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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-1712
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The Journal of Clinical Endocrinology & Metabolism Vol. 94, No. 2 428-433
Copyright © 2009 by The Endocrine Society

Effects of Somatostatin Analogs on a Growth Hormone-Releasing Hormone Secreting Bronchial Carcinoid, in Vivo and in Vitro Studies

M. van Hoek, L. J. Hofland, Y. B. de Rijke, F. H. van Nederveen, R. R. de Krijger, P. M. van Koetsveld, S. W. J. Lamberts, A. J. van der Lely, W. W. de Herder and R. A. Feelders

Departments of Internal Medicine (M.v.H., L.J.H., P.M.v.K., S.W.J.L., A.J.v.d.L., W.W.d.H., R.A.F.), of Clinical Chemistry (Y.B.d.R.), and of Pathology (F.H.v.N., R.R.d.K.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: M. van Hoek, M.D., Department of Internal Medicine–Bd289, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: m.vanhoek{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: A 56-yr-old woman presented with acromegaly, a pulmonary mass, and elevated levels of GHRH, GH, and IGF-I. Histological examination revealed a bronchial carcinoid with positive staining for GHRH. Somatostatin analogs (SAs) can play an important role in the treatment of neuroendocrine tumors, dependent on the somatostatin receptor subtype (sst) expression pattern. The sst pattern in bronchial carcinoids and effects of SAs have not been extensively investigated, particularly not for the recently developed universal SA SOM230 (Pasireotide) that has high affinity for sst1, 2, 3, and 5.

Objective: Our objective was to investigate the in vivo response of a GHRH-producing bronchial carcinoid to octreotide (OCT), its sst-expression profile, and in vitro responses to different SAs, including SOM230.

Methods: In vivo, 50 µg OCT was administered, and plasma GH and GHRH responses were determined. In vitro, the expression of ssts was analyzed by quantitative PCR. Furthermore, the effects of SOM230 and OCT on GHRH secretion were evaluated in primary cell cultures of the carcinoid tissue.

Results: In vivo, OCT administration fully suppressed GH and GHRH levels. In vitro, sst1 mRNA was most abundant, followed by sst2 and sst5. Both SOM230 and OCT inhibited GHRH production dose dependently (SOM230 100 nM vs. control, P = 0.01; OCT 110 nM vs. control, P = 0.05).

Conclusions: In this case of a GHRH-producing bronchial carcinoid, we demonstrated that SOM230 was a potent inhibitor of GHRH production in vitro and was at least equally potent compared with OCT. Therefore, SOM230 may be a potential therapeutic agent to control GHRH secretion in ectopic acromegaly.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Acromegaly is characterized by increased GH secretion and is usually caused by a GH-producing pituitary tumor. However, in less than 1% of cases of acromegaly, it is caused by ectopic secretion of GHRH. Ectopic GHRH secretion most commonly originates from a bronchial carcinoid but can also occur in pancreatic endocrine tumors and extra-pancreatic gastrinomas (1, 2, 3). The first choice of treatment for these neuroendocrine tumors is surgical removal. Nonetheless, adjuvant therapy is often necessary in nonresectable, disseminated, or recurrent tumors. Among various secondary treatment options, including radiotherapy, and chemotherapy, somatostatin analogs (SAs) are of great value in the medical management of these tumors (1).

The inhibitory effects of SAs on hormone secretion and cell proliferation are mediated via interaction with the somatostatin receptor (4, 5). To date, five somatostatin receptor subtypes (ssts) have been cloned and characterized (4, 5, 6). Not only do the majority of sst-positive tumors express multiple subtypes, there is also considerable variation in subtype expression between different tumor types and among tumors of the same type (7, 8).

