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Original Studies |
Interactions Cellulaires en Neuroendocrinologie, Unite Mixte de Recherche, UMR 6544, Centre National de la Recherche Scientifique (P.J., A.S., G.G., A.E.), and Assistance Publique, Hopitaux de Marseille, Laboratoire de Cancérologie Expérimentale (L.O., F.F.), Institut Fédératif Jean Roche, Faculté de Médecine Nord, 13916 Marseille Cedex 20; and the Department of Neurosurgery, Centre Hospitald-Universtaire Timone (H.D.), 13005 Marseille, France; and Biomeasure, Inc. (M.D.C., J.P.M.), Milford, Massachusetts 01757
Address all correspondence and requests for reprints to: Dr. Philippe Jaquet, Interactions Cellulaires en Neuroendocrinologie, UMR 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, boulevard Pierre Dramard, 13916 Marseille Cedex 20, France.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although a great deal of work has been directed toward study of human pituitary adenomas and control of GH-secreting tumors (6), little attention has been focussed on PRL-secreting tumors until the recent work of Shimon et al. (11). This research demonstrated SSTR5 selectivity in the regulation of PRL secretion from prolactinoma cells tested in vitro with the SSTR5 preferential agonist, BIM23268. The present work was aimed at confirming the SSTR5 selectivity of human prolactinomas. We analyzed a larger population of prolactinomas in vitro to address the following questions. 1) What is the quantitative pattern of expression of the five SSTR subtypes? 2) Using endogenous somatostatins or preferential SSTR2 or SSTR5 peptides, which is the more potent PRL suppressor in prolactinomas? 3) Knowing the dominant role of dopamine (DA) and its agonists in PRL inhibition, how do the somatostatin agonists compare in the control of PRL hypersecretion by human prolactinomas? Our data show a SSTR5 and SSTR1 phenotype of human prolactinomas that seems more cell specific than tumor specific. The significance of the SSTR1 expression is presently unknown. The SSTR5 preferential agonist is equipotent to the native somatostatins but less effective than DA agonists in the control of PRL secretion. The suppressive effects of BIM-23268 on PRL secretion correlate with the SSTR5 quantitative expression of the various tumors tested.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study was approved by the ethics committee of the
University of Aix-Marseilles (Aix-Marseilles, France) and was
undertaken after informed consent was received from each patient. Ten
patients (six women and four men), aged 28–57 yr, with
macroprolactinoma (n = 8) or microprolactinoma (n = 2) were
studied. Their endocrine status and neuroradiological characterization
of the tumors were documented before any treatment. Basal PRL levels
were expressed as the mean of six consecutive measurements obtained
every 4 h during a 24-h period. DA sensitivity was assessed by an
acute test using a single oral 2.5-mg dose of
bromocriptine (Parlodel, Novartis, Basel, Switzerland).
Blood samples were withdrawn hourly for 4 h to measure PRL. The
sensitivity to DA agonist was expressed as the percent decrease in PRL
from the basal to the nadir value during the bromocriptine
acute test. In seven patients (P1–P7), magnetic resonance imaging
(MRI) revealed adenomas with a 9- to 25-mm maximal diameter either
enclosed in the pituitary fossa or with moderate suprasellar extension.
These patients were operated on using transsphenoidal surgery, and
postsurgical normalization of PRL levels was achieved. In contrast,
patients 8–10 presented with highly invasive macroadenomas and
received, initially, treatment with quinagolide (Norprolac, Novartis),
with the dosage rapidly increased up to 150 µg/day. After 2–3
months, due to partial inhibition of hyperprolactinemia, the
quinagolide daily doses were, according to tolerance, increased up to
300–450 µg/day. In no case did any of these three men achieve normal
PRL values during long term DA agonist therapy. Repetitive MRI
follow-up showed no evidence of tumor shrinkage in these three
patients. Such long term observations characterized the subclass of
patients presenting with prolactinomas resistant to DA agonists therapy
(12). Subsequently, due to either the persistence or the worsening of
tumoral symptoms, patients 8–10 underwent decompressive partial tumor
removal by transfrontal neurosurgery. The clinical endocrine and
morphological status of each patient is summarized in Tables 1
and 2.
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PRL and GH were measured using commercial kits (Immunotech, Marseilles, France; Medgenix Diagnostics, Fleurus, Belgium). Normal values for PRL ranged from 1–24 µg/L in women and from 1–17 µg/L in men. Among the 10 patients, none presented with GH or insulin-like growth factor I values over the normal range, ruling out any somatomammotropin-secreting adenoma.
