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Institut National de la Santé et de la Recherche Médicale, Unité 369 (J.T., P.C., F.R., A.C., B.R.) and Laboratoire d’Histologie et Embryologie Moléculaires (J.T., P.C., C.R.), Faculté de Médecine Lyon RTH-Laennec, 69372 Lyon, France; and Département de Radiopharmacie et de Radioanalyse (R.C.), Hôpital Neurologique, 69003 Lyon, France; and Pharmacology Department, Medical School, Vrije Universiteit Brussel (E.L.H.-P.), B-1090 Brussels, Belgium
Address all correspondence and requests for reprints to: Prof. J. Trouillas, INSERM U369 Faculté de Médecine Lyon RTH-Laennec, rue Guillaume Paradin, F-69372 Lyon Cedex 08, France. E-mail: u369{at}laennec.univ-lyon1.fr
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Abstract |
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From plasma PRL and GH concentrations of rats bearing the tumors and tumor messenger RNA contents, tumors were classified as PRL (SMtTW2), somatotroph (SMtTW10), or somatomammotroph (SMtTW5) tumors. Two lineages (SMtTW3 and SMtTW4) represented variants producing PRL and GH but with a high predominance of PRL. With the exception of SMtTW4 tumors, which were malignant, all the tumors were benign and differed in their growth rate. Hormone production and growth of tumors with a PRL or a somatomammotroph phenotype were reduced by about 90% under BR treatment, whereas somatotroph tumors and the PRL malignant tumors were totally insensitive to BR. D2 receptor messenger RNA was present in all BR-sensitive tumors and was not detected in BR-resistant tumors.
In conclusion, using five lineages of SMtTW tumors that are representative of the most frequent tumors encountered in human pituitary pathology, we found a full concordance between tumor responses to BR and the expression of D2 receptor by the tumors. The identification of a tumor lineage with a malignant phenotype, secreting high amounts of PRL and presenting a resistance to BR, supports the idea that Da-resistant prolactinomas are aggressive tumors.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We developed an animal model of pituitary tumors: the spontaneous rat transplantable PRL tumors (SMtTW). Spontaneous PRL-secreting tumors of the aged female Wistar-Furth rat were propagated by serial transplantations under the kidney capsule of rats of the same strain. Two lineages, SMtTW1 and SMtTW2, were first characterized (9). Hormonal and immunocytochemical analyzes revealed that they were only secreting PRL. SMtTW2 tumors were responsive to Da agonists. Indeed, BR and quinagolide (CV 205–502) were capable of inducing either a shrinkage of the tumor or, at least, an inhibition of tumor growth and a normalization of plasma PRL concentration (10).
We present here the characteristics of five lineages of SMtTW tumors that differ in their GH/PRL secretion characteristics, growth rate, benignity, and sensitivity to the Da agonist, BR. In these rat pituitary transplantable tumors that seem very similar to the human pituitary adenomas, we have found a close relationship among D2 receptor expression, tumor growth inhibition by Da agonist, and PRL/somatotroph cell differentiation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The main characteristics of the strain and the procedure for the graft had been presented, in detail, in the initial description of the model (9). Briefly, each lineage was maintained by serial transplantations of tumor fragments under the kidney capsule. At each passage, the amount of grafted tumoral tissue was carefully controlled. Tumors, removed by sterile technique, were cut into small cube-shaped pieces of 2 mm, weighing about 5 mg. Fragments from a given tumor were grafted in 3 animals for the maintenance of the lineage and in up to 80 animals for the establishment of tumor growth curve or Da agonist treatment. The time interval between 2 passages varied from 3–10 months, depending on the growth rate of the tumors. In most cases, tumor passages were performed 6 months after graft. The size of the tumors was evaluated in vivo by palpation, by ultrasonography (10), or by measurements of plasma hormone concentrations (9, 10), knowing that there was a good relationship between plasma hormone levels and the size of the tumors.
