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Interdisziplinäres Stoffwechsel-Centrum (U.P., S.A.), Endokrinologie, Diabetes, und Stoffwechsel, Med. Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany; Department of Neuropathology (C.M.), Klinikum der Friedrich-Schiller-Universität Jena, 07740 Jena, Germany; Institute of Pathology (W.S.), Marien Krankenhaus, 22087 Hamburg, Germany; Department of Neurosurgery (M.B.), Friedrich-Alexander University, 91054 Erlangen-Nürnberg, Germany; Division of Endocrinology (S.P.), University of Duisburg-Essen, D-45122 Essen, Germany; and Department of Pharmacology and Toxicology (S.S.), Bayerische Julius-Maximilians-Universität, 97078 Würzburg, Germany
Address all correspondence and requests for reprints to: Dr. Stefan Schulz, Department of Pharmacology and Toxicology, Bayerische Julius-Maximilians-Universität, Versbacher Str. 9, 97078 Würzburg, Germany. E-mail: stefan.schulz{at}toxi.uni-wuerzburg.de.
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Abstract |
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Methods: Acromegalic patients, cared for in a university referral center, were either operated on without pretreatment (group A, n = 14) or pretreated with octreotide [median (minimum-maximum): dose 1250 (300–1500) µg/d for 5.6 (3–9) months] before surgery (group B, n = 20). In group B octreotide reduced GH secretion by more than 50% in 14 patients (70%) (GH responders). Six patients with less than 50% GH suppression were considered GH nonresponders. We used a panel of extensively characterized antibodies to determine the immunocytochemical sst status in somatotroph adenomas and compared their expression between the groups.
Results: All group A tumors demonstrated immunoreactive sst2A, and all but one had sst5. A similar pattern was found in the GH responders of group B. In contrast, none of the GH nonresponders exhibited detectable sst2A (sst2A: GH responders vs. GH nonresponders, P < 0.0001), whereas sst5 was found in 70%. sst1 and sst3 were detected in 85 and 24% of all cases, independent of previous octreotide treatment.
Conclusions: Our findings suggest that octreotide resistance in GH-secreting adenomas occurs due to a selective loss of sst2A. The persistent expression of sst1 and sst5 receptors suggests that these tumors are potential targets for pan-somatostatin analogs.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The biological effects of somatostatin are mediated by five distinct G protein-coupled receptors (sst) termed sst1-sst5 (6, 7). Most GH-secreting pituitary adenomas express mRNA predominantly for sst2 and sst5, whereas sst1 and sst3 are moderately expressed or lacking, as is the case for sst4. Studies using subtype-selective somatostatin analogs have shown that both sst2 and sst5 are involved in the regulation of GH secretion from human pituitary adenomas (8). Whereas somatostatin binds with high affinity to all five somatostatin receptors, octreotide binds with high affinity only to sst2 and with only moderate affinity to sst5 (7).
Recent evidence suggests that the efficacy of octreotide may relate to the somatostatin receptor subtypes and density. sst2 mRNA expression was lower and sst5 mRNA expression was higher in adenomas that were only partially responsive to octreotide, compared with octreotide-responsive tumors. Moreover, in octreotide nonresponsive tumor cells, the sst5-specific compound BIM23244 was quite effective in suppressing GH secretion (8).