The currently available SAs for clinical use, octreotide (OCT) and lanreotide (LAN), preferentially bind to sst2. Therefore, the efficacy of these SAs is largely dependent on the sst expression pattern. This may explain why in most reported patients with ectopic acromegaly, GHRH secretion can only partially be controlled by treatment with OCT or LAN (9). SOM230 is a recently developed SA that binds with high affinity to sst1, 2, 3, and 5 (10). Because of this universal sst binding profile, SOM230 may be more effective compared with OCT and LAN, particularly in tumors without predominant sst2 expression.

sst expression pattern in bronchial carcinoids and the effects of different SAs on GHRH production in vitro have not been extensively investigated. In this case report, we present a patient with a GHRH-secreting bronchial carcinoid, the in vivo tumor response to OCT, as well as the sst expression profile and in vitro responses to different SAs, including SOM230.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Case report

A 56-yr-old woman was referred to our hospital with suspected acromegaly. Initially, she presented with persistent cough and hemoptysis elsewhere. A chest x-ray and computed tomography had shown a pulmonary paramediastinal process in the right-upper lobe with a diameter of 4 cm and an enlarged lymph node in the central mediastinum. Bronchoscopic examination identified a tumor with an easily bleeding surface of which it was impossible to obtain material for histological examination. Bronchoalveolar lavage did not yield malignant cells.

In the past 3 yr, the patient had noticed significant growth of hands and feet, and a deepening of her voice. She experienced excessive sweating, especially in the palms of her hands. Five years earlier she underwent surgery for bilateral carpal tunnel syndrome. On physical examination the patient had acromegalic features, including exaggerated nasolabial folds, mild frontal bossing, macroglossia, thick lips, and large, grossly shaped hands and feet. Blood pressure was 110/80 mm Hg and heart rate 76 per minute.

Laboratory examination revealed elevated GH and IGF-I levels [6.1 µg/liter (normal <5.0) and 149.7 nmol/liter (normal 14–42), respectively], confirming the diagnosis of acromegaly. Chromogranin A levels were elevated (159 µg/liter, normal values 10–100); on magnetic resonance imaging, the pituitary was not enlarged. However, plasma GHRH levels were clearly elevated (0.1 µg/liter, normal range 0.01–0.06), indicating ectopic GHRH production. Somatostatin receptor scintigraphy [OctreoScan (Covidien, Hazelwood, MO); Fig. 1Go] showed intense tracer uptake in the right hemithorax, subtle tracer uptake in the central mediastinum, and physiological uptake in the pituitary area. Mediastinoscopy obtained biopsy material from lymph node locations 2, 4 left, 4 right, and 7. None of the biopsies showed malignant cells.


Figure 1
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  		FIG. 1. Somatostatin receptor scintigraphy and computed tomography (CT) images of the bronchial tumor. A, Anterior view of somatostatin receptor scintigraphy. B, Posterior view of somatostatin receptor scintigraphy. C, Computed tomography image.

 
Subsequently, a lobectomy of the right-upper pulmonary lobe and lymph node removal from location 4 on the right were performed. On pathological examination the lymph nodes were free of malignancy. In the partial lung resection, a tumor with a diameter of 4 cm was identified. The tumor consisted of a trabecular and insular growth of uniform eosinophilic tumor cells with finely granular cytoplasm. The nuclei were uniform, round to oval, with a finely granular chromatin pattern. Mitoses were sparse (less than two per 2 mm2), and there was no necrosis or invasion of tumor cells in surrounding tissue or vessels. The tumor was classified as a typical carcinoid. Histology is shown in Fig. 2AGo. Additional immunohistochemical analysis showed no staining for GH (1:400; BioGenex Laboratories Inc., San Ramon, CA). GHRH staining (1:800; CHEMICON International, Inc., Temecula, CA) of the tumor cells was positive (Fig. 2Go, B and C). Postoperatively, GHRH, GH, and IGF-I levels all decreased to levels within the reference range and remained so during the next 3 yr follow-up: GHRH, undetectable; GH, 0.3 µg/liter; and IGF-I, 36.2 nmol/liter.


Figure 2
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  		FIG. 2. Immunohistochemical examination of tumor material. A, Hematoxylin-eosin; magnification, x20. B, GHRH immunohistochemical staining; magnification, x20. C, GHRH immunohistochemical staining; magnification, x40.

 
The patient gave written informed consent for participation. Our local Medical Ethics Committee approved the protocol.

In vivo OCT administration

Preoperatively, 50 µg OCT was administered to the patient at 0 min. Blood samples were drawn at –15, 15, 45, 105, 165, 225, 285, 345, 405, 465, 525, and 585 min for determination of serum GHRH and GH levels.

