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Pituitary Unit of the Department of Neurosurgery (M.L., P.M., R.B., M.G.), Department of Pathology (F.M., M.R.T.), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, University Vita-Salute, 20132 Milan, Italy; and Departments of Internal Medicine (E.C., D.G., F.C.) and Pathology (M.P.), Ospedale Molinette, University of Turin, and Department of Neurosurgery (G.F.), Centro Traumatologico Ortopedico, 10100 Turin, Italy
Address all correspondence and requests for reprints to: Marco Losa, M.D., Department of Neurosurgery, Istituto de Ricovero e Cura a Carattere Scientifico San Raffaele, Via Olgettina 60, 20132 Milan, Italy. E-mail: losa.marco{at}hsr.it
Abstract
To investigate the effects of octreotide administration on the growth rate of GH-secreting pituitary adenomas, we measured both the Ki-67 labeling index (LI) and the apoptotic index in tumor specimens from octreotide-treated or matched untreated acromegalic patients. Thirty-nine patients who received octreotide until the day of or the day before surgery and 39 untreated patients matched for sex, age, tumor size, extension, and invasiveness were studied. Immunocytochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick endlabeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. The Ki-67 LI and apoptosis were counted on separate slides in at least 1000 evaluable cells.
Octreotide-treated patients showed a lower Ki-67 LI (1.8 ± 0.3%) than untreated controls (3.8 ± 0.7%; P < 0.02). Overall, the mean Ki-67 LI of treated patients was 53% lower than that in untreated patients. The antiproliferative effect of octreotide occurred independently of tumor extension and invasiveness. Octreotide-treated and untreated patients showed similar apoptotic indexes (0.6 ± 0.2% and 0.8 ± 0.3%, respectively). There was a positive correlation between the Ki-67 LI and the apoptotic index (r = 0.29; P < 0.03).
Our study demonstrates that acromegalic patients receiving chronic octreotide treatment have a lower value of the proliferation marker Ki-67, but no significant difference in the apoptotic index compared with matched untreated patients. The antiproliferative effect of octreotide on GH-secreting adenomas should imply a lower risk of tumor growth during long-term chronic treatment with the drug.
SOMATOSTATIN PLAYS AN important role in the regulation of GH secretion in humans. The effect of somatostatin is mediated through high affinity, G protein-coupled membrane receptors that are expressed in all somatostatin-target organ systems. Five somatostatin receptor subtypes have been cloned and characterized (1, 2). The five somatostatin receptors have a tissue-specific distribution and the majority of responsive tissues express multiple somatostatin receptor subtypes (3). In contrast to native somatostatin, which binds to all five somatostatin receptors with high affinity, the long-acting somatostatin analogs, octreotide, lanreotide, and vapreotide, bind with high affinity to somatostatin receptor subtype 2, with lower affinity to subtypes 3 and 5, and have no affinity to subtypes 1 and 4 (4).
Octreotide was introduced in the medical treatment of active acromegaly about 15 yr ago and quickly gained widespread acceptance as a secondary as well as a primary therapy because of its efficacy and tolerability (5, 6). Octreotide not only inhibits GH secretion, but also reduces tumor size in 30–40% of acromegalic patients (7, 8, 9), although the degree of tumor shrinkage is only marginal in most cases. Studies reporting the morphological effects of chronic treatment with octreotide on GH-secreting adenomas have yielded conflicting results (10, 11, 12, 13, 14). Degenerative changes in treated tumors, such as capillary reduction, fibrosis, and necrosis, were noted by most researchers (10, 12, 13). However, the most striking observation was the marked heterogeneity of morphological changes (14), which might be explained by the well known different expression of functional somatostatin receptors among various GH-secreting adenomas and even within a single tumor (15).