Immunocytochemistry
Tumoral tissue obtained at transsphenoidal (n = 7) or
transfrontal (n = 3) neurosurgery was in part placed in 10%
formalin and embedded in paraffin. Immunocytochemistry was carried out
on 5-µm sections using a monoclonal antibody directed against human
PRL (1:200 dilution; Immunotech), and a human GH
polyclonal antiserum (1:2000; DAKO Corp., Hamburg,
Germany). The antihuman LHß, FSHß, TSHß, and 
-subunit
monoclonal antibodies were obtained from Immunotech.
Automated immunohistochemistry with avidin-biotin peroxidase complex
was performed using a Ventana 320 device (Ventana Systems, Strasbourg,
France). The intensity of cell labeling was expressed as the percentage
of cell labeling by a given antibody as observed by the same
investigator.
Detection of SSTRs
Ribonucleic acid (RNA) preparation. Total RNA was extracted from 15–30 mg tissue from each tumor using the SV total RNA isolation system (Promega Corp., Lyon, France). To prevent any contamination by genomic DNA, the RNA samples were treated with 30 U ribonuclease-free deoxyribonuclease I (Roche Molecular Biochemicals, Mannheim, Germany) at 37 C for 90 min, followed by phenol-chloroform extraction and ethanol precipitation. Depending on the tumor, 5–36 µg RNA were obtained.
Combined quantitative RT-PCR. Total RNA was reverse transcribed into complementary DNA (cDNA) using 1 µg hexamers (Pharmacia Biotech, Orsay, France) and Moloney murine leukemia virus reverse transcriptase as described by the manufacturer (Life Technologies, Inc., Paris, France).
The 5'-exonuclease (Taq Man; Roche Molecular Systems, Inc., Alameda, CA) assay that produces a direct proportional readout for the progression of PCR reactions was used (13). Amplification of cDNA derived from 50–150 ng total RNA was performed in a 50-µL reaction volume with a buffer consisting of 10 mmol/L Tris-HCl (pH 8.3; 25 C), 50 mmol/L KCl, 10 mmol/L ethylenediamine tetraacetate, and 5 mmol/L MgCl2 in the presence of 200 µmol/L deoxy (d)-ATP, dCTP, dGTP, 400 µmol/L dUTP, 1 µmol/L of each primer, 200 nmol/L of the probe, 1 U Amp Erase UNG, and 1.25 U Ampli-Taq gold polymerase (Perkin Elmer Corp., Paris, France). The probe comprised 20–30 nucleotides with 5'-end substitution with a fluorophore (FAM) and a quencher substitution at the 3'-end (TAM). The synthetic SSTR cDNA primers used in the PCR reaction were 19- or 20-mer as follows: SSTR1: sense, 1411–1433; antisense, 1511–1492; probe, 1442–1463; SSTR2: sense, 10–29; antisense, 109–91; probe, 58–32; SSTR3: sense, 1188–1206; antisense, 1254–1236; probe, 1209–1234; SSTR4: sense, 1282–1301; antisense, 1362–1343; probe, 1331–1301; and SSTR5: sense, 1103–1119; antisense, 1156–1139; probe, 1137–1121. The annealing-extension temperatures were: SSTR1, 66 C; SSTR2, 56 C; SSTR3, 70 C; SSTR4, 66 C; and SSTR5, 70 C. Forty cycles of two-step PCR reaction-annealing extension at specified temperatures for 30 s and denaturation at 95 C for 20 s were performed on an ABI Prism 7700 sequence detection apparatus (Perkin Elmer Corp.). For quantitation of the data, SSTR messenger RNA (mRNA) levels were, in the same reaction, normalized to the GAPDH mRNA levels. The control GAPDH primers were as follows: sense, 222–240; antisense, 322–303; and probe, 277–301. For each measurement, three independent RT-PCR analyses were performed. To create standard curves for each SSTR mRNA and GAPDH mRNA, RNAs were produced by in vitro transcription from linearized templates corresponding to SSTRs and GAPDH cDNA constructs using T7 or T3 polymerases as previously described (14). The synthesized RNAs were reverse transcribed to cDNA for each parameter as described above.