Quantitative PCR of ssts

Quantitative PCR was performed as described previously (11). Briefly, poly-A+ mRNA was isolated from carcinoid tissue using Dynabeads oligo (deoxythymidine)25 (Dynal AS, Oslo, Norway). cDNA was synthesized using the poly A+ mRNA, which was eluted from the beads in 40 µl H2O for 2 min at 65 C, using oligo (deoxythymidine)12–18 primer (Invitrogen, Breda, The Netherlands). One twentieth of the cDNA library was used for quantification of sst mRNA levels. A quantitative PCR was performed by TaqMan Gold nuclease assay (PerkinElmer Corp., Foster City, CA) and the ABI PRISM 7700 sequence Detection System (PerkinElmer, Groningen, The Netherlands) for real-time amplifications, according to the manufacturer’s protocol. The assay was performed using 15 µl TaqMan Universal PCR Master Mix (Applied Biosystems, Nieuwerkerk a/d Ijssel, The Netherlands), 500 nmol/liter forward primer, 500 nmol/liter reverse primer, 100 nmol/liter probe, and 10 µl cDNA template, in a total reaction volume of 25 µl. After an initial heating at 50 C for 2 min and 95 C for 10 min, samples were subjected to 40 cycles of denaturation at 95 C for 15 sec and annealing for 1 min at 60 C.

The detection of hypoxanthine-phosphoribosyl-transferase (HPRT) mRNA served as a control and was used for normalization of the sst mRNA levels. The primer and probe sequences that were used for the detection of sst1, sst2, sst3, sst5, and HPRT mRNAs have been described previously (11, 12).

The relative amount of sst mRNA was determined using a standard curve generated from known amounts of human genomic DNA. For determination of the amount of HPRT mRNA, a standard curve was generated of a pool of cDNAs from a human cell line known to express HPRT. The relative amount of sst mRNA was calculated relative to the amount of HPRT mRNA and is given in arbitrary units. Each sample was assayed in duplicate. sst2 expression of the tumor was compared with the expression in 12 GH-secreting adenomas. All patients gave their written informed consent for participation. Our local Medical Ethics Committee approved the protocol.

Cell dispersion and cell culture

Single cell suspensions of the carcinoid tissue were prepared by enzymatic dissociation with collagenase and dispase as described in detail previously (13). For short-term incubation of monolayer cultures, the dissociated cells were plated in 48-well plates (Corning BV Life Sciences, Schiphol-Rijk, The Netherlands) at a density of 50,000 cells per well per 1 ml culture medium. After 3–4 d the medium was changed, and 72-h incubations with and without test substances were initiated (n = 4 wells per test substance). The test substances consisted of SOM230 and OCT in concentrations of 10 and 100 nM/liter. OCT was obtained from Novartis Pharma AG (Basel, Switzerland). SOM230 was a gift from Novartis Pharma AG. Control wells only received culture medium. The cells were cultured at 37 C in a CO2 incubator. The culture medium consisted of MEM with Earle’s salts supplemented with 10% fetal calf serum, penicillin (1 105 U/liter), Fungizone (0.5 mg/liter; Bristol-Myers Squibb Co., Princeton, NJ), and L-glutamine (2 mmol/liter). Media and supplements were from Invitrogen. At the end of the incubation, the media were collected and stored at –20 C until determination of hormone concentrations.

Hormone determinations

GH (reference <5.0 µg/liter) and IGF-I levels (reference values for age group 14.0–42.0 nmol/liter) were measured by a fluorescent immunoassay (Diagnostic Products Corp., Los Angeles, CA). GHRH in serum and conditioned medium from cultured carcinoid tumor cells was measured by an enzyme immunoassay (Phoenix Europe GmbH, Karlsruhe, Germany). The intraassay and interassay coefficients of variation were less than 5% and less than 14%, respectively. The assay is highly specific for detecting GHRH, with a 100% cross-reactivity with GHRH (amino acids 1–40) and a 80% cross-reactivity with GHRH (amino acids 1–37). In healthy individuals, GHRH levels ranged between 0.01 and 0.06 µg/liter9.

Statistical analysis

All data on hormone release are expressed as means ± SE (n = 4 wells per test substance). All analyses were performed with SPSS version 12.0 (SPSS, Inc., Chicago, IL). To determine differences between substance effects in cell cultures, data were analyzed by Mann-Whitney U testing. Statistical significance was considered at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
In vivo OCT administration

Figure 3Go shows GHRH and GH levels after administration of 50 µg OCT at 0 min. GHRH levels decreased to undetectable levels at 285 min. After 405 min, GHRH levels gradually increased. After OCT administration GH levels decreased to 0.3 µg/liter at 105 min, followed by a gradual increase to initial values.