Three lineages (SMtTW4, SMtTW5, and SMtTW10) were followed during 5, 7, and 5 passages. The oldest lineages (SMtTW2 and SMtTW3), established in 1984 and 1986, were studied during 16 and 13 passages, respectively. At the 12th passage, the growth rate of SMtTW3 tumors suddenly changed, and a sublineage (SMtTW3') has been individualized. The characteristics of each tumor lineage were established from more than 80 rats (SMtTW2 n = 380; SMtTW3 n = 226; SMtTW3' n = 10; SMtTW4 n = 95; SMtTW5 n = 82; SMtTW10 n = 90).
Tumor growth curves were generated from measurements of tumor weight obtained at the time of death of rats, from 3 months to 8–10 months after graft. PRL and GH measurements were performed every month and at the time of killing.
Animal treatments
The sensitivity of each tumor lineage to BR was studied at the
following passages; SMtTW2 = 4th passage,
SMtTW4 = 7th passage, SMtTW5 and
SMtTW10 = 5th passage. For SMtTW3 lineage, 2
experiments were performed at the 10th (SMtTW3) and 12th
passage (SMtTW3'). BR treatment was conducted as previously
reported (10). Four months after graft, tumor-bearing rats were divided
into 2 groups with the same spectrum of tumor size. One group (BR
group, n = 10) received daily sc injections of 2
bromo-
-ergocryptine (5 mg/kg·day) for 2 months. Ten animals served
as control (control group).
Immunoassay for hormones
Blood samples were taken by retroorbital puncture, under
ketamine anesthesia, during the experiment and by decapitation on the
day of death. Blood was collected on EDTA. Plasma PRL and GH
concentrations were measured by RIA with the reagents kindly provided
by the NIDDK. Concentrations of PRL and GH were expressed in terms of
the NIDDK standard reference preparations, rat PRL (rPRL) RP-2 or rGH
RP-2. For PRL, the intraassay variability was 12.6%, and the
interassay variability was 11.1%. For GH, the cross-reactivity with
PRL was 0.16%.
Processing of tumors for morphological and immunocytochemical
studies
Tumors were removed immediately after decapitation, separated
from kidney tissue, measured, washed, and weighed. For light
microscopy, tumor fragments were fixed in Bouin-Hollande solution,
embedded in Paraplast, and cut into 5-µm sections. Histological
observations were performed after staining with Masson trichrome,
Herlant tetrachrome, and PAS-Orange G.
Immunocytochemical studies were performed on paraffin sections by the indirect immunoperoxidase method using the avidin-biotin complex. The duration of exposure to the primary antisera was 12 h; dilutions of the antibodies varied from 1:500 to 1:5000. The following rabbit antisera were used: anti-hLH (prepared by B. Claustrat), anti-rPRL and anti-17–39ACTH (prepared by M. P. Dubois), anti-rPRL and anti-rGH (obtained from Dr. Parlow, NIDDK). The specificity of the immune reactions was assessed as previously described (9).
In situ hybridization
Nonradioactive in situ hybridization was performed on
tissues embedded in Tissue-Teck, frozen, and stored at -80 C. Frozen
sections (8 µm) were cut at -20 C and mounted on
3-aminopropyltriethoxysilane 2% in acetone. They were fixed in
paraformaldehyde 4% in PBS, pH 7.4, for 20 min at room temperature,
then transferred to PBS and deshydrated in a graded series of ethanol
solutions (30%, 50%, 70%).
Two oligonucleotide probes were used: a 28-mer probe, 5' dCTC AAT CTC TTT ggC TCT TgA TAT gAT A-3', complementary to the region of PRL messenger RNA (mRNA) encoding aminoacids (110–118) of rPRL; and a 21-mer probe, 5' dATC gCT gCg CAT gTT gCC gTC-3', complementary to the region of GH mRNA encoding aminoacids (145–151) of rGH.
