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Endocrinological Oncology |
Institute of Experimental Clinical Research (A.F.) and Department of Immunoserology, Danish Cancer Society (O.M., B.M.), Department of Oncology (O.M., O.S.N.), Aarhus Kommunehospital, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Address all correspondence and requests for reprints to: Dr. Allan Flyvbjerg, M.D., D.Sc., Institute of Experimental Clinical Research, Aarhus Kommunehospital, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
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Abstract |
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In conclusion, IGFBP-2 levels are high in serum of epithelial ovarian cancer patients, and the increment in serum IGFBP-2 correlates positively with CA 125. Alterations in serum IGFBP-2 levels may, therefore, serve as a potential additional marker for ovarian cancer.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies have investigated the physiological roles of IGFs and IGFBPs in the female genital system by demonstrating the presence and physiological importance of IGFs, IGF receptors, and IGFBPs in the ovarian follicular system (3, 4). Furthermore, increased levels of IGFBP-2 have been demonstrated in malignant cyst fluid and in serum from ovarian cancer patients (5, 6), indicating a role of the IGF system in ovarian cancer.
The clinical and therapeutic problems in ovarian cancer patients are similar to those observed in malignant disease in general. The early states are usually without symptoms, and many patients have advanced tumors at the time of diagnosis. This problem has been addressed by recent, successful attempts at identifying serological tumor markers, of which two widely used in epithelial ovarian tumors are CA 125 (7) and tumor-associated trypsin inhibitor (TATI). These markers have proven to be reliable tools for differentiating between benign and malignant ovarian tumors, especially when used in combination (8, 9, 10).
The aim of the present study was to measure serum levels of IGFBP-2, IGFBP-3, CA 125, and TATI in patients with benign and malignant ovarian tumors, with special attention to possible mutual correlations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fasting serum samples were collected preoperatively from patients in departments affiliated with the Danish Ovarian Cancer Group. Approval for the study was achieved from the local Ethics Committee and the Danish Public Register, which process personal data. The patients were characterized in detail in terms of levels of tumor markers (serum CA 125 and TATI), general history, physical examination, macroscopical tumor during the primary operation, and histological diagnosis. The histological diagnoses were reviewed by senior pathologists affiliated with the Danish Ovarian Cancer Group. All patients with malignant ovarian tumors were characterized according to FIGO-stage (Fédération Internationale de Gynécologie et Obstétrique); Stages I and II: tumors localized to ovaries with/without local pelvic extension; Stages III and IV: tumors localized to ovaries with spread to small bowel, omentum, retroperitoneal nodes, or distant organs. At admittance to the department, all patients were found to be in good general health and to have adequate nutritional status at the time of presentation.
Three groups of postmenopausal age-matched patients were included in
the study. Group 1: 10 patients (mean age: 63 yr, range 51–76) with
benign ovarian tumors and normal CA 125 values (
35 U/mL); mean: 16
U/mL (range 5–35 U/mL); Group 2: 10 patients (mean age: 61 yr, range
53–77, with malignant epithelial ovarian tumors and moderately
elevated CA 125 values (200 U/mL); mean: 88 U/mL (range 7–184 U/mL);
Group 3: 10 patients (mean age: 62 yr, range 50–80, with malignant
epithelial ovarian tumors and high CA 125 values (>200 U/mL); mean:
794 U/mL (range 274-2057 U/mL). In Group 1, one patient had a dermoid
cyst, one patient had a granulosa cell tumor, two patients had simple
cysts, and six patients had cyst adenomas. In Groups 2 and 3, five
patients were in FIGO stages I and II, and fifteen patients in FIGO
stages III and IV. Sera from eight normal healthy age-matched (mean
age: 63 yr, range 52–78) female control subjects were used as
reference. In all cases, serum was frozen immediately after the blood
samples were drawn and kept at -80 C until analysis.
Tumor marker assays
Serum CA 125 was measured by an enzyme immunoassay using the CA 125-enzyme immunoassay kit (Abbott Laboratories, Diagnostics Division, North Chicago, IL), as previously described (8). Serum TATI was measured, as previously described (9, 10), using an RIA (Farmos Diagnostica, Oulunsalo, Finland). The intra- and interassay coefficients of variation were less than 8% and 12%, respectively, for both assays.
RIAs for IGFBP-2, IGFBP-3, and IGF-I
Serum IGFBP-2 and IGFBP-3 were measured by RIA (Diagnostic Systems Laboratories Inc., Webster, TX). Serum IGF-I was measured after extraction with acid-ethanol. In the RIA, we used a polyclonal rabbit IGF-I antibody (Nichols Institute Diagnostics, San Capistrano, CA) and recombinant human IGF-I for standard (Amersham International, Amersham, Buckinghamshire, UK). Monoiodinated IGF-I (125I-(Tyr31)-IGF-I) was obtained from Novo-Nordisk A/S, Bagsværd, Denmark. The intra- and interassay coefficients of variation were less than 5% and 10%, respectively, for all assays.