Taq Man PCR assay conditions for SSTR and GAPDH mRNAs. Using
the fluorogenic probes for SSTR receptors and GAPDH with the
experimental conditions defined above, we obtained a linear
relationship between the RNA concentration (previously transcribed into
cDNA) and the fluorescent signal (
RQ) for SSTR and GAPDH RNAs in
25–250 pg DNA target. For each unknown sample, we determined the RQ
values for both genes, and the results were expressed as picograms of
SSTR per pg GAPDH.
Cell culture studies
After surgery, fragments of each tumor were dissociated by mechanical and enzymatic methods (15), and 15 x 103 dispersed cells were plated in multiwell culture dishes coated with extracellular matrix from bovine endothelial corneal cells. Tumoral cells were cultured in DMEM supplemented with 10% FCS for 4 days before the start of the experiments. Subsequently, the cells were washed and cultured in serum-free defined DMEM supplemented with antibiotics, insulin, transferrin, and selenium as previously described (15). The effects of various doses of the DA agonist quinagolide (selected while patients 8–10 were treated with this drug) and of the somatostatin agonists, SRIF14, SRIF28, BIM-23268, BIM-23197, and octreotide, on inhibition of PRL release were measured over an 8- to 14-h period, as indicated in Results. Each drug concentration was tested in quadruplicate culture wells (Costar 3524, Brumath, France). Quinagolide and octreotide were supplied by Novartis. Somatostatin-14 and somatostatin-28 were purchased from Sigma Chemical Co. (Saint-Quentin Fallavier, France). BIM-23268 and BIM-23197 were provided by Biomeasure, Inc. (Milford, MA). Quinagolide was initially prepared as a 10-3 mol/L solution in 70% ethanol. The somatostatin analogs were dissolved in 0.01 mol/L acetic acid and 0.1% purified BSA (Life Technologies, Inc., Cergy Pontoise, France). The drugs were initially prepared as a 10-3 mol/L solution and stored at -80 C. At the end of experiments, culture media were collected and stored frozen for PRL and GH measurements.
Statistics
The results are presented as the mean ± SEM. Statistical significance was determined by Mann-Whitney test. To measure the strength of association between pairs of variables without specifying dependencies, Spearman order correlations were run. P < 0.05 was considered significant in all tests.
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Results |
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RT-PCR quantitative analysis demonstrated, in all prolactinomas,
the presence of SSTR5 mRNA, which was the dominant receptor subtype in
7 of 10 tumors (Fig. 1). The level of
SSTR5 expression varied from 38–17,000 pg/pg GAPDH regardless of
tumoral status, i.e. invasive or noninvasive adenomas. The
SSTR2 transcripts, although detected in all tumors, were at a much
lower level of expression. The mean value of 148 ± 83 pg/pg GAPDH
for SSTR2 mRNA contrasted sharply with that of 5648 ± 1918 pg/pg
GAPDH obtained for SSTR5 mRNA. In only one resistant prolactinoma (P8),
expressing very low levels of SSTR transcripts, was the expression of
SSTR2 mRNA slightly greater than that of SSTR5 transcripts. The mean
level of expression of SSTR1 transcripts in this series was 1296
± 669 pg/pg GAPDH, and it was present to varying degrees in all
tumors. In 4 prolactinomas (P1, P3, P6, and P10), regardless of whether
they were DA-resistant or -sensitive tumors, the expression of SSTR1
mRNA was equivalent to or greater than that of SSTR5 mRNA. Finally
(data not shown), the expression at very low levels (extremes, 11–52
pg/pg GAPDH) of SSTR3 and SSTR4 mRNAs was detected in a minority (3 of
10) of these tumors: P6, P10 for SSTR3 (ranging from 49–52 pg/pg
GAPDH) and P6, P7, and P10 for SSTR4 (ranging from 11–35 pg/pg GAPDH).
According to the individual profiles, represented in Fig. 1, when SSTR5
mRNA was the largely predominant subtype (P4, P5, and P7), the SSTR1
transcript was poorly expressed. Conversely, P1 and P3 macroadenomas
with high levels of SSTR1 mRNA presented with low levels of SSTR5 mRNA.
In this series, SSTR transcript expression was not different between
invasive and noninvasive tumors. The only exception (case P8) was a
highly aggressive tumor (leading after 2 successive interventions to
death). It was characterized by minimal SSTR transcript expression.
This pattern of dedifferentiation was not observed in the 2 other
DA-resistant adenomas.