In the present study, we examined the immunocytochemical somatostatin receptor status in GH-secreting adenomas after long-term octreotide treatment. We show that immunoreactive sst2 and sst5 receptors were detected in all patients considered responders. In contrast, none of the patients considered nonresponders exhibited detectable sst2 receptors, whereas sst5 was positive in the majority of these cases.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Acromegaly was diagnosed according to clinical criteria including nonsuppressibility of plasma GH concentration to less than 1 µg/liter during an oral glucose tolerance test (9). Tumor tissue was analyzed from two groups of patients. Group A consisted of 14 acromegalic patients with microadenomas (n = 9) operated on without any pretreatment or patients with small macroadenomas (n = 5) not consenting to participate in a clinical trial on preoperative octreotide therapy (Table 1
). Group B consisted of 20 acromegalic patients with preoperative octreotide therapy [median (minimum-maximum) 1250 (300–1500) µg/d sc for 5.6 (3–9) months] (Tables 2 and 3). None of these patients had received any other treatment for acromegaly before entering the study. Biochemical response to octreotide pretreatment was defined as a decline of the mean GH concentration during an 8-h, nine-point GH profile of at least 50%. All patients were investigated before octreotide therapy and immediately before surgery. GH and IGF-I concentrations were determined using two commercially available RIAs [GH: RIA (Sorin, Sallugia, Italy), international reference preparation 80/505, intra- and interassay coefficient of variation (CV) 4.9 and 3,8%, and a chemiluminescence immunometric assay (Nichols Institute Diagnostics GmbH, Bad Nauheim, Germany), international reference preparation 80/505, intra- and interassay CV 5.4 and 7.9% in patients 3, 6, 7, 15, and 16; IGF-I: RIA-CT (Mediagnost, Reutlingen, Germany), assay sensitivity of 0.1 µg/liter, intra- and interassay CV 7.2 and 8.6%, and a chemiluminescence immunometric assay (Nichols Institute Diagnostics), assay sensitivity of 6 µg/liter, intra- and interassay CV 5.2 and 5.7% in patients 3, 6, 7, 15, and 16]. Tumor volume response was defined as a decline of the tumor volume of at least 20% (10). Tumor volume was examined by magnetic resonance imaging before octreotide treatment and immediately before surgery. Tumor volume was calculated according to the formula of Di Chiro and Nelson: volume = height x length x width x 
/6 (10). All tumor specimens were fixed in formalin and then embedded in paraffin. Pathological classifications of the tumors were performed according to the World Health Organization classification of 2004.
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Polyclonal antisera were generated against the carboxy terminal tails of the somatostatin receptor subtypes sst1, sst2A, sst3, and sst5. The identity of the peptides is given in Table 4. Peptides were coupled to keyhole limpet hemocyanin and injected into rabbits for antibody production. Antibodies were affinity purified against their immunizing peptides as described (11).
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Plasmids encoding the human sst1, sst2A, sst3, and sst5 receptors were obtained from UMR cDNA Resource Center (Rolla, MO; www.cdna.org). Human embryonic kidney (HEK)-293 cells were stably transfected and grown on coverslips overnight. Cells were then fixed and incubated with 1 µg/ml anti-sst1 (9498), anti-sst2A (0786), anti-sst3 (4823), or anti-sst5 (0917) antibodies followed by cyanine 3.18-conjugated secondary antibodies (Amersham, Braunschweig, Germany). Specimens were mounted and examined using a TCS-NT laser-scanning confocal microscope (Leica, Québec, Canada) as described (11, 12).
Western blot analysis
Membranes were prepared from stably transfected HEK-293 cells as well as fresh tumor specimens. Cells and tissues were lysed and glycoproteins were enriched using wheat germ lectin agarose beads as previously described (12, 13). Beads were washed five times in lyses buffer, and adsorbed glycoproteins were eluted with sodium dodecyl sulfate sample buffer for 20 min at 60 C. Samples were then subjected to 8% SDS-PAGE and immunoblotted onto nitrocellulose. Blots were incubated with 1 µg/ml anti-sst1 (9498), anti-sst2A (0786), anti-sst3 (4823), or anti-sst5 (0917) antibodies followed by peroxidase-conjugated secondary antibodies and enhanced chemiluminescence detection (Amersham).
Immunohistochemistry
Seven-micrometer paraffin sections were cut and floated onto positively charged slides and immunohistochemically stained as previously described (11). Briefly, sections were dewaxed, microwaved in 10 mM citric acid (pH 6.0) for 20 min at 600 W, and subsequently incubated with 2 µg/ml anti-sst1 (9498), anti-sst2A (0786) anti-sst3 (4823), or anti-sst5 (0917) antibodies overnight at 4 C. Staining of primary antibody was detected using biotinylated goat antirabbit IgG or biotinylated goat antimouse IgG followed by incubation with avidin-biotinylated peroxidase solution. Tissue was then rinsed and stained with 3,3'-diaminobenzidine-glucose oxidase for 15 min. Cell nuclei were lightly counterstained with hematoxylin. For immunohistochemical controls, the primary antibody was omitted, replaced by preimmune sera, or adsorbed with several concentrations ranging from 1 to 10 µg/ml of homologous or heterologous peptides for 2 h at room temperature. Normal human pituitary and pancreatic tissue was included in each batch of staining as a positive control.