Western ligand blotting (WLB) and immunoprecipitation of serum IGFBPs
WLB, SDS-PAGE, and ligand blot analysis were performed in serum from all patients and controls according to the method of Hossenlopp et al. (11), as previously described (12). Two microliters of serum was subjected to SDS-PAGE (10% polyacrylamide) under nonreducing conditions. Specificity of the IGFBP bands was ensured by competitive coincubation with unlabeled IGF-I purchased from Bachem, Bubendorf, Switzerland. The identity of the IGFBPs detected on the WLB was confirmed by immunoprecipitation with specific antibodies for IGFBP-2 and IGFBP-3 (Upstate Biotechnology Incorporated, Lake Placid, NY). When serum was immunoprecipitated with specific IGFBP-2 and IGFBP-3 antibodies, IGFBP-2 appeared as a single 32-kDa band, and IGFBP-3 as a 38- to 42-kDa doublet.
IGFBP-3 protease assay
The IGFBP-3 protease assay was performed as previously described (13). 125I-IGFBP-3 (30.000 cpm) (Diagnostic System Laboratories, Webster, TX) was incubated for 18 h at 37 C. Two microliters of serum was drawn from patients, controls, and term-pregnant (TP) women and subsequently subjected to SDS-PAGE as described above. Gels were fixed in a solution of 7% acetic acid, dried, and autoradiographed. The amount of proteolysis was calculated as a ratio of the absorbance of fragmentated 125I-IGFBP-3 over the sum of all 125I-IGFBP-3 related optical densities in that lane and expressed as a percentage.
Quantification of WLB and IGFBP-3 protease assay
Autoradiograms were quantified by densitometry using a Shimadzu CS-9001 PC dual-wavelength flying spot scanner. The relative density of the bands was measured as arbitary absorbance units per square millimeter (AU/mm2).
Statistics
Results are given as mean \ SEM. Data were analyzed by Mann-Whitney’s rank sum test for unpaired comparisons. Coefficients of correlation between tumor makers and IGFBPs were evaluated using liniar regression. A P-value less than 0.05 was regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2)
Ovarian cancer patients had higher serum IGFBP-2 levels than
controls. IGFBP-2 levels measured by RIA were 253% above average level
in control subjects (1773 \ 168, range 841–3493) vs.
502 \ 58 (range 333–730) µg/L; P < 0.01) and
105% higher by WLB (43 \ 7, range 9–122) vs. 21
\ 2 (range 8–33) AU/mm2; P < 0.05)(Fig. 1). No difference in IGFBP-2 was found between patients with benign
ovarian tumors and healthy controls [RIA: 681 \ 82 (range
206–893) vs. 502 \ 58 µg/L; not significant
(NS)][WLB: 19 \ 3 (range 4–36) vs. 21 \ 2
AU/mm2; NS]. When patients with ovarian cancer were
divided into one group with moderately increased (200 U/mL) and one
group with highly increased (>200 U/mL) serum CA 125 levels, the
former group had serum IGFBP-2 levels (estimated by RIA) 169% above
average level in control subjects (1350 \ 165, range 841–2625)
µg/L; P < 0.001), and a trend towards increased
levels was seen when estimated by WLB. The latter group came out with
serum IGFBP-2 levels (by RIA) 338% above average level in control
subjects \[2197 \ 228 (range 1273–3493) µg/L;
P < 0.001\] and elevated levels (by WLB) amounting to
167% \[56 \ 10 (range 23–122) AU/mm2;
P < 0.001\] (Fig. 1). A representative WLB, and
immunoprecipitate of serum, with a specific IGFBP-2 antibody is shown
in Fig. 2.
