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Original Studies |
Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 75012 Paris, France
Address all correspondence and requests for reprints to: Dr. Nathalie Boulle, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 avenue Arnold Netter, 75012 Paris, France.
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Abstract |
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Group 2 tumors contained 10 times more IGF-II protein than group 1 tumors or normal adrenal tissue (P < 0.001), indicating efficient translation of IGF-II mRNA in malignant tumors. Western ligand blotting detected various functional IGFBPs in normal adrenocortical glands and tumors: a doublet of 39–42 kDa identified by immunoblotting as IGFBP-3, a band at 32 kDa, and bands at 29–30 and 24 kDa. Total IGFBP-3 protein levels were similar in the two groups of tumors. By contrast, malignant tumors differed from benign ones by specific expression of the 32-kDa IGFBP. Immunoblotting identified this 32-kDa band together with a proteolytic fragment of 25 kDa as IGFBP-2, and quantitative analysis showed significantly higher levels of total IGFBP-2 in malignant tumors than in benign tumors (P < 0.001). Despite enhanced levels of IGBP-2 protein in malignant tumors, no increase in IGFBP-2 mRNA levels was detected, suggesting post-transcriptional regulation of this IGFBP.
These results confirm the major role of IGF-II in adrenocortical tumorigenesis and suggest that IGFBP-2 may be a regulator of IGF-II proliferative effects in this tumor system.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In human adult adrenocortical cells, Western ligand blotting revealed five secreted IGFBPs with apparent molecular weights of 39–44, 34, 29, and 24 kDa; the 39–44 kDa doublet being identified as IGFBP-3 (15, 16). A similar profile has been found in conditioned medium from human fetal adrenocortical cells (2). In this model, ACTH did not regulate the expression of the IGFBPs, in contrast to the findings in adult bovine adrenocortical cells (17, 18). IGFBP mRNA expression has also been described in normal human adrenals (2), showing different IGFBP mRNA profiles in fetal and adult adrenocortical glands. In contrast to these reports on normal human adrenals, nothing is known about the expression of IGFBPs and their possible role(s) in adrenocortical tumors.
In the present work, we investigated some as yet unknown aspects of the IGF/IGFBP system in adrenocortical sporadic tumors. We determined the amounts of IGF-II protein in 18 adrenocortical tumors with normal or high IGF-II mRNA levels. We report here elevated content of this growth factor in malignant tumors compared to that in benign ones. We also analyzed the expression of various IGFBPs and found an enhanced IGFBP-2 content in adrenocortical tumors overexpressing the IGF-II gene. This suggests that IGFBP-2 may regulate IGF-II effects in malignant adrenocortical tumors.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen patients, aged 16–69 yr, were included in this study.
Tumors were defined as benign, suspect, or malignant and grouped on the
basis of IGF-II mRNA expression, measured by dot blot and Northern blot
assays, and compared to normal adult adrenocortical tissue (Table 1
) (11). Each group (group 1, normal
IGF-II gene expression; group 2, IGF-II gene overexpression) contained
nine patients. A normal human adrenal gland was obtained from a patient
who underwent large nephrectomy for kidney cancer. Tissue fragments
were frozen immediately after surgery in liquid nitrogen and stored at
-80 C until protein and RNA extractions.
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Proteins were extracted as previously described (19). Frozen tissues (average weight, 100–300 mg) were quickly homogenized on ice in 3 mL ice-cold 1 mol/L acetic acid containing protease inhibitors (1 mmol/L ethylenediamine tetraacetate, 1 mmol/L phenylmethylsulfonylfluoride, 1 µg/mL leupeptin, 1 µg/mL pepstatin, 1 µg/mL aprotinin, and 3 µmol/L antipain) using a Brinkmann Polytron (Brinkmann Instruments, Westbury, NY). The homogenates were incubated for 1 h at 0 C and centrifuged at 13,000 rpm for 15 min at 4 C. The supernatant was removed and saved, and the pellet was washed twice in homogenization buffer. The supernatants obtained at each step were pooled and frozen at -80 C. Aliquots of supernatant were saved for protein determination (Bio-Rad protein assay, Bio-Rad, Richmond, CA) and for IGF and IGF-binding protein assays.
