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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2156
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2104-2109
Copyright © 2005 by The Endocrine Society

Somatostatin Analogs in Vitro Effects in a Growth Hormone-Releasing Hormone-Secreting Bronchial Carcinoid

Maria Chiara Zatelli1, Pietro Maffei1, Daniela Piccin, Chiara Martini, Federico Rea, Domenico Rubello, Angelo Margutti, Michael D. Culler, Nicola Sicolo and Ettore C. degli Uberti

Section of Endocrinology (M.C.Z., D.P., A.M., E.C.d.U.), Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, 44100 Ferrara, Italy; Department of Medical and Surgical Sciences (P.M., C.M., N.S.), Clinica Medica 3, and Department of Thoracic Surgery (F.R.), University of Padua, 35100 Padua, Italy; Nuclear Medicine Service (D.R.), Rovigo Hospital, 45100 Rovigo, Italy; and Biomeasure Incorporated/IPSEN (M.D.C.), Milford, Massachusetts 01757-3650

Address all correspondence and requests for reprints to: Ettore C. degli Uberti, Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. E-mail: ti8{at}unife.it.


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results
 Discussion
 References
 
A 29-yr-old woman presented with acromegaly, pituitary gland enlargement, and an isolated pulmonary mass of 3.3 cm in diameter, which displayed a very high tracer uptake after OctreoScan. Plasma GHRH levels were markedly elevated. The patient underwent left lung upper lobectomy, and histopathology disclosed a bronchial atypical carcinoid. The tissue was examined for somatostatin (SRIH) receptor subtypes (SSTRs) 1–5 expression by RT-PCR. Cultured tumor cells were treated with SRIH, lanreotide (BIM-23014), or SRIH analogs selective for SSTR2 (BIM-23120), SSTR5 (BIM-23206), or SSTR1 (BIM-23926). GHRH was measured in the medium after 6 h, and cell viability was assessed after 48 h. RT-PCR analysis showed expression of SSTR1, -2, and -5. GHRH secretion was significantly reduced by SRIH (–50%), Lan (–35%), as well as by the SSTR2, SSTR5, and SSTR1 selective agonists (–55, –75, and –20%, respectively), whereas cell viability was not affected.

Our data show SSTR expression in a GHRH-secreting bronchial carcinoid and provide evidence that, in vitro, selective SSTR activation differently inhibit ectopic GHRH secretion. These findings suggest that SSTR-specific SRIH analogs may be useful in the medical therapy of GHRH-secreting bronchial carcinoids.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results
 Discussion
 References
 
ACROMEGALY IS A syndrome characterized by GH hypersecretion, usually sustained by a pituitary somatotroph adenoma. Ectopic tumors account for less than 1% as a cause of acromegaly, and they are mostly due to bronchial GHRH-secreting carcinoids (1, 2). The therapy of choice for ectopic acromegaly is surgical removal of the primary tumor. However, GHRH normalization is not always achieved because in some cases multiple distant metastases are already present at diagnosis or complete resection of the tumor is not possible (2). Although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin (SRIH) analogs are now preferred as a second-line therapy (2). SRIH receptor (SSTR) expression has been indirectly demonstrated by means of 111In-octreotide scintigraphy in several case reports of ectopic GHRH-producing neuroendocrine tumors (3, 4, 5, 6, 7, 8). Moreover, immunostaining for SSTR subtypes 2A and 3 has recently been documented in a case of GHRH-secreting bronchial carcinoid (8). In addition, SMS 201–995 and SRIH-14 have been reported to consistently and directly suppress in vitro GHRH hypersecretion from a bronchial carcinoid (9) and a pancreatic tumor (10), respectively. However, the direct effects of different SSTR selective agonists on GHRH release and cell viability in bronchial carcinoids in vitro have not been investigated so far. Indeed, such information could be of interest to possibly predict the response to SRIH analogs, especially when complete surgical removal cannot be achieved.

We here report the investigation of in vitro response to different SSTR selective agonists of a bronchial GHRH-producing carcinoid from a patient with acromegaly.