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In all 10 prolactinoma cell cultures, the effects of SRIF14,
BIM-23268, BIM-23197, and octreotide were studied over an 8-h
incubation period. As shown in Table 3,
in all cultures, the native somatostatin SRIF14 produced a 52 ±
7% maximal inhibition of PRL release. A superimposable inhibitory
effect was also achieved by maximal concentrations of the SSTR5
preferential analog BIM-23268. In contrast, BIM-23197 inhibited PRL
release by 23 ± 5%. Interestingly, a 46 ± 2% inhibition
of PRL release with BIM 23197 occurred in cultures of tumors P4, P6,
and P8, which were the tumors expressing the highest levels of SSTR2
mRNA. In all cases, the octreotide-induced inhibition of PRL was weak
or nonsignificant (12 ± 3%). The degree of PRL inhibition by
SRIF14 and BIM-23268 and the level of SSTR5 mRNA were correlated
(P < 0.04 and P < 0.08,
respectively). No correlation between SSTR2 (or SSTR1) mRNA expression
and inhibition of PRL release was observed in the series. Thus, these
results support the observation of an inhibitory effect of the SSTR5
preferential agonist, which correlates with the expression of SSTR5
transcripts in prolactinomas.
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). The SSTR5 preferential compound
BIM-23268 was a more potent inhibitor of PRL suppression than the
SSTR2-preferring compound BIM-23197 in all instances. The
EC50 values for PRL suppression were 0.23 ± 0.19 and
0.44 ± 0.24 nmol/L, respectively, for the three DA-sensitive and
the three DA-resistant prolactinomas. In experiments with one tumor
(P9), a biphasic PRL response was observed as a 45% stimulation of PRL
release at lower concentrations of BIM-23268, followed by a 49%
inhibition of PRL release at higher concentrations. Finally, the SSTR2
preferential analog BIM-23197 was ineffective in suppressing PRL
secretion in four of six tumor cell cultures. In the two
BIM-23197-responsive tumors, one sensitive and one resistant (P4 and
P8), BIM-23197 also produced a dose-related suppression of PRL, but at
concentrations 50- to 100-fold higher than that required by
BIM-23268.
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In the same 10 tumors, classified as either sensitive (n = 7)
or resistant (n = 3) to dopaminergic drugs, we compared the
effects of maximal doses of quinagolide and SS agonists, either alone
or in combination, on inhibition of PRL release in vitro
(Fig. 3). In controls (medium alone), GH
release from the tumor cells was undetectable in 9 of 10 cases. In only
1 tumor (P6) did GH release (0.2 vs. 4 ng/8 h for PRL)
represent 5% of the hormone secretion. The mean maximal inhibitory
effects of dopaminergic and somatostatinergic agonists are presented
separately for the 7 DA-sensitive and the 3 DA-resistant tumors. In the
sensitive tumors, as expected, the DA agonist quinagolide induced a
75 ± 6% inhibition of PRL release. In comparison, a 54 ±
8% inhibition was achieved by SRIF14, SRIF28, and BIM-23268. In no
instance, even in the 3 tumors expressing the highest levels of SSTR2
mRNA, was any significant additive effect of BIM-23197 and BIM-23268
observed. In the 3 experiments performed with resistant prolactinomas,
as expected, the maximal inhibition of PRL release with quinagolide was
only 44 ± 4%. As previously observed in prolactinomas sensitive
to DA, a superimposable inhibition of PRL was achieved with the native
somatostatins and BIM-23268. Again, no additive inhibitory effects on
PRL inhibition occurred when BIM-23197 and BIM-23268 were combined in
the resistant tumor cell cultures.
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all tumors, quinagolide and BIM-23268 induced a dose-dependent
inhibition of PRL release. The mean maximal inhibition of PRL release
was obtained at 1 and 0.1 nmol/L, respectively, with BIM-23268 and
quinagolide. The mean dose-response curve elicited by BIM-23268
required higher concentrations of this analog compared to those of
quinagolide. In the three tumor cell cultures sensitive to quinagolide,
the EC50 was 0.03 ± 0.01 nmol/L with quinagolide
vs. 0.23 ± 0.23 nmol/L with BIM-23268. A
superimposable pattern was also obtained with quinagolide and BIM-23268
in the two resistant tumors studied. These data demonstrate a better
efficacy, achieved at lower concentrations, with the DA superagonist
quinagolide than with the SSTR5 agonist.