The oligonucleotides were labeled at the 3' end with digoxigenin-11-2',3'-dideoxy-uridine-5'-triphosphate (digoxigenin-11-ddUTP) (1 nmol/µl) using terminal deoxynucleotidylexotransferase TdT (Boehringer Mannheim, Mannheim, Germany). The labeling mixture (40 µl) contained 25 mM Tris-HCl (pH 6.6), 200 mM potassium cacodylate, 0.25 mg/ml BSA, 7.5 mM CoCl2, 1 nM digoxigenin-11-ddUTP, 25 U TdT, and 20 pM oligonucleotide. After a 2-h incubation at 37 C, the labeled oligonucleotide was separated from the unreacted compounds by precipitation in ethanol (2 vol) 3 M sodium acetate, pH 5.2 (0.1 vol). The final precipitate was resuspended in 40 µl sterile water.
Sections were placed in the prehybridization buffer, consisting of 50% deionized formamide in 4 x SSC (1 x SSC = 0.15 M sodium chloride, 0.015 M sodium citrate, pH 7) for 2 h at 37 C. From 50–100 µl hybridization buffer (depending on the size of the section), containing 0.5 ng/µl labeled rPRL or rGH probe, were applied to the section. Hybridization buffer consisted of 50% deionized formamide, 4 x SSC, 10% Dextran sulfate, 1 x Denhardt’s solution (0.02% Ficoll, 0.02% polyvinylpyrrolidone, 0.02% BSA), and 0.5 mg/ml denatured salmon sperm DNA. Hybridization was carried out overnight at 37 C for rPRL probe or 42 C for rGH probe, under coverslips sealed with rubber cement. After hybridization, sections were washed as follows: 2 h in 2 x SSC at room temperature, 30 min in 2 x SSC at 37 C or 42 C, 30 min in 1 x SSC at 37 C or 42 C. Bound oligonucleotides were detected using alkaline phosphatase conjugated to sheep antidigoxigenin antibodies (Boehringer Mannheim) at 1:500 dilution in 1% normal sheep serum containing 100 mM Tris-HCl, 160 mM NaCl, pH 7.5. After an overnight incubation at 4 C, the sections were treated for 2–4 h with 4-nitroblue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate as substrate in 100 mM Tris-HCl, 100 mM NaCl, 50 mM MgCl2, pH 9.5. The specificity of the reaction was checked by: 1) incubation in the absence of probe; 2) treatment of sections with ribonuclease before hybridization; and 3) preincubation with an excess of unlabeled probe (5 ng/µl). All controls were negative.
Preparation of D2 receptor complementary DNA (cDNA)
The probe used for the detection of rat D2 receptor
mRNA was a cDNA fragment obtained by RT-PCR from total RNA extracted
from normal rat pituitary. The following primers were used to amplify a
rat 396-bp D2 receptor cDNA fragment. The sense primer 5'
TTCAgA gCC AAC ATg AAg ACA CCA 3' begins at position 840 in the rat
D2 receptor mRNA, and the antisense primer 5' gCT TTC TgC
ggC TCA TCg TCT TAA 3' begins at position 1213 in rat D2
receptor mRNA sequence. One microgram of total RNA was reverse
transcribed in 20 µl of 10 mM Tris-HCl (pH 8.3), 90
mM KCl, 1 mM deoxynucleotide triphosphate, 30
pM primer antisense, 20 U ribonuclease inhibitor, 1.5
mM MgCl2, and 200 U of Moloney murine leukemia
virus reverse transcriptase (Promega Corp., Madison,
WI). The reaction was carried out at 42 C for 2 h and
stopped by boiling.