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

A 29-yr-old woman was referred in February 2002 for evaluation of acromegaly, dating back almost 10 yr. Endocrine evaluation (Table 1Go) disclosed elevated IGF-I and GH levels, which paradoxically responded to oral glucose load. Biochemical screening for multiple endocrine neoplasia type 1 was negative. Pituitary magnetic resonance imaging (MRI) disclosed a homogeneous enlargement of the pituitary gland with suprasellar extension, with no evidence of a pituitary adenoma (Fig. 1Go, A and B). Chest x-ray disclosed an isolated mass of 3.3 cm in diameter, located in the basal portion of the left superior pulmonary lobe, as confirmed by means of lung MRI (Fig. 2Go). Bronchoscopy showed external compression of the left bronchial tree as well as a highly vascularized tumor wall, but the biopsy was not diagnostic. Total body OctreoScan showed a very high tracer uptake at the pulmonary mass and a lower but still high uptake at the pituitary gland (Fig. 3Go, A and B). On the basis of the imaging investigations, plasma GHRH levels were measured and found to be markedly elevated (Table 1Go).


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  		TABLE 1. Baseline endocrine evaluation

 


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  		FIG. 1. Pituitary gland MRI. A pituitary gland enlargement was observed before (A, lateral view; B, frontal view) surgical removal of left lung tumor. Further pituitary MRI showed a reduction in pituitary gland diameters at 2 yr (C and D).

 


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  		FIG. 2. Tumor imaging. Left lung tumor (arrow) documented by chest x-ray (A, lateral and B, frontal view), CT scan (C, before and D, after contrast), MRI scan (E, lateral and F, frontal view). Direct imaging of the left apical pulmonary lobe before (G) and after (H) cutting the tumor.

 


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  		FIG. 3. Total body and pituitary 111In-DTPA-octreotide scan. A, Whole-body 111In-DTPA-octreotide scan showing an area of intense radiotracer uptake (arrow) in the superior left lung (lesion to background ratio 9.5). Anterior and posterior whole-body scans were obtained 4 and 24 h after radiotracer administration before (I) and after (II) surgical removal of the tumor. The somatostatin receptor scintigraphy was performed by iv injection of 111 MBq (3 mCi) of 111In-DTPA-octreotide (OctreoScan, Tyco, Mallinckrodt, distributed in Italy by Altana Pharma). A dual-head {gamma}-camera used for scintigraphic examination (Axis, Picker International, Highland Heights, OH) was equipped with a medium-energy, parallel hole collimator. The following parameters were used for acquisition: circular orbit, 60 x 2 steps, 25 sec each, 64 x 64 matrix, and processing, low-pass filter, cut-off 0.4, order 5. Transaxial, coronal, and sagittal images of the pituitary region were obtained. B, Pituitary 111In-DTPA-octreotide scan was performed by iv injection of 111 MBq (3 mCi) of 111In-DTPA-octreotide. Tomographic (single-photon emission-computed tomography) acquisition of the head was obtained 4 and 24 h after radiotracer administration before (I, II, III) and after (IV, V, VI) removal of the left lung tumor. A dual-head {gamma}-camera used for scintigraphic examination was equipped with a medium-energy, parallel hole collimator. The scan showed an area of intense radiotracer uptake (arrow) in the pituitary gland (lesion to background ratio 10.7).

 
In May 2002 the patient underwent left upper lobectomy (Fig. 2Go), and histopathology disclosed an atypical carcinoid infiltrating the bronchial wall, without involvement of regional lymph nodes. During follow-up, until September 2004, the patient was free of disease, as confirmed by normal GH (basal levels 2.62–4.26 µg/liter, suppressing to < 1 µg/liter under oral glucose load), IGF-I (268 µg/liter), and GHRH (1.9 pg/ml) values as well as partial regression of acral enlargement. All other endocrine parameters resulted in the normal range; in particular, serum prolactin levels as well as urinary 5-hydroxyindoleacetic acid normalized, and TSH levels were in the normal range under L-thyroxine treatment. The postoperative chest MRI imaging did not reveal any residual mass. Pituitary MRI showed a significant reduction in the pituitary volume (Fig. 1Go, C and D), and total-body OctreoScan failed to disclose any pathological uptake (Fig. 3AGo). Informed consent of the patient was obtained for disclosing clinical investigation and performing the in vitro study.

