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Original Studies |
Diagnostics Systems Laboratories, Inc. (J.K., A.D.), Toronto, Ontario, Canada M5G 1X5; Diagnostics Systems Laboratories, Inc. (J.M.), Webster, Texas 77598; and Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto (J.K., A.S.), Toronto, Ontario, Canada M5G 1L5
Address all correspondence and requests for reprints to: J. Khosravi, Ph.D., Diagnostics Systems Laboratories, Inc., Mount Sinai Hospital, Room 653, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5. E-mail: jkhosravi{at}mtsinai.on.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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75–80%), and smaller proportions (20–25%) are associated
with the low molecular mass IGFBPs (IGFBP-1, IGFBP-2, IGFBP-4, IGFBP-5,
and IGFBP-6) or exist (1%) in the free form
(5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Dysregulation and/or overexpression of the IGF system have long been implicated in the etiology of both benign and malignant proliferative disorders (3, 4, 15, 16, 17, 18, 19). Malignant cells of various origins have been shown to express various components of the IGF system (3, 4, 11, 12, 13, 18, 19, 20, 21, 22), and increased IGF levels, as seen in acromegaly, have been found in association with benign prostatic hyperplasia (BPH) (23, 24) and colonic tumors (25, 26). A high level of circulating IGF-I has been more recently identified as a risk factor for the development of prostate, breast, and lung cancers (27, 28, 29, 30), whereas overexpression of both IGF-I and IGF-II has been linked to colorectal cancers (31). In prostate, both benign and malignant cells have been found to express IGFs, IGFBPs, and their respective receptors (18, 23). IGF-I has been shown to promote prostate cell growth, whereas prostate-specific antigen (PSA) has been identified as an IGFBP-3 protease, presumably capable of augmenting tissue access to the IGF peptides (18, 23, 32).
In men over 50 yr of age, cancer of the prostate (CaP) and BPH are among the most commonly diagnosed malignant and benign proliferative disorders, respectively (33). However, the serum level of PSA, the most reliable predictor of CaP available to date, is also increased in BPH, resulting in a diagnostic gray zone for PSA values in the range of approximately 4–10 µg/L (34). In addition, a PSA level below 4 µg/L does not necessarily indicate disease-free status, because a significant number of men with organ-confined CaP reportedly have normal serum PSA levels (35). These significant limitations of PSA testing invariably result in a diagnostic dilemma, resulting in the loss of an opportunity for early cancer detection or avoidance of unnecessary surgical approaches to a readily treatable benign disorder, BPH. Although the ratio of free/total PSA levels in serum is significantly reduced in CaP, and its determination is now used to heighten the diagnostic accuracy of PSA testing (36, 37), there is still a great need to further improve our ability to discriminate between BPH and prostate cancer (35).
In view of the growing evidence describing association of the IGF system with cancer, we investigated differences in serum levels of IGF-I and levels of intact, fragment, and total IGFBP-3 in a group of patients with BPH and CaP. The age-matched patient populations were carefully selected to have total PSA in the diagnostic gray zone range. Because of the highly complex nature of IGF regulation (3, 4, 8, 11, 15), particularly involving proteolysis (13, 14), we postulated that investigation of IGF-I and IGFBP-3 variants in relation to free and total PSA levels might help identify better approaches for enhancing differential BPH/CaP detection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serum samples from 159 patients with BPH (75 men aged 55–75 yr; mean age ± SD, 65.6 ± 6.0) or prostate cancer (84 men aged 52–75 yr; mean age ± SD, 64.8 ± 6.2) were provided by Dr. E. P. Diamandis (Mount Sinai Hospital, Toronto, Canada). The samples were from patients with total PSA levels between 1.75–13.5 µg/L and histologically confirmed disease status at biopsy. All specimens were residuals from routine or research tests samples and were stored frozen at -70 C, with fewer than 3 freeze/thaw cycles until analysis.
Analytical methods
IGF-I, intact IGFBP-3, fragment IGFBP-3, and total IGFBP-3 were assayed by ACTIVE enzyme-linked immunosorbent assay (ELISA) kits manufactured by Diagnostics Systems Laboratories, Inc. (Webster, TX). These assays are based on noncompetitive two-step ELISA involving a solid phase capture antibody and a soluble horseradish peroxidase-labeled detection antibody. The Diagnostics Systems Laboratories, Inc., nonextraction IGF-I ELISA is a modification of a previously described method involving acid-ethanol extraction (38) and has been demonstrated to yield results highly parallel to those of the extraction assay (27). The IGF-I ELISA has a minimum detection limit of 1 ng/mL, a dynamic range of up to 600 ng/mL, and intra- and interassay coefficients of variation (CVs) of 4.5–8.6% and 3.3–6.8%, respectively. In the present study the average intraassay CV for IGF-I was 3.6%, which is well within the previously reported limits (27, 38, 39).