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and 3)
The RIA did not reveal any difference in mean IGFBP-3 levels
between patients with benign ovarian tumors and controls \[4421
\ 460 (range 1822–6646) vs. 4249 \ 439 (range
2256–5617) µg/L; NS\]. In contrast, the ovarian cancer patients had
decreased levels of IGFBP-3, both considered as a whole \[2893
\ 190 (range 1587–4787) µg/L; P < 0.01\] and after
separation according to moderately increased \[2686 \ 162 (range
1992–3807) µg/L; P < 0.01\] and high \[3099
\ 342 (range 1587–4787) µg/L; P < 0.01\] serum CA 125
levels (Fig. 3A). The WLB did not show any difference in serum IGFBP-3
levels between patients with benign ovarian tumors and controls
\[264 \ 32 (range 7–341) vs. 282 \ 20
(184–352) AU/mm2; NS\]. As with the RIA, patients with
ovarian cancer had decreased levels of IGFBP-3 by WLB, both when all
patients were included \[67 \ 21 (range 0–250)
AU/mm2; P < 0.001\] and after division
into moderately increased \[55 \ 25 (range 0–216)
AU/mm2; P < 0.001\] and high \[79
\ 25 (range 0–250) AU/mm2; P < 0.001\]
serum CA 125 levels (Fig. 3B). A representative WLB and
immunoprecipitate of serum with a specific IGFBP-3 antibody is shown in
Fig. 2. The mean serum IGF-I levels were decreased in patients with
ovarian cancer \[63 \ 6 (range 31–104) µg/L; P
< 0.001\] when compared with patients with benign ovarian tumors
\[118 \ 6 (range 83–146) µg/L\] and control subjects
\[129 \ 16 (range 91–156) µg/L\].
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and 5)
The percentage of IGFBP-3 proteolysis was 7.4 \ 1.6% (range
5.2–10.5) in normal control subjects (n = 8); 11.1 \ 1.2%
(range 8.1–21.4) in patients with benign ovarian tumors (n = 10);
14.5 \ 2.2% (range 7.1–28.6) in patients with ovarian cancer
and CA 125 200 U/mL (n = 10), and 17.1 \ 2.9%
(range 7.3–36.0) in ovarian cancer patients having CA 125 values more
than 200 U/mL (n = 10) (Fig. 4). The mean values were not
significantly different. For comparison, the proteolysis in serum from
TP subjects was 68.3 \ 2.1% (n = 8). A representative
IGFBP-3 protease autoradiograph is shown in Fig. 5.
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)
CA 125 correlated with serum IGFBP-2, both by RIA (r = 0.71;
P < 0.001) (Fig. 6) and by WLB (r = 0.52;
P < 0.003), whereas no correlation was found between
CA 125 and IGFBP-3 or IGFBP-3 protease activity. In contrast, serum
TATI correlated negatively with IGFBP-3 (r = -0.55;
P < 0.001) and positively with IGFBP-3 protease
activity (r = 0.56; P < 0.001)(Fig. 4B). No
correlation was found between serum TATI and serum IGFBP-2.
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When patients with ovarian cancer were divided into FIGO-stages I and II (tumors localized to ovaries with/without local pelvic extension) and FIGO-stages III and IV (tumors localized to ovaries with spread to small bowel, omentum, retroperitoneal nodes, or distant organs), significantly higher levels of serum CA 125 (566 \ 145 vs. 71 \ 31 U/mL; P < 0.01) and serum IGFBP-2 (2001 \ 188 vs. 1090 \ 80 µg/L; P < 0.01) levels were seen in patients in stages III IV when compared with patients in stages I II. No differences were seen between tumor staging and levels of serum TATI, IGFBP-3 (WLB and RIA), IGFBP-3 proteolytic activity, or IGF-I.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In 1983, Bast et al. (7) described a tumor marker for epithelial ovarian cancer, CA 125, that allowed early diagnosis of viable cancer cells and made it possible to quantify variations in the number of these cells during the course of the disease. CA 125 is a large glucoprotein molecule with an unknown biochemical structure and biological function. In serum, the antigen is increased in approximately 90% of patients with ovarian carcinomas and in a number of other ovarian and nonovarian benign and malignant diseases (8). Recent investigations have demonstrated that measurement of TATI may supplement the information obtained by CA 125 (8, 9, 10). TATI is a proteinase inhibitor whose physiological target proteases are trypsin and acrosin (15, 16). Furthermore, TATI is believed to protect normal cells from the digestive effect of trypsin (17). TATI is also known to be a potent inhibitor of trypsin and tumor-associated trypsin(ogen)-1 and -2 (TAT-1 and TAT-2). TAT-1 and TAT-2 can activate prourokinase, which may start a protease cascade that may facilitate the invasion of tumor cells. Accordingly, TATI may play a role in the protection of normal tissue against tumor cell invasion through inhibition of TAT-1 and TAT-2.
In the present study, the finding of elevated serum IGFBP-2 levels in patients with ovarian carcinomas was in accordance with a previous report (5). The elevated IGFBP-2 levels were demonstrated both by RIA and WLB. The major new finding in the present study is that the higher IGFBP-2 levels correlated positively with circulating CA 125 levels, thereby suggesting that the rise in serum IGFBP-2 levels may be of ovarian origin. This hypothesis is supported by the finding in a recent study by Kanety et al. (6), reporting high levels of IGFBP-2 in malignant ovarian cyst fluid in vivo. To identify the mechanisms responsible for this increase, the authors measured IGFBP-2 messenger RNA (mRNA) in 12 malignant and 4 benign epithelial ovarian neoplasms (6). IGFBP-2 mRNA was measurable in all ovarian specimens, but 2- to 30-fold higher levels were found in malignant tumors than in benign tumors. Furthermore, it was reported that the IGFBP-2 mRNA levels were higher in invasive tumors than in tumors with borderline malignant pathology (6). By the use of WLB, Western immunoblotting, and immunohistochemistry, it was demonstrated that the increased IGFBP-2 mRNA levels were translated into increased production of IGFBP-2 peptide (6).