Tissue collection and isolation of RNA and RT-PCR

Tissue samples were collected under sterile conditions at the time of surgery, following the guidelines of the local committee on human research. A fragment was immediately frozen in liquid nitrogen and stored at –80 C until RNA isolation was performed with TRIzol reagent (Invitrogen, Milano, Italy). Gene expression was evaluated by reverse transcription (RT) and carried out as described before (11), followed by PCR analysis. The cDNA (1 µl of RT reaction) was amplified by PCR in 50 µl with 1 U Taq DNA polymerase (Promega, Milano, Italy) under conditions recommended by suppliers, using the GeneAmp PCR system (Applera, Monza, Italy). PCR conditions and oligonucleotide primers for amplification are listed in Table 2Go. PCR products were run on a 2% agarose gel, visualized by ethidium bromide staining, and analyzed with the Fluor-S multiimager (Bio-Rad Laboratories, Milano, Italy). To confirm the correct identification of RT-PCR products, their specificity was verified by restriction enzyme digestion and direct sequencing (data not shown).


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  		TABLE 2. Primers and PCR conditions for GHRH, CgA, SSTRs, and GAPDH amplification

 
Primary culture

To investigate functional responses to SRIH and its analogs, we performed in vitro experiments with SRIH (Stilamin 250, Serono Pharma, Rome, Italy) and SRIH analogs (BIM-23014, BIM-23120, BIM-23206, BIM-23926, all provided by Biomeasure Inc., Milford, MA), whose affinities to the different SSTRs are listed in Table 3Go. Specificity and selectivity of the analogs were determined by radioligand binding assay (12), and the biological activity of SSTR selective agonists was evaluated as described before (11, 13).


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  		TABLE 3. SSTR specificity (IC50, nM)

 
To explore the effects of SRIH and its analogs on the bronchial carcinoid primary culture, a monolayer culture of tumor cells was performed from a portion of the fresh tissue as previously described (14). Briefly, tumor tissue was minced and enzymatically dissociated using 0.35% collagenase (Sigma, Milano, Italy) and 1% trypsin at 37 C for 60 min. Cell suspensions were filtered through double layers of gauze and washed twice with serum-free DMEM. Tumor cells were resuspended in DMEM with 10% fetal bovine serum and antibiotics, seeded in 96-well culture plates (~2 x 104 cells/well), and incubated at 37 C in a humidified atmosphere of 5% CO2-95% air. After 24 h, cells were incubated overnight with serum-free DMEM. A day later, cells were treated for 6 h with 10 nM SRIH or each SRIH analog, and then the medium was collected and stored at –20 C for later GHRH measurements. Medium was then replaced, and cells were treated with 10 nM SRIH or each SRIH analog for another 48 h for cell viability experiments. Given the limited amount of primary cultured tissue, it was not possible to perform dose-response studies. Therefore, the 10-nM dose was selected on the basis of compound affinity for each specific receptor and previous experience. Cell culture media and supplementations were from EuroClone Ltd. (Torquay, UK).

Hormone assays

GHRH levels in the patient’s serum and the conditioned medium from cultured neuroendocrine tumor cells were measured using a RIA kit (Phoenix Pharmaceuticals Inc., Phoenix Europe GmbH, Karlsruhe, Germany). The assay has an IC50 of 25–35 pg/tube in a range from 1 to 128 pg/tube. The lower detection limit was 1.5 pg/tube with intra- and interassay coefficients of variation of 5.2 and 6.8%, respectively. The assay is highly specific for detecting GHRH because the employed anti-GHRH antibody does not react with other human peptides, as stated by the suppliers.