The developmental rationale, analytical specifications, and performance characteristics of intact, fragment, and total IGFBP-3 ELISAs have been recently reported (40). Briefly, the assays are based on a similar principle described for IGFBP-1 (41), involving a common capture antibody combined with three different detection antibodies for preferential detection of intact, fragment or total IGFBP-3 levels. The antibody selection was based on evaluation of a polyclonal and a panel of previously characterized anti-IGFBP-3 N-terminal, C-terminal, and midregion monoclonal antibodies (mAb) (42, 43). In the assays, IGFBP-3 (intact and C-terminally truncated variants) is first captured by a mAb-recognizing epitope(s) in the N-terminal region of IGFBP-3. Next, the captured variants are quantified by a polyclonal Ab for measuring total IGFBP-3, a C-terminal specific mAb for measuring intact IGFBP-3, or a mAb with enhanced reactivity for proteolyzed IGFBP-3 for measuring fragmented IGFBP-3 (40). As previously reported (40), all three assays were calibrated against intact recombinant IGFBP-3, as individual assay calibration with intact, fragment, or combinations of intact and fragment IGFBP-3 would have been problematic, particularly with respect to consistency of preparations and standardization. The common calibration approach is the primary reason for the detection of comparatively higher immunoreactivity levels by fragment IGFBP-3 ELISA, which binds significantly better to proteolyzed IGFBP-3 than the intact molecule (40). The IGFBP-3 ELISAs have dynamic ranges of 2–100 µg/L, a lower detection limit of about 0.04 µg/L, and intra- and interassay CVs of 3.4–7.9% and 5–8.3%, respectively. In the present study the average intraassay CVs were 3.8% for intact, 3.3% for fragment, and 4.5% for total IGFBP-3 ELISAs.
Concentrations of free and total PSA were determined by Hybritech Tandem-R total and free (44) noncompetitive immunoradiometric methods (Hybritech, Inc., San Diego, CA).
Data analysis
The ELISA results were analyzed using the data reduction packages included in the Labsystems Multiskan microplate ELISA reader (Labsystems, Helsinki, Finland) with cubic spline (smoothed) curve fit.
The analysis of differences between IGF-I and IGFBP-3 concentrations in the two groups of subjects was performed with the nonparametric Mann-Whitney U test. Association of IGF-I and IGFBP-3 variants in serum with the other continuous parameters was examined using Spearman correlation. Receiver operating characteristics (ROC) curves were constructed by plotting sensitivity vs. (1 - specificity), and the areas under the ROC curves (AUC) were calculated. Univariate and multivariate unconditional logistic regression models were developed to evaluate the ability of IGF-I and IGFBP-3 levels to predict the presence of prostate cancer. The plots were established by StatView (Abacus Concepts, Inc., Berkeley, CA). The statistical analysis was performed by SigmaStat (SPSS, Inc., Chicago, IL), and SAS (SAS Institute, Inc., Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In serum samples from a group of subjects with total PSA in the
range of 1.75–13.5 µg/L, IGF-I and intact IGFBP-3 levels were
significantly higher in those with CaP than in those with BPH
(P < 0.001), whereas changes in fragment and total
IGFBP-3 were statistically insignificant (Table 1
). In these samples, the mean
(±SEM) IGF-I and intact IGFBP-3 levels were
101.2 ± 5.45 µg/L (range, 10.9–220) and 1.12 ± 0.072
mg/L (range, 0.14–2.71) in BPH and 126.6 ± 4.89 µg/L (range,
28–218) and 1.48 ± 0.068 mg/L (range, 0.32–2.78) in CaP
patients. As expected (36), the total PSA levels were
relatively similar, whereas the free PSA levels were significantly
lower in CaP vs. BPH patients and were 0.757 ± 0.049
µg/L (range, 0.15–2.59) and 1.01 ± 0.056 µg/L (range,
0.31–3.15), respectively.
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). Interestingly, in both BPH and CaP
patients, IGF-I levels correlated more tightly with intact (r =
0.73–0.82) than with total (r = 0.54–0.70) IGFBP-3, whereas
fragment IGFBP-3 was negatively related to IGF-I in BPH (r =
-0.36; P < 0.018) and not at all in CaP (r <0.1;
P = 0.4).