Assessment of staining patterns
All slides were evaluated by the same investigator, who was blinded for the results of octreotide on GH and tumor volume. The presence or absence of staining and the depth of color and the number of cells showing a positive reaction as well as whether or not the staining was localized to the plasma membrane were noted. Tumors were categorized as positive only when they exhibited a moderate to strong plasma membrane and/or cytoplasmic staining in the majority of tumor cells (>50%), which was easily visible with a low-power objective.
Statistics
When data distribution was normal, means ± SE were used; otherwise median values (median, range: minimum-maximum) were calculated. Normal distribution was tested by the Shapiro-Wilks’ W test. Nonparametric statistics was calculated by a 
2 test. If the number of observations was equal or below seven, Fischer’s double-sided exact P value was calculated. Between-group comparisons were analyzed by the Mann-Whitney U test. If the sample size was equal or less than 20, the value 2p, where p is 1 minus the cumulative (one sided) probability of the respective U statistic, was calculated. The computations for this probability value are based on the assumption of no ties in the data (ranks). This limitation usually leads to only a small underestimation of the statistical significance of the respective effects. Comparison of paired values was done using Wilcoxon’s signed rank test. Correlations were calculated using Spearman rank order R. The level of significance was defined as P < 0.05. Statistical evaluation was performed with Statistica software (Statsoft Inc., Tulsa, OK).
Informed written consent was obtained from the patients of the preoperative treatment group. The study was performed in agreement with the Declaration of Helsinki as revised in 1983 and the general outlines of good clinical practice. The study protocol was approved by the hospital ethical committee.
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Results |
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Specificity of the antisera was monitored using immunofluorescent staining of stably transfected HEK-293 cells. When these cells were stained with anti-sst1 (9498), anti-sst2A (0786), anti-sst3 (4823), or anti-sst5 (0917) antibodies, prominent immunofluorescence was detected only in cells expressing the appropriate receptor but not in cells transfected with other somatostatin receptors or empty vector (Fig. 1). Whereas sst2A-, sst3-, and sst5-like immunoreactivity (Li) was predominantly localized at the level of the plasma membrane, sst1-Li was seen at the plasma membrane as well as in the cytosol (Fig. 1). Subsequently somatostatin receptor antisera were tested for possible cross-reactivity with other proteins present in human HEK-293 cells. The results depicted in Fig. 1 show that the somatostatin receptor antibodies anti-sst1 (9498), anti-sst2A (0786), anti-sst3 (4823), and anti-sst5 (0917) detected distinct broad bands migrating at the expected molecular weights only in cells expressing the appropriate receptor but not in cells transfected with other somatostatin receptor subtypes. These results indicate that somatostatin receptor antibodies selectively detected their cognate receptor and did not cross-react. The anti-sst1 (9498), anti-sst2A (0786), anti-sst3 (4823), or anti-sst5 (0917) antibodies were then used for immunohistochemical staining of normal human pancreatic and pituitary tissues. As shown in Fig. 2, each of the antibodies produced distinct patterns of staining in pancreatic islands and anterior pituitary cells. Whereas sst2A- and sst5-Li were predominantly localized at the plasma membrane of nearly all pancreatic islet cells, sst1-Li and sst3-Li were detected as punctual staining at the plasma membrane and in the cytosol of distinct cell populations (Fig. 2). Similar subcellular staining patterns were obtained in pituitary tissues, i.e. sst2A- and sst5-Li were predominantly present at the plasma membrane, whereas sst1-Li and sst3-Li were seen at both plasma membrane and in the cytosol (Fig. 2). We then examined the expression of sst2A and sst5 receptor proteins in normal human pituitary and in GH-secreting adenoma. When membrane preparations from these tissues were electrophoretically separated and blotted onto nitrocellulose, the antisera revealed broad receptor-like bands with molecular weights similar to that observed for recombinant somatostatin receptors. Specifically, the anti-sst2A antibody (0786) detected a broad band migrating at molecular mass (Mr) 55,000–75,000, and the anti-sst5 antibody (0917) detected a broad band migrating at Mr 45,000–55,000 (Fig. 1). In membrane preparations from GH adenomas substantially stronger immunoreactive bands, migrating at similar molecular weights as in normal pituitary, were detected for both sst2A and sst5, suggesting that these receptors are strongly overexpressed in GH adenomas (Fig. 1). All immunoreactive bands were completely abolished by preabsorption of the antisera with 10 µg/ml of their immunizing peptides (Fig. 1).