The cDNA fragment was amplified with Taq DNA polymerase (Promega Corp.) in 100 µl of the following mixture: 50 mM KCl, 10 mM Tris-HCl (pH 9), 0.1% Triton X-100, 30 pM primers, 1.5 mM MgCl2, 1.5 mM deoxynucleotide triphosphate, and Taq DNA polymerase (5 U). The cDNA fragment was amplified for 35 cycles: 94 C, 1 min; 58 C, 1 min; 72 C, 1 min. An aliquot of the PCR reaction was submitted to electrophoresis in a 2.5% agarose gel in 0.089 M Tris-borate, 0.089 M boric acid, 0.002 M EDTA. The product was visualized by ethidium bromide (5 mg/ml) staining. To verify its identity, the PCR product was digested with 10 U SacI (Boehringer Mannheim) that produced the expected fragments of 134 and 262 bp.
Northern blot and slot blot analyzes
Total RNA was isolated from tumors by extraction in 4
M guanidinium isothiocyanate, according to Chirgwin
et al. (11). Total RNA (10 µg for PRL and GH mRNAs and 40
µg for D2 receptor mRNA) was denatured at 65 C in 2.2
M formaldehyde; fractionated by electrophoresis on 1%
agarose, 2.2 M formaldehyde gel; and transferred onto a
nylon membrane that was prehybridized, then hybridized at 42 C
overnight with 32P-labeled cDNA probes in hybridizing
buffer containing 50% deionized formamide, 5 x SSC, 5% dextran
sulfate, 0.5% SDS, 1 x Denhart’s solution, and 150 µg/ml
denatured salmon sperm DNA.
The membrane was washed in 2 x SSC for 20 min at room temperature, 2 x SSC-0.5% SDS for 45 min at 65 C, and 0.2 x SSC-0.5% SDS for 45 min at 65 C and was autoradiographed using Kodak X-Omat LS films (Eastman Kodak Co., Rochester, NY) for 12 h to 7 days.
Quantification of mRNAs was performed using slot blots, according to White and Bancroft (12). After RNA absorption on nylon membrane, hybridization steps were carried out as described above. Autoradiogram signals were quantified using a CCD video camera (Sony AVC-D5CE from Sony, Tokyo, Japan) coupled to an image analyzer (Crystal Sapphire from Quantel, Montigny le Bretonneux, France). Results were expressed in arbitrary units or in percent of the value obtained in SMtTW2 tumors for PRL, or SMtTW10 tumors for GH. After dehybridization, slot blots were hybridized with a 32P-labeled glyceraldehyde-3-phosphate-dehydrogenase cDNA to control RNA loading and to normalize the results.
The rat GH and PRL cDNA probes were those previously described (13). D2 receptor mRNA was detected using the 396-bp cDNA fragment described above. CDNA fragments were labeled using the random primed DNA labeling kit from Boehringer Mannheim. The specific radioactivity was about 109 cpm/µg DNA. The specificity of detection of GH, PRL, and D2 receptor mRNAs was controlled by Northern blot using total RNA extracted from normal rat pituitaries and rat liver as positive and negative controls, respectively.
Expression of results
All data are given as the mean ± SEM; the
number (n) of rats, tumor samples, or sera used in each experiment is
indicated in the legends of the figures or the table. Statistical
analyzes were performed using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The variability in
the growth rate of the SMtTW5 tumors was such that it was
difficult to get a representative curve. SMtTW2 tumors
exhibited a lower growth rate than the other tumors (Fig. 1A). In the
case of the SMtTW3 lineage, the rate of tumor growth was
elevated during the first 11 passages. At the 12th passage, it became
much lower; and it was named SMtTW3' from that point on
(Fig. 1B). SMtTW10 tumors were characterized by a rapid
initial growth rate, followed by a stabilization of the size of the
tumors between the 5th and the 9th month (Fig. 1C). It must be noticed
that, whatever the lineage, tumors began to grow after a lag period of
3–4 months after the graft.