IGF RIAs
IGF assays were performed as previously described (19, 20). Lyophilized supernatants were dissolved in 1 mol/L acetic acid containing 1 mg/mL BSA (IGFBP free, Biomerieux, Paris, France) and 0.15 mol/L NaCl and centrifuged (4,000 rpm; 30 min at 0 C). The IGFs in the supernatants were then dissociated from their binding proteins by acid-gel filtration on an Ultrogel AcA 54 column (IBF, Villeneuve-la-Garenne, France). At this step, the eluted fraction saved for IGF assays contained IGF-I and IGF-II of low molecular mass (7.5 kDa). IGF-I was assayed by RIA using anti-IGF-I antibodies provided by Drs. Frankenne and Hennen (Liege, Belgium). IGF-II was determined by an IGF-II protein binding assay using IGFBPs extracted from cerebrospinal fluid, as previously described (21).
Western ligand and immunoblotting
Western ligand blotting was performed according to the method of Hossenlopp et al. (22). Lyophilized supernatants were suspended in 100 mmol/L Tris, pH 7.5, and 200 µg protein extract was submitted to SDS-11% PAGE under nonreducing conditions. Proteins were transferred to nitrocellulose and probed with a mixture of [125I]IGF-I and [125I]IGF-II (4 x 105 cpm each). The blots were then exposed to x-ray films for about 2 weeks at -80 C. To allow comparisons between different experiments, the same human control serum (3 µL) was used for each gel.
Nitrocellulose membranes for immunoblotting were prepared as described for ligand blotting, except that electrophoresis of IGFBP-2 was performed under reducing conditions to achieve better signal resolution. Antihuman IGFBP-3 (anti-hIGFBP-3) serum (1:1000) was provided by Dr. Binoux (INSERM U-142, Paris, France). Antibovine IGFBP-2 (anti-bIGFBP-2) polyclonal antibodies (1:2000) were purchased from Upstate Biotechnology (Lake Placid, NY). According to the manufacturers, the anti-bIGFBP-2 antibodies show 0.1–0.5% cross-reactivity with IGFBP-1, -3, -4, and -5. For the anti-IGFBP-3 antibodies, cross-reactivity with IGFBP-1 was 1%, and no cross-reaction was found with the other IGFBPs (23). Anti-hIGFBP-3 antibodies were incubated for 1 h at 37 C whereas anti-bIGFBP-2 antibodies were incubated overnight at 4 C. Immunoreactive proteins were visualized using the Amersham ECL System (Amersham, Aylesbury, UK).
For IGF-II immunoblotting, 250 µg extracted protein were loaded on a 12.5% gel under nonreducing conditions. After transfer, the blots were probed with an antirat IGF-II monoclonal antibody (1:500) purchased from Upstate Biotechnology (Lake Placid, NY). This antibody was specific to rat and human IGF-II and showed less than 10% cross-reactivity with hIGF-I.
RNA extraction and Northern blotting
Total RNA was extracted by the CsCl/guanidine isothiocyanate method (24). Eight micrograms of total RNA were loaded onto a 1.2% agarose-2.2 mol/L formaldehyde gel, submitted to electrophoresis, and transferred to GeneScreen Plus membrane (DuPont-New England Nuclear, Boston, MA). The membranes were baked for 2 h at 80 C to fix the RNA and hybridized as previously described (25) with hIGFBP-2, hIGFBP-3, or hIGFBP-6 32P-labeled complementary DNA probes, provided by Dr. Binoux (INSERM U-142). The signal of each IGFBP was normalized to the intensity of the 28S ribosomal RNA detected by ethidium bromide staining of the gel. For Northern blot comparisons, 8 µg total RNA extracted from the same human liver were used as a reference sample.
Densitometry
Western ligand blots, immunoblots, and Northern blots were analyzed by scanning with a GS700 imaging densitometer and the molecular analyst data system (Bio-Rad, Richmond, CA).
Statistical analysis
Data are expressed as the mean ± SEM. The two groups of tumors were compared by Mann-Whitney’s U test for unpaired data, using StatView software (Abacus Concepts, Berkeley, CA). P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 18 adrenocortical tumors studied were classified into 2 groups
on the basis of their IGF-II mRNA levels (Table 1
). A strong
correlation between malignancy and overexpression of the IGF-II gene
has been previously described in adrenocortical tumors (9, 11), such
that group 1 tumors (normal IGF-II mRNA levels) are predominantly
benign, whereas group 2 tumors (high IGF-II mRNA levels) are
malignant.
IGF-I and IGF-II proteins were determined in a normal adrenal gland and
for the two groups of tumors. IGF-I and IGF-II contents in the
reference adrenal gland were 0.65 and 1.45 ng/mg protein, respectively.