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To know whether the combination of the DA agonist quinagolide and
the SSTR5 preferential agonist BIM-23268 could produce a synergistic
effect on PRL inhibition, both drugs, alone and in combination, were
tested at various doses in one DA-sensitive and one DA-resistant
prolactinoma. In these experiments, the dose response to BIM-23268 was
determined in the presence of quinagolide at a concentration previously
determined to correspond to its EC50 for PRL suppression
(Fig. 5). The maximal inhibitory effects
on PRL release were 82% and 40% in cell cultures from the
DA-sensitive and DA-resistant adenomas, respectively. At 1–10 nmol/L
of either quinagolide or BIM-23268, no additivity could be demonstrated
by combining the two compounds. In the DA-sensitive adenoma, partial
additivity occurred at 10-11-10-9 mol/L
concentrations of BIM-23268 in combination with quinagolide at
10-12 mol/L. A similar slight additivity was also observed
in the resistant cell culture adenoma when the cells were cotreated
with quinagolide at 10-10 mol/L and BIM-23268 at
10-10 or 10-9 mol/L.
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Discussion |
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The dominant expression of SSTR5 in prolactinomas is in accord with the recent findings of Shimon et al. (11), who demonstrated the functional selectivity of SSTR5 agonists in prolactinomas. Our data clearly confirm the preferential efficacy of BIM-23268 on PRL inhibition. BIM-23268 has been shown in studies with membranes from transfected CHO-K1 cells expressing the different SSTR subtypes to have a binding affinity of 0.37 nmol/L (EC50) for SSTR5, 40-fold greater than that for SSTR2 (8). SSTR2 mRNA was weakly expressed in the majority of prolactinomas, in contrast to its constant expression in GH-secreting tumors (25). These data explain the inability of radiolabeled octreotide to visualize SRIF receptors in prolactinomas, as previously observed (17), as this agonist acts preferentially through the SSTR2 subtype. Similarly, in our cell culture studies, BIM-23197, which acts essentially through the SSTR2 subtype (27), was largely ineffective in suppressing PRL secretion.
The SSTR1 subtype was consistently found to be coexpressed with the SSTR5 subtype in all 10 prolactinomas studied. It was not correlated to either the level of PRL secreted in culture or the tumor mass evaluated by MRI (data not shown). The 2 cases that expressed the highest levels of SSTR1 mRNA (P6 and P10) were classified as either DA-sensitive or DA-resistant tumors, respectively. According to previous studies that used RT-PCR analysis, SSTR3 and SSTR4 mRNAs are poorly expressed or absent in prolactinomas. SSTR3 expression was only observed in 4 prolactinomas (20, 23), but was not found in 13 other tumors (21, 22). Similar weak expression of SSTR3 was observed in a third of our tumors. Finally, the tumoral pattern of SSTR5 and SSTR1 expression in prolactinomas diverges from the pattern of SSTR5 and SSTR2 mRNAs expressed in GH-secreting tumors (25). Such a difference can be interpreted either as a tumor-specific or a cell-specific phenotype. The cell-specific phenotypic interpretation is supported by recent data concerning the cell-specific localization of the SSTR subtypes in adult rat anterior pituitary cells (28, 29). Using double immunostaining with antibodies raised against the SSTR2–5 subtypes, they visualized both SSTR5 and SSTR2 receptors in the majority of GH cells, whereas in lactotrophs, SSTR5 labeling was largely dominant, and SST2A was found in only a few lactotrophs. Presently, we are lacking similar observations for the human adult pituitary. In one study (30) mRNA hybridization, receptor binding, and receptor immunocytochemistry methods were shown to be correlated. Consequently, it may suggest that our mRNA quantification correlates with expression of the SSTR subtypes at the cell membrane level. The correlation between SSTR5 mRNA levels and the effects of BIM-23268, on the one hand, and SSTR2 mRNA levels and the effects of BIM-23197, on the other hand, confirm that mRNA reflects the level of expression of their respective functional receptor subtypes. In contrast, we could not associate the presence of SSTR1 mRNA with any specific phenotype, questioning the functional significance of the presence of this mRNA.