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GH and PRL secretion. Six to eight months after graft, the
mean plasma levels of PRL and GH of tumor-bearing rats markedly
differed from one lineage to another (Table 1). In rats with SMtTW2
tumors, only plasma PRL concentration was increased; the mean plasma GH
concentration was not significantly different from that of control
rats. In contrast, plasma GH concentration of SMtTW10
tumor-grafted rats was very high (25,000-fold higher than normal
values), and the mean plasma PRL concentration was only slightly
elevated. In rats bearing either SMtTW3,
SMtTW4, or SMtTW5 tumors, plasma PRL
concentration was extremely high, whereas plasma GH concentration was
increased from 3- to approximately 60-fold. The mean PRL levels varied
from 13,000–144,000 ng/ml, i.e.
103–104 times the concentration in normal
Wistar/Furth female rats (15 ± 1.7 ng/ml). Plasma PRL
concentration of rats bearing SMtTW3' tumors
(i.e. SMtTW3 after the eleventh passage) was 10-
to 20-fold lower than that of rats bearing SMtTW3 tumors;
this difference was related to the difference in the size of
tumors.
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, confirmed that SMtTW2 tumors secreted only PRL and that
SMtTW10 tumors preferentially secreted GH. After a delay of
4 months, PRL secretion by SMtTW2 tumors increased
progressively, whereas the GH secretion by SMtTW10 tumors
increased abruptly and then plateaued. These changes in plasma hormone
concentrations correlated with the changes in tumor growth reported in
Fig. 1
, A and C.
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, a and c), except in
SMtTW10 tumors, where only few cells were positive (Fig. 3e). In contrast, GH-positive cells were only found in
SMtTW10 tumors; the intensity of the immunostaining and the
percentage of GH-positive cells varied from one tumor to another and
from one area to another, with a maximum of 80% of cells being
positive for GH (Fig. 3f). In all SMtTW tumors, the reaction with the
other antibodies was negative.
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, for SMtTW2 tumors. GH-positive cells were numerous
in SMtTW10 and SMtTW5 tumors (Fig. 3d). No GH
mRNA was detected in SMtTW2, SMtTW3, and
SMtTW4 tumors. Interestingly, in SMtTW5 tumors,
up to 90% of cells were found to contain both PRL (Fig. 3c) and GH
mRNAs (Fig. 3d). This finding indicates the presence of a high
proportion of double-secreting cells in the latter tumors. Results of
densitometric measurements of PRL and GH mRNA contents of the five
tumor lineages are reported in Fig. 4.
PRL mRNA content was high in SMtTW3 and SMtTW4
tumors and very low in SMtTW10. In contrast, GH mRNA
content was high in SMtTW10 tumors and very low in
SMtTW2, SMtTW3, and SMtTW4.
SMtTW5 tumors contained comparable amounts of both GH and
PRL mRNAs.
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). In
contrast, plasma PRL concentration was not altered by 2 months of BR
treatment of rats bearing SMtTW4 tumors (14,800 ±
5,800 ng/ml vs. 15,600 ± 9,100 ng/ml) or
SMtTW10 tumors (71 ± 40 ng/ml vs. 281
± 130 ng/ml). In SMtTW3-bearing rats, the situation was
more complex (Fig. 6). A decrease of
98% of plasma PRL was observed after 1 month of treatment. But, plasma
PRL levels increased during the second month of treatment. In
SMtTW3'-bearing rats that differ from
SMtTW3-bearing rats by a lower plasma PRL concentration
(330 ng/ml vs. 8,500 ng/ml), 1 month of BR treatment
also induced a 98% decrease of plasma PRL; but, during the second
month of treatment, plasma PRL concentration continued to decrease, to
reach normal values. BR treatment induced a decrease of 77% and 94%
in plasma GH levels in SMtTW3- and
SMtTW5-bearing rats, respectively (Fig. 5B). Plasma GH
concentration of rats with SMtTW4 and SMtTW10
tumors was not affected by the treatment.
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). BR treatment
induced a major inhibition of growth of SMtTW2,
SMtTW3, and SMtTW5 tumors but did not cause
their complete disappearance. The percent decrease of tumor weight
ranged from 86–92%, compared with matched controls
(SMtTW2, 0.44 ± 0.07 mg vs. 5.3 ±
0.8 mg; SMtTW3, 4.05 ± 0.53 mg vs.