Benign tumors (group 1) had similar levels of IGF-II protein as the
reference adrenal gland (Fig. 1A; mean,
2 ± 1.1 ng/mg protein). By contrast, malignant tumors (group 2)
showed a 14-fold increase in IGF-II protein content compared to the
control adrenal gland (mean, 20.5 ± 14.3 ng/mg protein). The
difference in IGF-II protein content between benign and malignant
tumors was significant at P < 0.001. This difference
was specific to IGF-II, as similar levels of IGF-I protein were
detected in the two groups of tumors and in the reference adrenal gland
(mean, 0.65 ± 0.23 and 1.06 ± 0.65 ng/mg protein in groups
1 and 2, respectively).
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, B and C, IGF-II
species of high molecular weight (apparent molecular weight 17–24
kDa), presumably precursor forms, were detected in malignant
adrenocortical tumors (tumors 14 and 16). Our failure to detect the
7.5-kDa IGF-II form in adrenocortical tumors (Fig. 1B) may be explained
by the detection limit of the immunoblot method. Malignant and benign tumors exhibit different IGFBP profiles
Ligand blotting, using a mixture of radiolabeled IGF-I and IGF-II,
was used to detect functional IGFBPs, i.e. IGFBPs that have
retained their binding capacity. Figure 2
shows the IGFBP profiles of normal adrenal tissue and tumors. Five
different bands were detected: a major doublet of 39–42 kDa and bands
at 32, 29–30, and 24 kDa; the 24-kDa band being fainter than the
others. All of these bands were detected in the normal adrenal gland
(Fig. 2) as in two other normal adrenals (data not shown). Figure 2
also shows that benign and malignant adrenocortical tumors exhibited
different IGFBP profiles. Densitometry revealed no significant
difference between the two groups of tumors in the amounts of the
39-/42-kDa doublet and the 29-/30- and 24-kDa bands. By contrast, the
32-kDa band was present in malignant tumors (eight of nine tumors;
group 2), but was absent in all of the benign tumors tested (n =
9; group 1; Fig. 2).
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Human polyclonal antibodies specific for IGFBP-2 and IGFBP-3 were
used to detect these proteins in adrenocortical tumor extracts (Figs. 3A and 4A).
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), and the binding activity
observed at 32 kDa on ligand blots (Fig. 2). An additional band was
detected by the antibodies at around 25 kDa, which probably corresponds
to a proteolytic fragment of the protein (Fig. 3A). Immunoreactive
32-/34- and 25-kDa IGFBP-2 were detected in all adrenocortical extracts
examined, including those from group 1 tumors. This contrasts with the
lack of functional IGFBP-2 activity in the latter tumors (see Fig. 2). Quantitative analysis showed that total immunoreactive IGFBP-2
was significantly higher in malignant tumors (group 2) than in benign
ones (group 1) or in the reference adrenal gland (P <
0.001; Fig. 3B).
IGFBP proteolysis may be related to the status of the tumor. However,
despite high amounts of the 25-kDa IGFBP-2 fragment in malignant
tumors, the extent of IGFBP-2 proteolysis, expressed as the percentage
of total IGFBP-2 processed, was similar in the two groups of tumors
(Fig. 3C).
IGFBP-3 antibodies detected two glycosylated forms of intact IGFBP-3
(39-/42-kDa doublet) and a proteolytic fragment of 30 kDa similar in
size to those observed in control serum (Fig. 4A). In contrast to
IGFBP-2, total IGFBP-3 content did not differ significantly in benign
and malignant tumors (P = 0.26; Fig. 4B). Surprisingly,
IGFBP-3 proteolysis was less important in malignant tumors than in
benign ones (P < 0.05; Fig. 4C).
Posttranscriptional regulation of IGFBP-2 probably occurs in adrenocortical tumors
We performed Northern blot analyses of RNA from adrenocortical tumors to determine whether the high IGFBP-2 protein content detected in malignant tumors results from higher mRNA levels. IGFBP-3 and IGFBP-6 mRNA levels were also investigated for comparison.
All three IGFBP mRNAs were detected in tumors and normal adrenal gland,
with IGFBP-3 mRNA giving the weakest signal (Fig. 5A). As shown in Fig. 5B, group 2 tumors
did not have higher levels of IGFBP-2 mRNA than group 1 tumors or
normal adrenal, although they exhibit enhanced levels of IGFBP-2
protein. Similar levels of IGFBP-3 mRNA were detected in the two tumor
groups. By contrast, malignant tumors had lower levels of IGFBP-6 mRNA
than benign tumors or the reference adrenal gland (Fig. 5B).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The IGF assay used here (21) preferentially measures the mature 7.5-kDa IGF-II peptide. However, IGF-II forms of higher molecular weight have also been described in various types of tumor (13, 26, 27). We did detect such precursor forms of IGF-II in malignant tumors by immunoblotting. This suggests that the amounts of IGF-II protein in these tumors may be even higher than those measured by our IGF-II assay. Large amounts of high molecular weight forms of IGF-II such as those detected in adrenal tumors have also been described in other tumors overexpressing the IGF-II gene. This indicates abnormalities of IGF-II processing in these tumor tissues (13, 26, 27, 28). Interestingly, these precursor forms of IGF-II are the major forms extracted from human fetal adrenal cortex, suggesting that adrenal tumor cells share similarities with fetal adrenal cells (29).