Due to the absence of a clear suppressive effect of somatostatin infusion in most patients with hyperprolactinemia (31), little attention has been given to the in vitro suppression of PRL by SRIF or its analogs in prolactinoma cells. In 2 in vitro studies examining 10 prolactinomas, 10–100 nmol/L SRIF14 produced a maximal suppression of PRL secretion of 32% vs. the control value (32, 33). More recently, Hofland et al. (23) compared the inhibitory effects of the DA agonists (bromocriptine and/or quinagolide) vs. those of somatostatin and 3 octapeptide somatostatin analogs in 7 prolactinomas. They concluded that, overall, PRL release was consistently inhibited by the DA agonists, but was only partially suppressed by SRIF28 in four cultures. The PRL-suppressive effects of the somatostatin analogs octreotide, lanreotide, and RC-160 were modest if any. Interest in the somatostatinergic control of prolactinomas has been recently increased due to the work of Shimon et al. (11), who showed that only the SSTR5-selective analogs, such as BIM-23268, are effective in suppressing PRL secretion by prolactinoma cells. In only 4 tumors (obtained from men harboring invasive macroadenomas) did BIM-23268 inhibit PRL release by 30–40%, and it proved in 2 cases to be more effective than SRIF14. Our data confirm and extend these previous observations concerning the selective efficacy of BIM-23268 on PRL suppression. At maximal concentrations, this compound produced a 26–90% inhibition of PRL release depending on the tumor; however, it was never stronger than the suppression obtained with the native, endogenous somatostatins. In contrast to the earlier study (11), no stimulatory effect of the SSTR2 preferential analogs was observed when used at maximal concentrations. In addition, in those tumors expressing SSTR2 mRNA, a partial suppression of PRL secretion was observed with BIM-23197. In no instance was additive suppression of PRL shown by the combination of the SSTR5 and SSTR2 preferential agonists. These data support the concept that the SSTR5 subtype is the primary SSTR subtype controlling PRL secretion. The EC50 for PRL suppression by BIM-23268 was 0.28 ± 0.10 nmol/L. The rather large SE serves to emphasize the large spectrum of sensitivity of individual tumors to somatostatinergic regulation. Similar observations were previously made using DA agonists in prolactinoma cultures (33). A subclass of 5–18% patients is characterized as resistant to DA agonist therapy (34). Such resistance, often associated with continued tumor growth, results from deficient regulatory mechanisms of the adenomatous cells. The major abnormality is a dramatic decrease in the number of DA D2 receptors, explaining the only partial effect of DA agonists on adenylyl cyclase activity. In such tumors it was of interest to know whether the SSTR5 agonist would be effective when the DA superagonist quinagolide was not (35). In the 3 resistant prolactinomas studied, similar partial PRL suppression with both quinagolide and BIM-23268 argues against such a proposition. It is likely that, in these resistant tumor cells, a common defect lies beyond the receptors that prevent inhibition of adenylate cyclase activity or of other transducing mechanisms. Quinagolide was more effective at lower concentrations than BIM-23268 in suppressing PRL secretion (EC50 = 0.012 ± 0.009 nmol/L). Even cotreatment of the tumor cells with both compounds did not achieve, at least at maximal concentrations, a significant additive effect on PRL inhibition. Taken together, these findings indicate that in prolactinomas as well as in other tumors, such as breast or prostate neoplasms, drug or hormone resistance identifies a subset of tumors that has lost their differentiated, normal functions, i.e. in the case of prolactinomas, regulation of PRL secretion (32). Unless future tumor studies demonstrate that in some prolactinomas PRL regulation is preserved by SSTR5 agonists but is resistant to dopaminergic control, the usefulness of SSTR5-selective agonists in the treatment of such tumors seems of modest interest. At present, the neurosurgical approach remains the only palliative therapy for DA-resistant prolactinomas that undergo progressive tumor growth despite long term treatment with high doses of DA agonists.
Finally, if the dominant role of SSTR5 on PRL release is clearly established, we have yet to understand the significance of its association with SSTR1 expression in prolactinomas. This receptor seems unable to mediate inhibition of cAMP formation (5). The recent availability of SSTR1-specific analogs (9) will certainly provide information about possible cross-talk between SSTR1 and SSTR5 in prolactinoma cells and their respective involvement in the control of tumor growth through the regulation of mitogen-activated protein kinase pathways (36).
On the other hand, it was indeed mandatory to properly define the SSTR receptor phenotype of lactotroph cells to understand the roles of the different SSTR in GH-secreting adenomas, which present in at least 50% of cases with mixed GH-PRL cell populations. Work is in progress in our group concerning the functional expression of SSTR in such pituitary adenomas.
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Acknowledgments |
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Footnotes |
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Received March 12, 1999.
Revised May 19, 1999.
Accepted May 21, 1999.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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