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Group A and group B patients were comparable with respect to sex and age. There were more microadenomas in group A (n = 5), compared with group B (n = 1, Tables 1
and 3). The distribution of sst1, sst2A, sst3, and sst5 was similar in micro and macroadenomas. In group A, 12 of 14, 14 of 14, four of 14, and 13 of 14 tumors were positive for sst1, sst2A, sst3, and sst5, respectively. The corresponding data for group B were 14 of 19, 13 of 20, four of 19, and 17 of 20. Groups A and B significantly differed for the expression of sst2A (P = 0.014) (Fig. 3). Neither the tumor classification (micro- or macroadenoma) nor the patients’ age or sex was related to the expression of sst1, sst2A, sst3, or sst5.
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Octreotide effect on GH concentration
Preoperative octreotide therapy significantly reduced the GH concentration by 67.6 ± 5.8% (n = 20). A GH decline of more then 50% [positive GH response (GH-R)] was observed in 14 of 20 patients, whereas six patients were classified as GH nonresponders [negative GH response (GH Non-R)]. The GH decline was significantly more pronounced in the GH-R, compared with GH Non-R (–81 ± 3.6% GH-R vs. –35.7 ± 7.1% GH Non-R, P < 0.0001) (Table 3). GH-R and GH Non-R were not significantly different with respect to age, sex, duration of octreotide therapy, the GH concentration before or after octreotide therapy, the percent of tumor volume reduction, or the number of volume responders. However, GH Non-Rs were all negative for sst2A, whereas13 of 14 GH-Rs were positive for the presence of sst2A (P < 0.0001). The GH-response, i.e. an at least 50% decline of the GH concentration in response to octreotide, correlated with the expression of sst2A (P = 0.002). None of the other parameters, i.e. the GH concentration before or during octreotide therapy, the duration of therapy, or the volume response, correlated with the expression of sst2A. No significant difference could be demonstrated for the presence of sst1, sst3, or sst5 for GH-R vs. GH Non-R.
Age- and sex-adjusted normalization of IGF-I concentration was achieved in three of 20 patients during preoperative octreotide therapy (Table 2). The basal IGF-I, the IGF-I concentration during octreotide, the percent decline of IGF-I, or qualitative normalization of IGF-I did not correlate with sst receptor expression.
Octreotide effect on tumor volume shrinkage
During preoperative octreotide therapy, the tumor volume declined by 24 ± 6.7% (n = 20). A tumor volume decline of more then 20% [positive volume response (Vol-R)] was observed in 12 of 20 patients, whereas eight patients were classified as volume nonresponders (Vol Non-R). The volume decline was significantly more pronounced in the Vol-R, compared with Vol Non-R [mean volume decline: Vol-R –49.7 ± 6.9% (n = 12) vs. Vol Non-R –4.3 ± 3.9% (n = 8), P < 0.0001] (Table 3). Vol-R and Vol Non-R were not significantly different with respect to age, sex, tumor size before therapy, duration of octreotide therapy, GH concentration before and during octreotide therapy, and the percent of GH reduction or the number of GH responders. However, Vol-R and Vol Non-R were significantly different for the presence of sst3. sst3 was absent in all patients with a significant volume reduction (Vol-R: sst3 0 of 12), whereas 50% of the patients without volume response were positive for sst3 (Vol Non-R: sst3 four of eight). The expression of sst3 was negatively correlated with the volume-response to octreotide (P < 0.02). None of the other parameters, i.e. the GH response to octreotide therapy, the duration of therapy, or the volume before therapy correlated with the expression of sst3. No significant difference could be demonstrated for the presence of sst1, sst2A, or sst5 for Vol-R vs. Vol Non-R.