Results were obtained by determining the mean value, after appropriate dilutions, where necessary, among three replicates in the serum and eight replicates in the conditioned medium from treated and untreated (control) primary cultured cells.

Cell viability

The effects of SRIH and SSTR selective agonists on cell viability in vitro were assessed by the CellTiter 96 Aqueous nonradioactive cell proliferation assay (Promega), a dimethyl thiazol diphenyl tetrazolium bromide-based colorimetric assay. Dimethyl thiazol diphenyl tetrazolium bromide is a widely accepted method for cell viability assessment, even when neuroendocrine cells are examined (14, 15) because the revealed absorbance strongly correlates to the cell number, independently of whether they are proliferating. Tetrazolium salts are especially useful for assaying the quantification of viable cells because they are cleaved to form formazan dye only by metabolic active cells.

Briefly, cells were incubated for 48 h in culture medium in the presence or absence of 10 nM SRIH and each SRIH analog. Treatments were renewed after the first 24 h of incubation. After 48 h, the staining solution was added to the plate, and the absorbance at 490 nm was recorded after 3 h using an ELISA plate reader (EASIA reader, Medgenix, Camarillo, CA). Results were obtained by determining the mean value among eight replicates in both treated and untreated (control) primary cultured cells.

Statistical analysis

Results are expressed as the mean ± SE of the mean (SE). Differences were evaluated by paired and unpaired Student’s t test, where P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patient and Methods
 Results
Discussion
 References
 
GHRH, chromogranin A (CgA), and SSTR expression

RT-PCR analysis showed that the tissue expressed GHRH, demonstrating that the bronchial carcinoid was indeed capable of expressing, and therefore likely secreting, GHRH. Moreover, the evidence of CgA expression confirmed the neuroendocrine origin of the tissue, where SSTR1, SSTR2, and SSTR5 were also expressed (Fig. 4Go). glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression ensured integrity of the cDNA.



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  		FIG. 4. GHRH, CgA, and SSTR expression. After RT reaction of total RNA from the tissue, PCR amplification of GHRH, CgA, SSTRs, and GAPDH using the primers indicated in Table 2Go was performed. PCR products were resolved on a 2% agarose gel. The expected PCR products are indicated with arrows. M, 100-bp PCR marker; G, GAPDH amplification; CgA, CgA amplification; GHRH, GHRH amplification; SSTRs, SSTR subtypes amplification.

 
Effect of SRIH and SSTR selective agonists on secretory activity

We found that primary cultured cells basally secreted GHRH (51.2 pg/ml). As shown in Fig. 5Go, SRIH treatment of primary cultured cells significantly reduced GHRH secretion (by 50%; P < 0.05), compared with untreated control cells. BIM-23014 (lanreotide, Lan) induced a 30% decrease (P < 0.05) in GHRH secretion. Treatment with the SSTR2 selective agonist, BIM-23120, resulted in an approximately 55% GHRH secretion inhibition (P < 0.05). The SSTR5 selective agonist, BIM-23206, also significantly reduced GHRH levels in conditioned medium (–75%; P < 0.05), whereas the SSTR1 selective agonist, BIM-23926, was less effective (–20%; P < 0.05).



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  		FIG. 5. Effect of SRIH and SSTR selective agonists on GHRH secretion by carcinoid primary culture. Primary cultured carcinoid cells were incubated in 96-well plates for 6 h with 10 nM SRIH or each SSTR selective agonist. Control cells were treated with vehicle solution. GHRH levels in the conditioned medium were measured by RIA among eight replicates in the conditioned medium from treated and untreated (control) primary cultured cells. Data are expressed as the mean ± SE percent hormone secretion inhibition vs. untreated control cells. *, P < 0.05; **, P < 0.01 vs. control.

 
Effect of SRIH and SSTR selective agonists on cell viability

Treatment with SRIH determined a reduction in carcinoid cell viability (~8%), which did not reach statistical significance. Lan induced a 7% decrease (P = not significant) in cell viability. Treatment with the SSTR2 selective agonist, BIM-23120, also reduced cell viability by 5% (P = not significant) as well as the SSTR5 selective agonist, BIM-23206 (–4%; P = not significant) or the SSTR1 selective agonist, BIM-23926 (–3%; P = not significant).

