as Anticancer Therapy
Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 71 - 81.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. F. Shariat, J. Walz, C. G. Roehrborn, A. R. Zlotta, P. Perrotte, N. Suardi, F. Saad, and P. I. Karakiewicz
External Validation of a Biomarker-Based Preoperative Nomogram Predicts Biochemical Recurrence After Radical Prostatectomy
J. Clin. Oncol., March 20, 2008; 26(9): 1526 - 1531.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
B. A. Teicher
Transforming Growth Factor-{beta} and the Immune Response to Malignant Disease
Clin. Cancer Res., November 1, 2007; 13(21): 6247 - 6251.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
D. J. Parekh, D. P. Ankerst, J. Baillargeon, B. Higgins, E. A. Platz, D. Troyer, J. Hernandez, R. J. Leach, A. Lokshin, and I. M. Thompson
Assessment of 54 Biomarkers for Biopsy-Detectable Prostate Cancer
Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 1966 - 1972.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt
The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights
Endocr. Rev., February 1, 2007; 28(1): 20 - 47.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
C. S.H. Ng, S. Wan, C. W.C. Hui, I. Y.P. Wan, T. W. Lee, M. J. Underwood, and A. P.C. Yim
Video-assisted thoracic surgery lobectomy for lung cancer is associated with less immunochemokine disturbances than thoracotomy
Eur. J. Cardiothorac. Surg., January 1, 2007; 31(1): 83 - 87.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
J. M. Schildkraut, W. Demark-Wahnefried, R. M. Wenham, J. Grubber, A. S. Jeffreys, S. C. Grambow, J. R. Marks, P. G. Moorman, C. Hoyo, S. Ali, et al.
IGF1 (CA)19 Repeat and IGFBP3 -202 A/C Genotypes and the Risk of Prostate Cancer in Black and White Men
Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 403 - 408.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. F. Shariat, M. W. Kattan, E. Traxel, B. Andrews, K. Zhu, T. M. Wheeler, and K. M. Slawin
Association of Pre- and Postoperative Plasma Levels of Transforming Growth Factor {beta}1 and Interleukin 6 and Its Soluble Receptor with Prostate Cancer Progression
Clin. Cancer Res., March 15, 2004; 10(6): 1992 - 1999.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
M. W. Kattan, S. F. Shariat, B. Andrews, K. Zhu, E. Canto, K. Matsumoto, M. Muramoto, P. T. Scardino, M. Ohori, T. M. Wheeler, et al.
The Addition of Interleukin-6 Soluble Receptor and Transforming Growth Factor Beta1 Improves a Preoperative Nomogram for Predicting Biochemical Progression in Patients With Clinically Localized Prostate Cancer
J. Clin. Oncol., October 1, 2003; 21(19): 3573 - 3579.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Wang, T. Habuchi, N. Tsuchiya, K. Mitsumori, C. Ohyama, K. Sato, H. Kinoshita, T. Kamoto, A. Nakamura, O. Ogawa, et al.
Insulin-like Growth Factor-binding Protein-3 Gene -202 A/C Polymorphism Is Correlated with Advanced Disease Status in Prostate Cancer
Cancer Res., August 1, 2003; 63(15): 4407 - 4411.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. Fizazi, J. Yang, S. Peleg, C. R. Sikes, E. L. Kreimann, D. Daliani, M. Olive, K. A. Raymond, T. J. Janus, C. J. Logothetis, et al.
Prostate Cancer Cells-Osteoblast Interaction Shifts Expression of Growth/Survival-related Genes in Prostate Cancer and Reduces Expression of Osteoprotegerin in Osteoblasts
Clin. Cancer Res., July 1, 2003; 9(7): 2587 - 2597.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. H. Ngo, R. J. Barnard, P. Cohen, S. Freedland, C. Tran, F. deGregorio, Y. I. Elshimali, D. Heber, and W. J. Aronson
Effect of Isocaloric Low-fat Diet on Human LAPC-4 Prostate Cancer Xenografts in Severe Combined Immunodeficient Mice and the Insulin-like Growth Factor Axis
Clin. Cancer Res., July 1, 2003; 9(7): 2734 - 2743.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
I. B. Roninson
Tumor Cell Senescence in Cancer Treatment
Cancer Res., June 1, 2003; 63(11): 2705 - 2715.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. F. Shariat, E. Gottenger, C. Nguyen, W. Song, M. W. Kattan, J. Andenoro, T. M. Wheeler, D. M. Spencer, and K. M. Slawin
Preoperative Blood Reverse Transcriptase-PCR Assays for Prostate-specific Antigen and Human Glandular Kallikrein for Prediction of Prostate Cancer Progression after Radical Prostatectomy
Cancer Res., October 15, 2002; 62(20): 5974 - 5979.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed