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Original Studies |
Department of Endocrinology (M.K., R.A.J., S.J.B.A., J.M.B., P.L.M.D., J.P.M., P.J.T., S.L.C., G.M.B., A.B.G.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE; and Neurochirurgische Klinik der Universität Erlangen-Nürnberg (J.H., R.F.), 91054 Erlangen, Germany
Address all correspondence and requests for reprints to: Prof. A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: a.b.grossman{at}mds.qmw.ac.uk
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-subunit, and TSH. RNA was extracted from tissue samples and, after
RT, a duplex PCR reaction with primers for the GHS-R gene and for the
housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was
performed, allowing semiquantitation of GHS-R expression. All the somatotroph adenomas (n = 8) showed a 2–10 times higher expression of the GHS-R gene compared to normal pituitaries. Higher than normal expression was shown in 5 of 18 tumors from patients with ACTH-secreting pituitary adenomas and in 1 of 3 ectopic ACTH-secreting carcinoid tumors. Two of the pituitary ACTH-secreting adenoma samples showed completely absent expression of the GHS-R, 8 showed expression similar to that of normal pituitary tissue, and 3 of the corticotroph adenoma tissue samples and 2 ectopic ACTH-secreting tumors showed a very low level of expression. One of 4 prolactinoma samples showed a high level of expression, 1 showed expression similar to that of normal pituitary, and 2 samples showed a very low level of expression. Nonfunctioning pituitary adenoma samples showed either absent or very low level expression of the GHS-R. The pancreatic gastrinoma sample showed expression similar to that of normal pituitary tissue, whereas 3 insulinomas showed low level expression of the GHS-R gene; a nonsecreting thymic carcinoid tumor showed no detectable expression.
In summary, although GHS-R messenger RNA is abundant in human somatotroph adenomas, it is also present in other pituitary adenomas, particularly ACTH-secreting tumors. These findings may explain the in vivo responses to GHSs in patients harboring such tumors. It also appears from our study that GHS-R may be expressed in other neuroendocrine tumors.
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Introduction |
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The effects of GHSs have been studied in patients with pituitary adenomas. GHS stimulate GH release in patients with acromegaly, but do not stimulate further PRL release in patients with prolactinomas (14, 15, 16, 17). In vitro, human somatotroph adenoma cells also respond to stimulation with GHSs (18). The most striking results, however, came from patients with Cushing’s syndrome. Ten patients with pituitary-dependent ACTH-secreting adenomas each showed a markedly exaggerated ACTH and cortisol response to hexarelin, one of the peptide GHSs (19). The rise in ACTH and cortisol after hexarelin was considerably higher than that after a near-maximal dose of CRH, whereas two patients with ectopic ACTH-secreting tumors showed no response.
Messenger ribonucleic acid (mRNA) quantitation has previously been used extensively to study gene expression in human pituitary adenomas (20, 21). Recently, human fetal pituitary cells has been shown to express and respond to GHRP-6 (22). We speculated that the GHS-R might be expressed in human pituitary adenomas arising from different cell types, particularly in tumors from patients with pituitary-dependent Cushing’s syndrome, and Cushing’s disease. Carcinoid tumors are also known to secrete a wide range of neuroendocrine hormones and contain a number of neurohormonal receptors (23). We therefore studied 41 pituitary tumors, 3 ectopic ACTH-secreting tumors, 4 pancreatic tumors, 1 gastrinoma, and 3 insulinomas, as well as a nonsecreting thymic carcinoid tumor, and compared the results with those from 7 normal pituitary glands. Our results clearly show the presence of GHS-R mRNA in a variety of different tumor types and suggest that the presence of GHS-R in corticotropinomas may well be responsible for the aberrant ACTH and cortisol responses to GHSs seen in patients with this condition.
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Materials and Methods |
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Pituitary adenomas were obtained at the time of transsphenoidal surgery (except for an ACTH-secreting pituitary carcinoma, which was obtained at autopsy). The tumor type was determined on the basis of clinical and biochemical findings before surgery, from morphological and immunocytochemical data, and with in vitro cell culture studies in some cases. The size of the pituitary tumors was determined by computed tomography/magnetic resonance imaging. Carcinoid tumors and pancreatic tumors were obtained at surgery. Seven normal human pituitaries were collected at autopsy (4–24 h postmortem) from patients with no evidence of endocrine abnormality.
A total of 41 pituitary adenomas was studied: 8 somatotroph adenomas, 4 lactotroph adenomas, 10 nonfunctioning pituitary adenomas (NFPA), 18 corticotroph tumors including 1 corticotroph carcinoma, and 1 FSH-secreting adenoma. Three ACTH-secreting ectopic tumors (of the bronchus, thymus, and pancreas), 3 pancreatic insulinomas, 1 gastrinoma, and 1 thymic nonsecreting carcinoid tumor were also studied. In addition, normal human kidney, liver, and peripheral lymphocytes and a parasellar meningioma were analyzed.
RT-PCR
Total RNA was obtained and reverse transcribed into
complementary DNA (cDNA) by a standardized technique as described
previously (24). The integrity of mRNA from each specimen was verified
by RT-PCR for the housekeeping gene, glyceraldehyde-3-phosphate
dehydrogenase (GAPDH; GenBank accession no. M33197). RT-PCR, with
omission of reverse transcriptase and with water replacing template,
was used as the negative control. The PCR was performed using primers
spanning one or more introns of the genes studied to allow for
exclusion of genomic DNA contamination (Table 1
). Primers for the GHS-R gene (GenBank
accession no. U60179) gave rise to a product of 484 bp; this product
was analyzed by restriction enzyme analysis (Fig. 1a) and then by direct sequencing,
confirming the expected product. A PCR reaction for the Pit-1 (GenBank
accession no. D10216) gene, which is only expressed in somato-, lacto-,
and thyrotroph cells, was also performed on ACTH- and FSH-secreting
tumors and on NFPAs. We used previously published primers that gave
rise to a product of 560 bp (25).
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). We used 100 ng cDNA, 200 µmol/L deoxynucleotides
(Promega Corp., Southampton, UK), 0.5 µmol GHS-R
primers, 0.1 µmol GAPDH primers, 1.5 mmol/L MgCl2, 0.125
U Taq (Promega Corp.), and TaqStart antibody
(Clontech, Heidelberg, Germany), according to the
manufacturers’ guidelines, in a 25 µL PCR reaction. For GHS-R and
GAPDH duplex PCR reaction, 28 cycles were performed at 94 C for 1 min,
54 C for 1 min, and 72 C for 1 min after a denaturing cycle of 95 C for
5 min. For the Pit-1 gene reaction, we used a 0.2 µmol primer
concentration, and 30 cycles were performed at 94 C for 30 s, 55 C
for 30 s, and 72 C for 45 s after a denaturing cycle of 95 C
for 3 min. A final extension cycle of 10 min at 72 C was used. The PCR
products were run on 2% ethidium bromide-stained agarose gels. The
absorbance values were measured for each band by densitometry (model
DS670 image densitometer, Bio-Rad Hemel-Hempstead, Hertfordshire, UK),
using the Molecular Analyst PC software for Bio-Rad’s Image Analysis
systems, and expressed as optical density units. A ratio between GHS-R
and GAPDH was obtained for each sample. Each cDNA sample was assayed
with duplex PCR on at least 2 separate occasions. Our normal pituitary
tissues defined a normal range of expression of the GHS-R gene relative
to the expression of GAPDH. If no expression of the GHS-R gene was
shown at 28 cycles in the duplex PCR, a single PCR with the GHS-R
primers only was performed at 34 cycles to determine whether any
expression was present at a lower level. In the description of our data
we use the terms similar, very low, high, and undetectable levels of
expression to describe tumors with a level of expression (GHS-R/GAPDH
ratio) within the range of the normal samples, below this range but
still detectable at 34 cycles, above this range (with a ratio >2
SD above the mean of the normal samples), or no detectable
level of expression (no band observed at 34 cycles), respectively.
Contamination of ACTH- and FSH-secreting tumors and NFPAs by somato-,
lacto-, or thyrotroph cells of nontumorous tissue was excluded by
confirming undetectable expression of the Pit-1 gene. In normal
pituitary tissue cDNA we were still able to detect Pit-1 and GHS-R
expression at a 1:50 dilution, suggesting that contamination of tumor
samples with normal pituitary would be detected at this level. Three
NFPA were considered noninformative because Pit-1 mRNA was expressed,
indicating possible contamination with nontumorous tissue in the
adenoma specimen; these were excluded from further analysis. The final
analysis, therefore, included 38 pituitary adenomas. Clinical details
are shown in Tables 2a and 2b.
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Pituitary adenoma tissue was transported to the laboratory in DMEM containing 10% heat-inactivated FCS, 0.06 g/L penicillin, 0.1 g/L streptomycin, and 2.5 g/L fungizone and buffered with HEPES (0.02 mmol/L), hereafter referred to as culture medium. Tumor tissue was washed three times with phosphate-buffered saline, cut into small pieces with a sterile scalpel, and dispersed by incubation for 40 min at 37 C in phosphate-buffered saline containing ethylenediamine tetraacetate (0.5 mmol/L) and 0.125% trypsin with periodic titration. Dispersed cells were harvested by centrifugation, washed once, and subsequently resuspended in culture medium. Cell viability was assessed using trypan blue exclusion and was more than 90% of the cells in all tumors studied after cell dispersion. Cell yield from each tumor varied from 1–65 x 106 cells.
The cells were plated in 24-well plates at approximately
105 cells/well in 2 mL medium. Cultures were incubated at
37 C in a humidified atmosphere of 95% air and 5% CO2 for
48 h to allow cell attachment to occur, after which time the
medium was collected. All pituitary hormones, including the
glycoprotein -subunit, were measured in medium, as described
previously (28).
Statistical analysis
Absorbance ratios of the GHS-R and the GAPDH bands were calculated in the duplex PCR reaction. ANOVA followed by post-hoc tests were used to calculate differences between groups of tissues. Significance was taken at P < 0.05.
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Results |
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-4). The GHS-R/GAPDH absorbance ratio
for normal pituitary tissue ranged between 0.09–0.4; in acromegalic
tissue, the GHS-R/GAPDH ratio ranged between 0.85–1.5, resulting in 2-
to 10-fold expression of the GHS-R gene in acromegalic tissue compared
to normal pituitary. A representative gel of a duplex PCR is shown in
Fig. 3, comparing normal pituitary tissue
with sample from patients with acromegaly or nonfunctioning tumors.
Figure 4 shows the in vivo GH
response to iv administration of 2 µg/kg hexarelin in 12 healthy
volunteers and 1 of the acromegalic patients whose tumor tissue was
also studied [subject 4; details of the protocol of hexarelin
administration have been published (6)]. The lower part of
Fig. 4 shows a cycling curve of a normal cadaver pituitary and of
acromegalic pituitary tissue. An increased GHS-R/GAPDH ratio was still
present when 2-fold diluted acromegalic samples were used to control
for the fact that normal pituitary tissue comprises approximately 50%
somatotrophs (29).
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shows a representative
ACTH-secreting pituitary sample with GHS-R expression and no detectable
Pit-1 expression. Two ACTH-secreting pituitary adenoma samples showed
absent expression of the GHS-R. Eight showed similar expression to
normal pituitary tissue. Three corticotroph tumors, including the
corticotroph carcinoma and pancreatic and thymic ACTH-secreting tumors,
showed low levels of expression (present at 34 PCR cycles, but not at
28 cycles). One of 4 prolactinoma samples showed expression similar to
normal, 2 showed very low level of expression, and the fourth showed
high expression (GHS-R/GAPDH ratio, 1.2). Although it is difficult to
exclude that this sample contained normal somatotrophs, the expression
of the gene was higher than that of normal tissue, suggesting that the
increased expression was unlikely to be due to contaminating normal
tissue. Four NFPA samples showed no expression of the GHS-R, whereas
the remaining 3 showed a very low level of expression. Figure 5 shows representative cycling curves of
the pituitary tumor samples.
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Full clinical details of the nonpituitary tumors are given in Table 2b.
Three patients presented with classical recurrent hypoglycemic attacks
and after the removal of the pancreatic lesion(s), consistent with
insulin-secreting islet cell tumors, showed clinical and biochemical
cure; all three insulinoma samples showed low level expression of the
GHS-R gene. The gastrinoma sample, from a patient presenting with
recurrent peptic ulceration, showed expression similar to that of
normal pituitary. None of the patients with nonpituitary tumors showed
signs of GH excess. A nonsecreting thymic carcinoid tumor, from a
patient with the multiple endocrine neoplasia syndrome type 1, showed
no detectable expression of the GHS-R gene. No GHS-R expression was
found in human kidney, lymphocytes, or liver or in a tissue sample from
a parasellar meningioma (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has recently been reported that GHS-R is present only on the
somatotrophs of rat pituitary and is absent from other cell types (2).
Our data clearly show that in corticotroph pituitary adenomas, GHS-R
may be variably expressed, although some ACTH-secreting tumors show no
detectable expression. Five ACTH-secreting pituitary adenomas showed
higher than normal expression of the GHS-R gene. A significant
proportion of the remaining tumors showed a level of expression similar
to that of normal pituitary tissue despite the fact that no detectable
Pit-1 gene expression was found, suggesting that the samples were not
contaminated with nontumorous pituitary tissue (Fig. 6). These data suggest that the receptor
must be present in some of the corticotroph adenoma cell population and
are in accordance with clinical data showing exaggerated ACTH responses
to GHSs in this group of patients (19). Adams et al.
recently reported their findings of the presence of GHS-R mRNA and
in vitro responsiveness to GHRP-2 in human somatotropinomas,
prolactinomas, and nonfunctioning pituitary tumors; however, they did
not report any data from corticotroph adenomas (31). Their findings are
concordant with our demonstration of GHS-R expression, although double
labeling immunochemistry would be necessary to show the precise cell
types expressing the GHS-R.
Little is known concerning the regulation of expression of the GHS-R gene, although it has been reported that estrogens may have a positive effect on GHS-R expression (32). It has also been shown that GH-deficient rats show overexpression of the receptor (33). Interestingly, one of our patients with a macroprolactinoma (no. 9) had been GH deficient over the preceding 2 yr before surgery, with subnormal GH reserve on dynamic tests and low IGF-I levels compared to an age-matched reference range; this patient showed a higher than normal expression of the GHS-R gene. However, some of our patients with NFPA were also GH deficient at the time of the transsphenoidal surgery, with very low or undetectable GHS-R expression. An alternative explanation for the overexpression of the GHS-R gene in patient 9 is possible: during the in vitro hormone secretion test, this tissue released TSH as well as PRL, and TSH was also positive in the tumor tissue on immunocytochemistry. It is possible that this tumor arose from a progenitor of the somato-, lacto-, and thyrotroph cell population that might express the GHS-R gene.
Ectopic ACTH-secreting tumors may arise from many sites, including the lung, pancreas, and thymus. These tumors characteristically produce and secrete a whole range of neuroendocrine peptides. We can now add another member to this list of these peptides and receptors: the GHS-R. Low level expression was found in a thymic and a pancreatic ACTH-secreting carcinoid, and very high expression was found in a bronchial carcinoid sample, whereas no expression was found in a nonsecreting thymic carcinoid tumor. A GHRH- and ACTH-secreting carcinoid tumor has recently been reported to respond to GHRP-6 stimulation with calcium influx (34), confirming our data demonstrating the presence of the GHS-R in such tumors. Ghigo et al. (19) have suggested that GHSs may be useful in the differential diagnosis of pituitary vs. ectopic ACTH-secreting tumors, because their two patients with ectopic ACTH-secreting tumors did not respond to GHS with any stimulation of the pituitary-adrenal axis, whereas patients with pituitary-dependent Cushing’s disease showed an exaggerated response. Our finding of the presence of the GHS-R in ectopic tissue suggests that patients with tumors expressing this receptor may also respond to GHSs. Indeed, suggestions that other neuropeptide secretagogues may completely discriminate between ectopic and eutopic ACTH secretion have generally been disproved; thus, desmopressin responsiveness was recently reported in a bronchial carcinoid that expressed vasopressin receptors (35), and such absolute distinction may never be possible. However, detection of GHS-R transcripts in human pituitary adenomas and other tumorous tissue does not necessarily imply translation and functional protein expression, and further studies are needed to detect the GHS-R protein in these samples. The presence of GHS-R in ectopic endocrine tumors is not surprising, but the role of these receptors is unclear; the possible targeting (blocking) of the receptor suggests that this could be the basis for new therapeutic approaches.
In summary, we have shown enhanced expression of the GHS-R in a proportion of pituitary tumors, especially somatotroph and corticotroph tumors. We speculate that this expression is responsible for the marked GH and pituitary-adrenal responses, respectively, to GHSs seen in many patients with these tumors. GHS-R may also be expressed in nonpituitary neuroendocrine tumors.
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Acknowledgments |
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Footnotes |
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Received February 3, 1998.
Revised June 3, 1998.
Accepted July 9, 1998.
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,
GAPDH; 
, GHS-R.
). Open
symbols represent samples with no detectable expression under
any conditions; filled symbols at the zero GHS-R/GAPDH
ratio represent samples with very low level expression.