26.8 ± 4.4 mg; SMtTW5, 2.1 ± 1.3 mg
vs. 17.7 ± 3.7 mg). In contrast, the mean weight of
SMtTW4 and SMtTW10 tumors was not modified by
the 2 months of BR treatment.
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) revealed that
D2 receptor mRNA tumor content was very high in the tumors
secreting exclusively or predominantly PRL (SMtTW2 and
SMtTW3) and was significantly lower in SMtTW5
somatomammotroph tumors. It is worth noticing that SMtTW2
and SMtTW3 tumors that exhibited different growth rates did
not differ in their D2 receptor mRNA content. Considering
either the five tumor lineages as a whole or only the D2
receptor-positive tumor lineages, there was no relationship between
D2 receptor mRNA tumor content and tumor weight.
D2 receptor transcripts could neither be detected in
malignant prolactinomas (SMtTW4) nor in somatotroph
SMtTW10 tumors. Data of Fig. 7 illustrate the relationship
between the action of BR on tumor growth and the D2
receptor mRNA content of the tumors from the five lineages. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The responsiveness of the tumors to BR treatment seems to be linked to their differentiation characteristics, with one exception (i.e. SMtTW4 tumors that presented a malignant phenotype). Tumors exhibiting a predominant PRL phenotype or a somatomammotroph phenotype were very sensitive to BR, whereas tumors with a somatotroph differentiation were completely resistant. Indeed, BR had no effect on the growth of SMtTW10 tumors and did not modify their hormone production and secretion activities. BR treatment remarkably reduced the development of prolactinomas (SMtTW2 and SMtTW3) and somatomammotroph adenomas (SMtTW5). In both cases, the tumor mass obtained at the end of treatment represented about 10% of the mass of the tumors that developed in untreated animals. Accordingly, hormone production by the BR-treated tumors (and thus, plasma hormone concentrations) remained at a level varying from 6% to less than 1% of the level reached in untreated tumor-bearing rats. It is worth noticing that the production of GH by either SMtTW3 tumors producing high amounts of PRL and small amounts of GH (the average PRL/GH plasma concentration ratio reaching values 1000-fold higher than the normal value) or by SMtTW5 tumors producing PRL and GH in more similar amounts (PRL/GH plasma concentration ratio being about 10-fold higher than in normal rats) was also reduced by the BR treatment. Taken together with immunocytochemical data, the latter observation suggests that, in SMtTW5 tumors, a majority of cells were capable of synthesizing both PRL and GH. These cells are expected to possess D2 receptors mediating the action of BR. In the case of SMtTW3 tumors, two possibilities might be considered: either GH is synthesized by PRL-producing cells sensitive to BR, or tumors contain a few cells with a somatotroph differentiation that express D2 receptors. The parallel reduction of PRL and GH secretion by SMtTW3 and SMtTW5 tumors, in response to BR, is reminiscent of the action of BR in acromegalic patients, where a decrease of GH under BR treatment is more commonly observed in mixed GH/PRL tumors than in pure GH adenomas (7).
A full concordance between the tumor responsiveness to BR treatment and the level of expression of D2 receptor (as assessed at the mRNA level) was found for all the tumor lineages. Quantitative analyzes of D2 receptor mRNA included that of the two mRNA isoforms, because slot blots were carried out using a cDNA probe corresponding to a region common to the D2L and D2S (14, 15, 16). These two isoforms are coupled to adenylate cyclase via inhibitory G proteins (17). Prolactinomas and somatomammotroph tumors, highly responsive to BR, exhibited a high D2 receptor mRNA content. The level of D2 receptor mRNA in these tumors was much higher than that found in normal pituitary glands, in which D2 receptor transcripts could only be detected using polyA-enriched RNA (data not shown). In contrast, in somatotroph adenomas (SMtTW10 tumors) and in the SMtTW4 carcinomas (with a highly preferential PRL secretory activity), no D2 receptor transcript could be detected. The lack of D2 receptor expression in SMtTW4 tumors might be directly or indirectly linked to the malignant phenotype of these tumors. All human PRL carcinomas so far reported, except one, were resistant to BR.