Figure 3
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  		FIG. 3. Plasma GHRH and GH levels after administration of 50 µg OCT at 0 min.

 
sst expression

Figure 4Go shows the sst expression pattern of the bronchial carcinoid in vitro. The most abundantly expressed sst was sst1. There was a moderate expression of sst2. Expression of sst3 was virtually absent, whereas there was low sst5 expression.


Figure 4
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  		FIG. 4. sst expression pattern of the bronchial carcinoid tissue.

 
Figure 5Go shows that the sst2 expression is not different from the mean sst2 expression level in 12 GH-secreting pituitary adenomas.


Figure 5
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  		FIG. 5. Comparison of sst expression pattern of the GHRH-secreting bronchial carcinoid and 12 GH-secreting pituitary tumors.

 
In vitro GHRH production

In Fig. 6Go the results of the 72-h carcinoid cell culture experiments are shown. Both SOM230 and OCT dose dependently decreased GHRH production by the carcinoid cells. There was a significant difference in GHRH production between the cultures exposed to SOM230 100 nM compared with the control culture (P = 0.01) and the SOM230 10 nM cultures (P = 0.05). Although SOM230 showed a trend toward stronger suppression of GHRH production, the differences between SOM230 10 nM and OCT 10 nM, and SOM 230 100 nM and OCT 100 nM cultures were not statistically significant. In the 24-h cultures, the results for SOM 230 were similar (SOM230 10 nM vs. control and SOM230 100 nM vs. control; –23.6%, P = 0.11 and –43.2%, P = 0.01, respectively; data not shown).


Figure 6
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  		FIG. 6. GHRH levels in response to 72 h incubation with SOM230 and OCT. *, P = 0.01; **, P = 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this report we present clinical and functional characteristics of a GHRH-secreting bronchial carcinoid. In vivo administration of OCT induced a complete suppression of plasma GHRH and GH levels. The sst expression pattern of the tumor showed high expression of sst1 and sst2 mRNA, and low expression of sst5. SOM230 and OCT both showed dose-dependent inhibition of GHRH production in in vitro cell cultures, which was significant for SOM230 100 nM compared with controls.

GHRH-producing bronchial carcinoids are a rare cause of acromegaly (1, 2). The bronchial tumor in our report met the criteria of Losa and von Werder (14) for ectopic extracranial acromegaly. Normalization of GH and IGF-I plasma levels suggests complete removal and absence of metastatic disease. However, complete resection is not always possible, and in about 30% of GHRH-producing bronchial carcinoids, metastases are present (15). In these cases, SA therapy has an important role. Although clinical improvement is common, the clinical response to SA therapy is difficult to predict (16, 17, 18) and depends, at least in part, on the sst expression pattern of the tumor. Most reports on bronchial carcinoids do not describe sst expression patterns of the tumor, although intense tracer uptake on somatostatin receptor scintigraphy suggests the expression of sst2 and, to a lesser extent, sst5 (19, 20). We found an intense tracer uptake of the tumor with somatostatin receptor scintigraphy. By quantitative PCR we demonstrated and quantified sst1, sst2, and sst5 expression of the tumor material, with sst1 being most abundantly expressed. This is in line with findings of Zatelli et al. (9) in a bronchial carcinoid. However, in their report no quantification on the relative amounts of sst expression was performed. Interestingly, quantitative sst2 expression by the bronchial carcinoid was comparable with the sst2 expression level by GH-secreting pituitary adenomas.