IGFBPs locally modulate IGF actions, so IGFBP expression and activity must also be studied to understand the proliferative effects of IGF-II on adrenocortical tumor cells. Western ligand and immunoblotting were thus performed to evaluate the presence of functional and immunoreactive IGFBPs in adrenocortical tumors.
Western ligand blotting detected several functional IGFBPs in adrenocortical tumor tissues: a major doublet of 39–42 kDa identified as IGFBP-3, a band at 32 kDa corresponding to IGFBP-2, and bands at 29–30 and 24 kDa.
The most prominent finding of our study was the specific overexpression of IGFBP-2 in tumors with high levels of IGF-II gene expression. Thus, in adrenocortical tumors, malignant phenotype is associated with specifically high levels of IGF-II and IGFBP-2. This view is supported by the observation of Logié et al. (manuscript in preparation), who detected large amounts of IGFBP-2 in culture medium from the NCIH295R cell line derived from a human adrenocortical carcinoma (30). Although the tissues used in the present work contain various cell types, the latter observation further suggests that IGFBP-2 is produced by tumor cells themselves. The high levels of IGF-II/IGFBP-2 expression described for malignant tumors are also reminiscent of those observed in fetal adrenal glands, suggesting that the tumor cells may have dedifferentiated to a fetal state (4, 8, 31).
Several studies have suggested that IGFBP-2 expression may be associated with malignancy (32, 33, 34, 35), but the exact role of IGFBP-2 in adrenocortical tumor growth remains unknown. Both stimulatory and inhibitory effects of IGFBP-2 on IGF activity have been reported, depending on the model examined (36, 37). The high levels of IGFBP-2 detected in malignant adrenocortical tumors are consistent with a stimulatory role for IGFBP-2 in this tumor model. IGFBP-2 may increase the proliferative effects of IGF-II by binding to the cell membrane or to the extracellular matrix, thus facilitating IGF-II access to its receptor (38, 39, 40). Proteolysis is another possible mechanism for regulating IGFBP-2/IGF-II interactions (41, 42, 43). IGFBP-2 proteolysis indeed occurred in adrenocortical tumor extracts, and large amounts of the IGFBP-2 proteolytic fragment were present in malignant tumors. By decreasing IGF-II affinity, IGFBP-2 proteolysis may increase IGF-II bioavailability and enhance its proliferative effects on adrenocortical tumor cells. Although it is tempting to suggest that IGFBP-2 modulates the proliferative effects of IGF-II, this remains to be demonstrated. The high levels of IGF-II and IGFBP-2 proteins in adrenocortical tumors can be interpreted differently. For instance, IGF-II and IGFBP-2 may be coregulated in these tumors, or IGF-II may regulate IGFBP-2 expression or protect IGFBP-2 from degradation, thus increasing its half-life. Further studies are required to elucidate the interactions between these two proteins.
Normal adult adrenal glands contained functional IGFBP-2, whereas no IGFBP-2 could be detected in benign adrenocortical tumors by Western ligand blotting. Cohen et al. (44) obtained similar results for benign prostatic hyperplasia, showing a significant reduction in IGFBP-2 expression in cells isolated from patients with benign prostatic hyperplasia compared to normal prostatic cells. These two observations suggest that some dysregulation of IGFBP-2 may also occur in tumors of benign phenotype.
The molecular mechanisms leading to enhanced IGFBP-2 protein levels in malignant adrenocortical tumors remain unclear. Parallel Northern and Western blot analyses revealed discrepancy between IGFBP-2 mRNA and protein levels in benign and malignant tumors. These might be explained by posttranscriptional mechanisms, such as modifications in mRNAs translation efficiency, that would lead to different expressions of IGFBP-2 in benign and malignant tumors.