The D2 receptor expression pattern in SMtTW tumors seems very similar to that found in human pituitary tumors. Indeed, it is well known, since 1980, that D2 receptors are present in most human prolactinomas and that their concentration varies from one prolactinoma to another (18). However, in humans, it is difficult to study the relationship between sensitivity to Da agonists and D2 receptor expression. Indeed, a tumor which is sensitive and regresses under treatment is not subjected to surgery. In contrast, the resistant tumors are removed if necessary, but these cases are so sparse that it is difficult to get large series. Da agonist-resistant prolactinomas are supposed to represent the most severe cases of the disease (19, 20). Recently, we have shown that BR-resistant tumors were significantly more frequent (30 vs. 5%) in men than in women and that all of them were invasive or recurrent (20). Resistance to Da agonists has been correlated to a decrease of D2 binding sites (2) or to a decrease of D2 receptor expression (21). A search for mutation in the D2 receptor gene as a cause of resistance to Da, in a total of 76 prolactinomas or somatoprolactinic adenomas, was negative (22). Secondary resistance to BR is often encountered in human pituitary tumors. The SMtTW3 tumor lineage, characterized by a rapid growth, could be representative of this situation, because a partial escape to BR action was observed during the second month of treatment. The sublineage SMtTW3' exhibiting a slower growth rate retained its sensitivity to BR. With our rat pituitary tumor models, we demonstrate a clear relationship between the action of BR on tumor growth and PRL secretion and the presence of D2 receptor mRNA. However, no relation could be found between D2 receptor expression and either the weight or the growth rate of tumors. The identification of a tumor lineage with a malignant phenotype secreting high amounts of PRL and characterized by a resistance to BR, associated with a lack of D2 receptor expression, supports the idea that Da agonist-resistant prolactinomas are aggressive tumors.
The five lineages of SMtTW tumors, reported here, present important molecular and functional features of the normal pituitary, and they constitute a good panel of the tumors encountered in human pituitary pathology. On one hand, SMtTW tumors are known to express membrane receptors not only for Da but also for pituitary adenylate cyclase-activating polypeptide (23), somatostatin, TRH, and angiotensin II (unpublished data). On the other hand, these tumor lineages have morphological and secretory characteristics similar to those of the most frequent human pituitary tumors, i.e. prolactinomas and somatotroph and somatoprolactinic adenomas (reviewed in Ref. 24).
The different lineages of SMtTW tumors may serve as experimental systems to document the effects of new drugs acting on the growth and/or secretion of human pituitary adenomas. They could also be considered as privileged models for studies aiming at the discovery of factors responsible for the alterations of PRL and/or GH cell proliferation. SMtTW tumor lineages that were established from spontaneous primary rat pituitary tumors do not give information on pathogenesis of pituitary tumors, but they may be used to analyze the relevancy of new histological or biological markers to distinguish adenomas from carcinomas or to provide parameters of tumor evolution. Indeed, there is a lack of pituitary tumor markers, and the diagnosis of pituitary carcinoma is based only on the presence of metastases. SMtTW tumors exhibiting a benign or a malignant phenotype may be very useful in finding criteria of malignancy or prognostic factors.
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Acknowledgments |
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Footnotes |
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Received May 22, 1998.
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) and GH (
)
concentrations, as a function of time after graft. A,
SMtTW2 lineage; B, SMtTW10 lineage.
Symbols and vertical bars represent the
mean ± SEM of hormone concentrations measured on
3–12 rats at different passages (SMtTW2, 2nd–16th
passages; SMtTW10, 2nd–5th passages).