We examined the effects of OCT in vivo and, for the first time, compared the in vitro effects of OCT and the new universal SA SOM230 on GHRH production. OCT binds with high affinity to sst2, with moderate affinity to sst3 and sst5, and does not bind to sst1 and sst4. The binding affinity of SOM230 for sst1, sst3, and sst5 is 30, five, and 40 times higher, respectively, compared with OCT, whereas binding affinity to sst2 is 2.5 times lower (9, 10). In agreement with the demonstrated sst2 expression, we found that OCT was able to suppress GHRH and GH production in vivo with a sustained inhibition for 6 h after a single injection. The decrease in GH levels can be explained by an indirect effect via GHRH, as well as by a direct effect of OCT on the GH-producing cells in the pituitary. This could explain the decrease in GH preceding the decrease in GHRH levels. In vitro, both OCT and SOM230 suppressed GHRH production dose dependently, with SOM230 100 nM showing a significant inhibition compared with control cultures. Zatelli et al. (9) tested the effects of LAN and selective agonists of sst1, sst2, and sst5 on GHRH production by a bronchial carcinoid and found that the sst5-specific analog BIM-23206 induced the most pronounced inhibition (–75%), followed by the sst2-specific analog BIM-23120 (–55%) and LAN (–30%), whereas the sst1-specific analog BIM-23926 was less effective (–20%). Thus, the effects of SOM230 on GHRH production may be mediated via combined activation of sst2 and sst5, which is thought to exert a synergistic response (21), and possibly sst1 as well. Although sst1 is thought to be primarily involved in cell proliferation, sst1 expression has been demonstrated in GH-secreting pituitary adenomas and treatment of somatotropic adenoma cultures with an sst1-selective SA-induced inhibition of GH secretion (22). Activation of sst1 receptors also significantly suppressed GH secretion in vitro by pituitary adenoma cells from patients resistant or partially responsive to OCT or LAN (23). Considering the high sst1 expression in the bronchial carcinoid tissue, the SOM230-induced decrease in GHRH production may in part be attributed to sst1 activation as well.

Because of its universal sst binding affinity profile, SOM230 may be a promising therapeutic agent to control GHRH production in ectopic acromegaly. Cell culture experiments in GH-secreting adenomas, prolactinomas, and ACTH-producing adenomas (11, 24, 25, 26) showed that SOM230 was more potent than OCT in inhibiting hormone secretion. Based on the current in vitro results, we cannot conclude that SOM230 is a more potent inhibitor of ectopic GHRH production, although the inhibition was at least comparable to the inhibition by OCT. However, in most patients with ectopic acromegaly, treatment with sst2 preferential SA OCT and LAN does not result in complete normalization of GHRH levels (9), possibly due to the sst expression pattern of the tumor. In an in vivo single dose comparison of GH inhibition in acromegalic patients with GH-secreting adenomas, SOM230 was comparable and even superior in patients less responsive to OCT (25, 27). Currently, trials are performed with short- and long-acting SOM230 in patients with Cushing’s disease, acromegaly, and neuroendocrine tumors. Further studies should reveal whether SOM230 is effective in OCT-resistant patients with ectopic GHRH production.

SAs also may have growth-arresting effects that can result in tumor stabilization or even regression. In patients with acromegaly and other neuroendocrine tumors, treatment with SAs can stabilize tumor growth or even induce tumor shrinkage (28, 29). With respect to GHRH-secreting carcinoids, data are limited. Most studies show no tumor shrinkage (9), although one report shows regression of metastatic lesions after treatment with OCT (30). sst1 may be a specific target for control of tumor growth and is expressed by many tumor cell types (31). Selective sst1 activation has antiproliferative effects in vitro in GH- and prolactin-secreting adenomas and medullary thyroid carcinoma cells (22, 32). We did not assess the effects of OCT and SOM230 on cell growth. However, Zatelli et al. (9) found no effect of a selective sst1 agonist on cell viability of GHRH-secreting bronchial carcinoid cells, although this was assessed only during short-term incubation. Considering its affinity for sst1, the effect of SOM230 on tumor growth should be investigated in future studies.

In conclusion, in this case of a GHRH-secreting bronchial carcinoid, we have quantitatively demonstrated sst1, sst2, and sst5 expression, and have shown that SOM230 and OCT both inhibit GHRH secretion in in vitro cell culture experiments. Ultimately, individualized treatment according to tumor sst profile would be a major improvement in SA therapy in neuroendocrine tumors. In this respect, SOM230 is a promising agent for the treatment of hormone excess and possibly tumor growth.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online November 18, 2008

Abbreviations: HPRT, Hypoxanthine-phosphoribosyl-transferase; LAN, lanreotide; OCT, octreotide; SA, somatostatin analog; sst, somatostatin receptor subtype.

Received August 6, 2008.

Accepted October 14, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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