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The inverse relation of IGF-I and intact IGFBP-3
vs. free PSA prompted evaluation of various concentration
ratios for their cancer-discriminating ability. Among various
possibilities, ratios of IGF-I/free PSA, intact IGFBP-3/free PSA,
(IGF-I/total IGFBP-3)/free PSA, (intact IGFBP-3/total IGFBP-3)/free
PSA, and (IGF-I plus intact IGFBP-3)/free PSA were most discriminative.
For the above ratios, the median values were significantly different in
BPH vs. CaP subjects and were 94.91 and 185, 0.85 and 2.09,
56.26 and 82.4, 0.489 and 0.938, and 0.978 and 2.361, respectively. As
previously reported (36, 37), the median free/total PSA
ratio was lower in CaP than in BPH subjects (0.144 and 0.202,
respectively). Although the observed differences were all highly
significant (P < 0.001), the increases in the median
values of the new parameters in Cap vs. BPH patients ranged
from 1.46-fold (for IGF-I/total IGFBP-3)/free PSA ratio) to 2.46-fold
(for intact IGFBP-3/free PSA). The free/total PSA ratio showed a
relative change of only 1.39-fold. The median values and distributions
of three of the ratios, IGF-I/free PSA, intact IGFBP-3/free PSA, and
free/total PSA ratios, in patients with CaP vs. BPH are
plotted in Fig. 2.
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In attempts to better define the cancer-differentiating potential
of the measured and calculated parameters, ROC curves were constructed.
In general, ratios demonstrated better discriminating powers than the
individual variables. Ratios involving total PSA or fragment IGFBP-3
were the least discriminating, whereas those based on IGF-I, intact
IGFBP-3, and free PSA were the most discriminating. Compared with the
currently used free/total PSA (AUC, 0.689; 95% CI, 0.605–0.772),
several permutations, particularly the ratios of intact IGFBP-3/free
PSA (AUC, 0.737; 95% CI, 0.658–0.816), and IGF-I/free PSA (AUC,
0.728; 95% CI, 0.649–0.808) demonstrated better discriminative
potential (Fig. 3). The ratios of (intact
IGFBP-3/total IGFBP-3)/free PSA (AUC, 0.747; 95% CI, 0.670–0.824),
(IGF-I plus intact IGFBP-3)/free PSA (AUC, 0.733; 95% CI,
0.653–0.812), and (IGF-I/total IGFBP-3)/free PSA (AUC, 0.725; 95% CI,
0.646–0.805) also had potential, but involved measurement of a third
variable. We examined other functions involving IGF-I, intact IGFBP-3,
and free PSA (logarithmic ratios, difference), but none appeared
promising. The comparative abilities of IGF-I/free PSA, intact
IGFBP-3/free PSA, and free/total PSA ratio in differentiating between
BPH and CaP at ROC-selected cut-off points are summarized in Table 2.
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We developed univariate and multivariate logistic regression
models in attempts to further evaluate the cancer predictive value of
the new determinants. As shown in Table 3, using univariate analysis increased
levels of IGF-I/free PSA and intact IGFB-3/free PSA ratios were found
to be associated with increased probability for cancer. In multivariate
analysis, IGF-I and IGFBP-3/free PSA-based variables were considered
separately because of the strong correlation between these parameters
as well as to show their separate relation to PSA measurement. These
regression models were adjusted for IGF-I/free PSA or intact
IGFBP-3/free PSA as well as for total PSA, free/total PSA, and age, all
of which were considered continuous variables. These models of
multivariate analysis identified both IGF-I/free PSA (crude odd
ratio = 2.8; 95% CI = 1.72–4.6; P < 0.001)
and intact IGFBP-3/free PSA (crude odd ratio = 1.66; 95% CI
= 1.18–2.34; P < 0.004) as independent factors in
predicting the presence of CaP (Tables 4 and 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In comparative correlation analysis, free PSA correlated significantly
and inversely with levels of IGF-I and IGFBP-3 (intact and total) in
BPH, but not in CaP, patients. In contrast, no correlations were found
in comparisons involving total PSA. The latter may be expected, as the
circulating PSA measured by the total assays (sum of free PSA plus PSA
complexed with protease inhibitors) is considered enzymatically
inactive (34, 46, 47, 48). However, the inverse relation of
free PSA with IGF-I or IGFBP-3 in patients with BPH suggests that at
least a proportion of the free PSA in BPH may circulate in the
catalytically active form. Whether the reported trypsin-like activity
of free PSA in BPH patients and its inability to efficiently complex
with the protease inhibitor 
1-antichymotrypsin
(48) is responsible for its observed inverse relation to
IGF-I and IGFBP-3 remains to be investigated. We propose that reduced
IGFBP-3 proteolysis, resulting in potential enhancement of IGF
bioavailability at cellular levels, may be advantageous to tumor cell
growth during early development, whereas the same mechanism might
conversely protect the cells against the antiproliferative (apoptotic)
properties of the bioactive IGFBP-3 peptides (8, 9, 10, 11, 12, 13, 14). In
this context, we recently reported significant association of high
IGFBP-3 in primary breast tumor extracts with unfavorable prognostic
indicators of the disease (49), and more recently found
that total IGFBP-3 levels in breast nipple aspirate fluid were
directly, and IGFBP-3 fragment levels were inversely related to breast
cancer risk (50).