Therefore, treatment with SRIH or each SSTR selective agonist failed to significantly affect viability of primary cultured neuroendocrine tumor cells (not shown).


   Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
References
 
Extrapituitary GHRH secretion causing acromegaly is reported in 1–2% of patients, with bronchial carcinoids being the most common cause (70%), followed by pancreatic islet cell carcinoids (16, 17). In 90% of cases, the tumor originates in the subsegmental or greater bronchus, whereas in 10% the tumor is peripherally located or of the tumorlet type (18). The first report of a bronchial carcinoid causing acromegaly and enlargement of the sella dates back to 1958 (19), and approximately 50 cases have been reported in the literature to date (6).

The efficacy of SRIH analog therapy depends on the SSTR expression pattern on tumor cells, which shows great variations, depending on tumor type and the tissue. The possibility to identify the specific tissue SSTR expression pattern could offer a new individualized approach, sparing patients unnecessary treatments. The present case provides new useful information concerning therapy of ectopic acromegaly due to GHRH-secreting bronchial carcinoid.

Although SRIH analogs have been widely used for the treatment of acromegaly due to GH-secreting pituitary adenomas, medical treatment of acromegaly due to ectopic GH or GHRH secretion is less explored. GH-secreting pituitary adenomas appear to express mainly SSTR2 and SSTR5, with SSTR1 being expressed mainly in mixed GH-prolactin adenomas (15). Both octreotide and Lan present enhanced affinity for SSTR2 and SSTR5, and they are highly effective in terms of pituitary GH suppression in approximately 50% of acromegalic patients (20). The expression pattern of SSTR subtypes in bronchial carcinoids has not yet been extensively investigated. Indeed, OctreoScan has proved to be a valuable diagnostic tool to detect most bronchial carcinoids, including the few cases associated with ectopic GHRH secretion (3, 4, 5, 6, 7, 8). In previous studies, the high tracer uptake supported the presence of SSTR2 and/or SSTR5 in most of bronchial carcinoids. Also in the present case, by means of 111In-diethylenetriamine-pentacetic acid (DTPA)-octreotide scintigraphy, we showed the presence of SSTR2 and SSTR5 receptors in tumor cells, which we have confirmed, for the first time, by RT-PCR analysis. This technique also allowed us to demonstrate the expression of GHRH as well as SSTR1 subtype in bronchial carcinoid cells of a patient with ectopic acromegaly.

The functionality of SSTR subtypes in ectopic acromegaly from bronchial tumor cells has been investigated in very few cases, and the direct in vitro effects of different SRIH analogs or their capability to inhibit GHRH secretion through interaction with specific SSTRs are largely unknown.

It has previously been reported that SRIH-14, displaying high affinity for all five SSTRs, inhibits both GHRH and {alpha}-subunit secretion in vitro by liver metastases from ectopic GHRH-secreting bronchial carcinoma, showing a higher density of SRIH binding sites, compared with GH adenomas or GHRH-secreting insulinoma at autoradiography (10). Furthermore, perfusion with SRIH-14 of a GHRH-secreting pancreatic tumor (in the context of multiple endocrine neoplasia 1-related acromegaly) significantly reduced the GHRH secretion rate (from 18.2 to 12.4 pg/min x milligram wet weight; –32%) (21). However, no evidence was provided for SSTR subtype expression. SMS 201–995 treatment of tissue cultures from GHRH-secreting bronchial carcinoid tumor has been shown to reduce GHRH secretion by 58–76% (9), but SSTR subtype expression was not investigated in the neoplastic tissue. In the present case, we demonstrated the occurrence of SSTR1, SSTR2, and SSTR5 in tumor cells and the capacity of different SRIH analogs to significantly reduce in vitro GHRH secretion.