Conclusion
All tumors of patients with primary surgery expressed sst2A. In contrast, in pretreated patients, sst2A was only seen in tumors with a positive GH response. A significant decline of the GH concentration correlated with the presence of sst2A. sst3 was not expressed in the majority of the tumors, independent of the treatment group (negative expression of sst3: group A 71%, group B 79% of the patients, respectively). However, in pretreated patients a significant volume decline of the tumor correlated with the absence of sst3.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The production and characterization of the somatostatin receptor subtype-specific antibodies used has been described extensively (11, 12, 13, 14, 15). The somatostatin receptor subtype-specific antibodies used in this investigation have been characterized extensively. Several lines of evidence suggest that these antibodies selectively detect their target proteins in formalin-embedded human tissue. sst-transfected HEK-293 cells were selectively stained with the anti-sst antibody, whereas wild-type cells showed no staining. Western blot analysis of stable transfected HEK-293 cells detected a single band of the appropriate molecular weight only in sst-transfected cells; immunodot blot analysis showed that cross-reaction with other subtypes was excluded; and antisera unequivocally detected somatostatin receptor subtypes in human meningioma, breast and ovarian carcinoma, gastrinoma, insulinoma, neuroendocrine tumors, and in normal pancreatic tissue. Staining of all antisera was abolished by preincubation with the immunizing peptide.
Our findings are in agreement with a recent immunocytochemical study (16) and most findings of previous molecular studies using mRNA analysis and receptor autoradiography (17, 18, 19, 20, 21). Tumor mRNA levels may not necessarily reflect the protein receptor levels, and conflicting results between sst mRNA and immunohistochemistry have been reported in nonpituitary tumors (22). Hence, morphological localization of the receptor protein on cell membranes, as was performed in our samples, is necessary for precise evaluation of the tumor receptor status (16).
We clearly demonstrated that the presence of sst2A in somatotroph adenomas correlates with the decline of the GH concentration during therapy with somatostatin analog (SSA). This has already been suggested due to the correlation of sst2 mRNA expression with the degree of GH inhibition by SSA (20) in human somatotroph cells in vitro. Whereas these authors did not comment on the relationship of their in vivo results and the presence of sst subtype mRNA, their results predict our findings, albeit at a lower number of patients and after only a single octreotide dose. Patients with a GH decline of less than 50%, corresponding to our definition of biochemical nonresponders, demonstrated a low sst2A mRNA expression, compared with patients with a higher degree of GH suppression. Similar results were reported in seven, 10, and 15 acromegalic patients (23, 24, 25) in whom the expression of sst mRNA could be correlated to in vivo effects on GH suppression after either a single octreotide injection (23, 24) or 6 months octreotide long-acting release treatment after surgery (25). All reported a positive correlation between sst2 mRNA expression and octreotide effect on GH secretion. Thus, we extended and confirmed these findings of significantly reduced sst2A mRNA expression at the protein level and demonstrated immunocytochemically the absence of sst2A in patients nonresponsive to SSA.
In patients not treated with SSA, sst2A has been found consistently expressed on the mRNA and protein level (26). This is confirmed by our immunocytochemical data. All patients without octreotide treatment expressed sst2A. In contrast, in pretreated patients, sst2A was negative in GH nonresponders. It cannot be excluded that this difference in the expression of sst2A between pretreated and untreated patients may be related to a selection bias. Pretreated tumors were mostly macroadenomas, whereas tumors from patients with primary surgery were macroadenomas in only nine of 14 cases. Indeed, the presence of both sst2A and sst5 could possibly increase any restraining effect of physiological somatostatin secretion on the growth of a pituitary adenoma. However, whereas we cannot fully exclude the possibility of a selection bias, we found no correlation of the expression of sst2A with adenoma size, and none has been reported in the literature so far.