Identification of markers with inverse relation in CaP (i.e.
IGF-I and intact IGFBP-3 vs. free PSA) prompted examination
of several concentration ratios and measurement permutations in
relation to PSA. Among the various possibilities, ratios of total
IGF-I/free PSA, intact IGFBP-3/free PSA, (IGF-I/total IGFBP-3)/free
PSA, (intact IGFBP-3/total IGFBP-3)/free PSA, and (IGF-I plus intact
IGFBP-3)/free PSA appeared the most promising. By ROC analysis,
determination of IGF-I/free PSA and intact IGFBP-3/free PSA
demonstrated similar, if not better, discriminating potential than the
free/total PSA ratio. Although several other permutations, notably
ratio of (intact IGFBP-3/total IGFBP-3)/free PSA, showed better
discriminative power, the relative improvement may not be significant
enough to warrant inclusion of a third measurement component. However,
the potential of growth factor/tumor marker combinations was further
confirmed by multivariate analysis, which identified IGF-I/free PSA and
intact IGFBP-3/free PSA as independent parameters for discriminating
between BPH and CaP. As determined by the ROC analysis, at a cut-off
ratio of less than 0.28 the free/total PSA ratio identified 95% of
cancer patients with a specificity of 17%, confirming previous
findings (36, 37). This cut-off point yielded a positive
predictive value (PPV) of 55%. On the other hand, the
IGF-I/free PSA ratio and intact IGFBP-3/free PSA ratio at cut-off
values of 51.4 and 0.5, respectively, identified 95% of the patients
with a specificity of 20% and PPVs of 56% and 57%. Interestingly,
the IGF-I/free PSA ratio at a cut-off value of 273 identified 29% of
the cancer patients with a specificity of 95%, corresponding to a PPV
of 85%. Intact IGFBP-3/free PSA at a cut-off value of 3.5 also
detected 29% of patients with cancer with a specificity of 95% and a
PPV of 85%. Thus, the findings of IGF-I/free PSA ratios greater than
273 and intact IGFBP-3/free PSA ratios greater than 3.5 are highly
suggestive of the presence of CaP. As indicated in Table 2
, the cut-off
points based on 95% specificity should be the preferred cut-off
points, as cut-offs based on 95% sensitivity did not increase the PPV
over the free/total PSA ratio. The observation that IGF-I/free PSA or
intact IGFBP-3/free PSA analysis appeared to compliment free/total PSA
testing is of significant interest and warrants further investigations
of their relevance and potential diagnostic applications. We propose
that development of diagnostic algorithms and/or mathematical models
based on multivariate determinations of IGF-I, intact IGFBP-3, free and
total PSA, as well as other pertinent clinical indicators may
significantly improve the differential diagnosis of prostate
cancer.
In summary, in a group of subjects with total PSA in the diagnostic gray zone range, we identified significantly higher IGF-I and intact IGFBP-3 levels in those with CaP than in those with BPH. Because IGF-I and IGFBP-3 did not correlate with PSA in CaP, but were inversely related to free PSA in BPH patients, we postulate that reduced proteolysis of IGFBP-3 might be linked to the pathogenesis of prostate cancer. Statistical analysis of the various biomarkers identified IGF-I/free PSA and intact IGFBP-3/free PSA ratios as potential new indicators of prostate cancer and indicated the need for further examination of this concept.
Received March 29, 2000.
Revised July 31, 2000.
Revised October 25, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-antichymotrypsin is the major form of
prostate-specific antigen in serum of patients with prostatic cancer:
assay of the complex improves clinical sensitivity for cancer. Cancer
Res. 51:222–226.1-antichymotrypsin in prostate carcinoma. J
Korean Med Sci. 12:228–233.[Medline]
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