The IGFBP-2 overexpression was specific to malignant adrenocortical tumors, as neither IGFBP-3 (39–42 kDa doublet) nor the 29-/30- and 24-kDa proteins identified by Western ligand blot differed significantly between the benign and malignant groups. Preliminary experiments using specific antibodies indicated the presence of IGFBP-4, IGFBP-5, and IGFBP-6 in adrenocortical tumors, whereas IGFBP-1 was absent. However, the precise identity of the 29-/30-kDa band observed on ligand blot requires further confirmation.
In conclusion, we have performed an extensive characterization of IGF-II and IGFBPs in adrenocortical tumors. Our data confirm a major role for IGF-II in adrenocortical tumorigenesis and suggest that IGFBP-2 may be a regulator of the proliferative effects of IGF-II in this model. Further studies are needed to determine the molecular mechanisms by which IGF-II and IGFBP-2 are involved in the proliferation of adrenocortical tumor cells. Whatever the mechanisms, IGFBP-2 could represent, in concert with IGF-II, a new prognostic factor for adrenocortical tumors.
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Acknowledgments |
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Footnotes |
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Received October 29, 1997.
Revised January 28, 1998.
Accepted February 6, 1998.
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References |
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A. Peri, P. Luciani, B. Conforti, S. Baglioni-Peri, F. Cioppi, C. Crescioli, P. Ferruzzi, S. Gelmini, G. Arnaldi, G. Nesi, et al. Variable Expression of the Transcription Factors cAMP Response Element-Binding Protein and Inducible cAMP Early Repressor in the Normal Adrenal Cortex and in Adrenocortical Adenomas and Carcinomas J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5443 - 5449. [Abstract] [Full Text] [PDF]
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C. Martinerie, C. Gicquel, A. Louvel, M. Laurent, P. N. Schofield, and Y. Le Bouc Altered Expression of novH Is Associated with Human Adrenocortical Tumorigenesis J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3929 - 3940. [Abstract] [Full Text] [PDF]
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N. Boulle, C. Gicquel, A. Logie, R. Christol, J.-J. Feige, and Y. Le Bouc Fibroblast Growth Factor-2 Inhibits the Maturation of Pro-Insulin-Like Growth Factor-II (Pro-IGF-II) and the Expression of Insulin-Like Growth Factor Binding Protein-2 (IGFBP-2) in the Human Adrenocortical Tumor Cell Line NCI-H295R Endocrinology, September 1, 2000; 141(9): 3127 - 3136. [Abstract] [Full Text] [PDF]
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A. Logie, P. Boudou, L. Boccon-Gibod, E. Baudin, G. Vassal, M. Schlumberger, Y. Le Bouc, and C. Gicquel Establishment and Characterization of a Human Adrenocortical Carcinoma Xenograft Model Endocrinology, September 1, 2000; 141(9): 3165 - 3171. [Abstract] [Full Text] [PDF]
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G. von Wichert, P. M. Jehle, A. Hoeflich, S. Koschnick, H. Dralle, E. Wolf, B. Wiedenmann, B. O. Boehm, G. Adler, and T. Seufferlein Insulin-like Growth Factor-I Is an Autocrine Regulator of Chromogranin A Secretion and Growth in Human Neuroendocrine Tumor Cells Cancer Res., August 1, 2000; 60(16): 4573 - 4581. [Abstract] [Full Text]
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F. Wilkin, N. Gagné, J. Paquette, L. L. Oligny, and C. Deal Pediatric Adrenocortical Tumors: Molecular Events Leading to Insulin-Like Growth Factor II Gene Overexpression J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2048 - 2056. [Abstract] [Full Text]
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A. Hoeflich, O. Fettscher, H. Lahm, W. F. Blum, H. J. Kolb, D. Engelhardt, E. Wolf, and M. M. Weber Overexpression of Insulin-like Growth Factor-binding Protein-2 Results in Increased Tumorigenic Potential in Y-1 Adrenocortical Tumor Cells Cancer Res., February 1, 2000; 60(4): 834 - 838. [Abstract] [Full Text]
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M. M. Weber, C. Fottner, P. Schmidt, K. M. H. Brodowski, K. Gittner, H. Lahm, D. Engelhardt, and E. Wolf Postnatal Overexpression of Insulin-Like Growth Factor II in Transgenic Mice Is Associated with Adrenocortical Hyperplasia and Enhanced Steroidogenesis Endocrinology, April 1, 1999; 140(4): 1537 - 1543. [Abstract] [Full Text]
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and 
)
and IGF-II (
and •) levels in tumor extracts and in a normal human
adrenal gland were determined as described in Materials and
Methods. Groups 1 (normal IGF-II mRNA content) and 2 (high
IGF-II mRNA content) are described in Table 1