It has been demonstrated that both the activation of sst2A and sst5 suppress GH secretion. The functional association of these receptor subtypes results in additive/synergistic GH suppression in fetal pituitary and somatotroph adenoma cells (27, 28, 29). Because our definition of octreotide nonresponse includes only a gradual difference, i.e. a 50% suppression of GH, this insufficient GH response may well be the clinical correlate of the expression of only sst5. The presence of both sst2A and sst5 is probably necessary for a larger than 50% decline of the GH concentration in response to octreotide therapy.
An alternative explanation could be octreotide-induced down-regulation of sst2A. sst2A is present in all tumors without octreotide pretreatment as has been recently demonstrated in another large series of somatotroph adenomas by immunohistochemistry (16). The complete absence of sst2A in octreotide-treated tumors and the correlation of sst2A expression with a positive GH response suggest a possible receptor down-regulation of sst2A, induced by octreotide long-term treatment in a subgroup of somatotroph adenomas. Receptor down-regulation may be a dose- and time-dependent effect, which has so far not been observed in vitro due to the well-known difficulties of maintaining long-term human somatotroph adenoma tissue cultures.
The negative correlation of sst3 with tumor volume reduction is surprising because sst3 has been shown to induce apoptosis in vitro (30). However, Losa et al. (31) recently demonstrated that octreotide-treated and untreated pituitary tumors in acromegalic patients had similar apoptotic indexes, whereas the mean proliferation marker Ki-67 of treated patients was 53% lower than that in untreated patients (31). Therefore, tumor shrinkage may well be due to cell cycle arrest with reduced tumor growth, transmitted via sst2 and sst5 (32). Alternatively, tumor shrinkage may be related to the inhibition of hormone synthesis during SSA therapy. Morphological changes after octreotide therapy showed smaller nuclear and cytoplasmic areas in comparison with untreated tumors (33), and tumor volume reduction is rapidly reversed after cessation of SSA (34). Both observations indicate a possible volume reduction of individual cells rather than a reduction in cell numbers. Thus, tumor shrinkage may well be related to activation of sst2 and sst5 instead of sst3. Whereas we were unable to correlate the presence of sst2A and sst5 to tumor volume reduction, possibly due to the small numbers of observations, this does not exclude a functional effect related to these receptors. Whether the observed correlation of absent sst3 with tumor shrinkage is of functional relevance needs further investigation.
Conclusion
This is the first study comparing the immunocytochemical expression of sst subtypes in a large cohort of somatotroph adenomas, which were either primarily operated on or preoperatively treated with the somatostatin analog octreotide. In untreated tumors sst1, 2A, 3, and 5 were expressed in accordance with molecular analysis. In pretreated tumors the expression of sst2A was significantly correlated to the decline of the GH concentration, indicating the important role of this receptor subtype for the inhibition of GH secretion. The absence of sst2a in tumors unresponsive to the GH-lowering effect octreotide suggests down-regulation of the receptor during long-term treatment with SSA. Our data indicate that the role of sst3 is probably negligible for tumor volume reduction in somatotroph adenomas.
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Acknowledgments |
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Footnotes |
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Disclosure Summary: Authors S.A., C.M., W.S., M.B., S. P., S.S. and U.P. have nothing to declare.
First Published Online January 15, 2008
Abbreviations: CV, Coefficient of variation; GH Non-R, negative GH response; GH-R, GH response; HEK, human embryonic kidney; Li, like immunoreactivity; Mr, molecular mass; SSA, somatostatin analog; sst, somatostatin receptor; st, somatostatin receptor; Vol Non-R, volume nonresponder; Vol-R, positive volume response.
Received September 5, 2007.
Accepted January 3, 2008.
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