In this study, BIM-23206, a selective SSTR5 agonist, potently inhibited GHRH secretion in vitro (–75%). SRIH analogs with a selective affinity for SSTR2 (BIM-23120), mixed affinity for SSTR2 and SSTR5 (BIM-23014), or affinity for all SSTR subtypes (SRIH) were also capable of significantly suppress GHRH secretion, even if to a lesser extent (range from –30 to –55%). On the other hand, BIM-23926, a selective SSTR1 agonist, was less effective (–20%). These results might mirror the heterogeneous expression of SSTR subtypes in tumor cells or variability in expression levels of the individual SSTR. Moreover, these data confirm previous findings that SRIH analogs interacting selectively with a specific SSTR might achieve greater inhibitory results, compared with SRIH analogs interacting with multiple receptors (11). Indeed, as previously suggested, multiple SSTR activation may be not only synergistic (22) but also antagonistic (11) in a tissue-dependent fashion. The in vitro results confirm several clinical observations documenting the lack of complete normalization of GHRH plasma levels under treatment with octreotide, Lan, or SRIH 14 (Table 4Go) (23, 24, 25, 26, 27, 28, 29, 30). Our data would, therefore, suggest that selective SSTR5 agonists might be more effective in reducing GHRH secretion by bronchial carcinoids in clinical settings, even if further experimental evidence is needed before a possible clinical application.


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  		TABLE 4. Ectopic acromegaly from GHRH-secreting tumors: in vivo response to somatostatin analogs

 
In most of the published studies, medical therapy of acromegaly due to ectopic GHRH-secreting tumors with octreotide or Lan over a period of 2.5–36 months did not achieve a significant shrinkage of primary or metastatic neoplastic lesions (Table 4Go). On the other hand, Barkan et al. (26) observed a significant shrinkage of lung, bone, and liver metastases of a carcinoid of unknown origin under long-term treatment with octreotide at very low doses (100 µg/d) without obtaining, however, any normalization in GHRH plasma levels. Similarly, a clear-cut long-lasting antiproliferative effect of slow-release Lan on liver metastases of occult carcinoid with high proliferation index and immunoreactivity for SSTR1, -2, -3, and -5 has been recently shown (31).

The discrepancy between the in vivo inhibitory effects on GHRH secretion and the lack of a significant ectopic tumor shrinkage is in line with the present in vitro results. In fact, we documented the lack of any significant effect of SRIH or SSTR selective agonists on cell viability, notwithstanding a significant suppression of GHRH secretion, especially with BIM-23206, a selective SSTR5 agonist. We cannot exclude that longer treatments at higher doses with selective SSTR agonists might be able to inhibit in vitro cell viability and induce tumor shrinkage in vivo.

In conclusion, we have demonstrated the occurrence of functional SSTR1, SSTR2, and SSTR5 in a GHRH-secreting bronchial carcinoid causing ectopic acromegaly. Our in vitro findings suggest that the availability of SRIH analogs with enhanced affinity for the different SSTRs might offer a new therapeutic tool in the attempt to reach a better control of GHRH overproduction.


   Acknowledgments
 
We thank Dr. Massimo Scanarini (Department of Neurosurgery, University of Padua, Padua, Italy) and IPSEN Italia S.p.a. for their contribution to this work.


   Footnotes
 
This work was supported by grants from the Italian Ministry of University and Scientific and Technological Research [University of Ferrara: 60%-2002 and Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) 2002067251-003; University of Padua: MIUR 2002067251-004], Fondazione Cassa di Risparmio di Ferrara, and Associazione Ferrarese dell’ Ipertensione Arteriosa.

First Published Online January 25, 2005

1 M.C.Z. and P.M. contributed equally to this study and should both be considered first authors. Back

Abbreviations: CgA, Chromogranin A; DTPA, 111In-diethylenetriamine-pentacetic acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Lan, lanreotide; MRI, magnetic resonance imaging; RT, reverse transcription; SRIH, somatostatin; SSTR, receptor subtype.

Received November 2, 2004.

Accepted January 17, 2005.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
 References
 

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