Alternatively, the elevated circulating IGFBP-2 levels may be caused by
a modest degree of catabolism induced by the malignancy per
se. Support for this hypothesis is the low serum IGFBP-3 and IGF-I
levels and increased IGFBP-3 proteolysis demonstrated in patients with
ovarian carcinomas. However, other findings seem to argue against this
hypothesis. First, neither IGFBP-3, IGFBP-3 proteolytic activity, nor
IGF-I correlated with CA 125 or FIGO-stage. Furthermore, grouped
according to moderate and high CA 125 levels, patients with ovarian
carcinomas had similar changes in IGFBP-3 and IGF-I, whereas IGFBP-2
levels were steadily increasing with the severity of the disease and
the increasing CA 125 values. Finally, several (
25%) of the
ovarian cancer patients with high circulating IGFBP-2 and CA 125 levels
had high IGFBP-3 and IGF-I levels that were not different from those of
the healthy controls.
The second most pronounced change in the IGFBP system was the decreased levels of IGFBP-3 and the increased proteolytic activity against IGFBP-3. These changes did not correlate with CA 125, but TATI correlated inversely with circulating levels of IGFBP-3 and positively with the IGFBP-3 proteolytic activity. Increased IGFBP-3 proteolysis is a classical finding in pregnancy (18), postsurgical catabolism (19), severe illness (20), and noninsulin-dependent diabetes mellitus (21). As mentioned above, TATI may be an inhibitor of TAT-1 and TAT-2, factors that are known to activate prourokinase. Because recent evidence has suggested that plasminogen activators (i.e. tissue-type plasminogen activator, urokinase, and streptokinase) may act as potent IGFBP-3 proteolytic agents in pregnancy serum (22), it would be expected that TATI would correlate positively with IGFBP-3 and inversely with the IGFBP-3 proteolytic activity in serum, but the opposite was found in the present study. Thus, future studies are needed to elucidate the exact relationship.
The role of IGFBPs in general and of IGFBP-2 in particular, in relation to malignancy, is not known. It is of interest, however, that elevated levels of IGFBP-2 have been found in other forms of cancer. For example, a recent study showed that IGFBP-2 is produced by human prostate epithelial cells in culture (23). Other studies (24, 25) demonstrated elevated IGFBP-2 serum levels in patients with prostate cancer and a positive correlation between these levels and the circulating prostate-specific antigen, a useful marker for detection and monitoring of the disease (24, 25). Interestingly, the changes in serum IGFBP-2 in prostate cancer seem to bear similarities to the changes described here in patients with ovarian cancer. Future studies are needed to determine whether increased levels of circulating IGFBP-2 levels may be a general phenomenon in cancer.
In conclusion, we report increased circulating levels of IGFBP-2 in patients with epithelial ovarian cancer. The elevated serum IGFBP-2 levels correlated positively with CA 125, which is the best noninvasive tumor marker for epithelial ovarian cancer so far. Decreased serum levels of IGFBP-3 were found in patients with ovarian cancer. The IGFBP-3 levels did not correlate with CA 125, but correlated negatively with TATI, another less sensitive tumor marker for epithelial, serous ovarian cancer. Although measurements of IGFBP-2 do not have the tumor marking sensitivity or specificity of CA 125 and TATI, the changes in IGFBPs are clearly of theoretical interest and may have significant clinical importance. Accordingly, future studies are warranted to elucidate whether the changes in serum IGFBPs may play a role in the pathogenesis or prognosis in ovarian cancer. Such studies, measuring serum IGFBP-2 and IGFBP-3 in ovarian cancer, should ideally be conducted during chemotherapy, before the second-look operation, and in the follow-up period.
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Acknowledgments |
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Footnotes |
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Received October 23, 1996.
Revised February 5, 1997.
Accepted March 27, 1997.
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References |
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; the same patients separated into
those with CA 125 values 
); and serum CA 125
values > 200 U/mL, 
), 10 patients with benign ovarian tumors
(
), and 8 age-matched controls (
). Values are given as mean
± SEM. *, P < 0.05; **,
P < 0.01 when compared with normal controls.
,
n = 10) and serum CA 125 values > 200 U/mL (
, n =
10).