The question of whether octreotide treatment exerts an antiproliferative effect on GH-secreting adenomas has not been thoroughly investigated. The rate of growth of the pituitary tumor depends on the balance between the proliferating cells and the loss of tumor cells by apoptosis (programmed cell death) and ischemic or hemorrhagic events (16, 17). Few studies investigated this issue in GH-secreting adenomas; octreotide-treated acromegalic patients showed a significant reduction of the Ki-67 labeling index (LI) compared with untreated patients (18, 19), whereas no difference in the apoptotic index was detected in similarly treated patients (20, 21). However, no study reported the results of both proliferation and apoptotic indexes in the same tumors.
With the aim to verify the existence of an antiproliferative effect of octreotide treatment in acromegalic patients, we compared the Ki-67 LI and apoptotic index of GH-secreting adenomas from patients treated with octreotide until surgery or from matched untreated patients.
Subjects and Methods
Patients
Eligible patients were all patients with active acromegaly operated on between 1990 and 1999 in one of the two participating centers [San Raffaele Milan, Italy and Centro Traumatologico Ortopedico (Turin)] who were receiving treatment with octreotide until the day of or the day before surgery. Minimal duration of octreotide therapy for inclusion into the study was 2 months at a daily dose of at least 0.2 mg, sc. Diagnosis of active acromegaly was based on the clinical picture, demonstration of GH hypersecretion (usually confirmed by the failure of serum GH to suppress below 2 µg/liter during an oral glucose tolerance test and elevated levels of IGF-I), and a pituitary tumor demonstrated on magnetic resonance imaging (MRI). Gonadal status in premenopausal women was defined according to menstrual status. Postmenopausal women were considered hypogonadal unless they were receiving E replacement therapy. Men were classified according to their basal T level. Pituitary tumor size was estimated by measuring the maximum anteroposterior, vertical, and horizontal diameters on MRI. A reduction of at least 20% of any tumor diameter on a posttreatment examination, if available, was considered significant.
Untreated patients were randomly selected from all of the other acromegalic patients operated on in the same period who had not received octreotide or other somatostatin analogs. Untreated patients were matched for age (within 10 yr), sex, tumor size (defined as micro- or macroadenoma), extrasellar extension of the tumor (yes or no), and invasion of the cavernous sinus on the preoperative MRI (yes or no). When more than one untreated patient matched a case patient, the one operated nearest to the case patient was selected for the study. Classification of tumor characteristics for octreotide-treated patients was based on the pretreatment MRI scan.
The following exclusion criteria were applied to both octreotide-treated and untreated patients: 1) previous pituitary surgery, 2) previous pituitary radiotherapy, and 3) clinical and histological diagnosis of pituitary apoplexy. Moreover, untreated patients were not eligible for the study if they had received treatment with octreotide or another somatostatin analog, even when therapy had been stopped months or years before pituitary surgery.
Histological analysis
Surgically removed specimens were immediately fixed in 10% buffered formalin and subsequently embedded in paraffin. Standard hematoxylin-eosin sections were used for diagnosis. Analysis of MIB-1 immunostaining and terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling (TUNEL; see below) was conducted on tumoral tissue from the same paraffin-embedded block used for immunocytochemical analysis.
MIB-1 immunostaining
Proliferation activity of the tumor was determined by calculating the percentage of cells exhibiting the Ki-67 antigen, a nuclear protein of unknown function expressed only in cycling cells (17). To this aim we used the monoclonal antibody MIB-1 (Immunotech, Marseilles, France), which reacts with an epitope encoded by a 1002-bp fragment of the Ki-67 cDNA (22). At variance with other methods, MIB-1 antibody is suitable for use in paraffin-fixed material. Technical details have been previously described (23). Briefly, MIB-1 immunostaining was performed on 4-µm sections mounted on glass slides treated with poly-L-lysine and dried until ready for use. Tissue sections were dewaxed, and endogenous peroxidase activity was blocked. Then, after antigen retrieval by microwave treatment (two passages at 850 watts of 5 min each), sections were incubated with nonimmune rabbit serum at room temperature for 20 min to block nonspecific links and then incubated at 37 C for 60 min with MIB-1 monoclonal antibody diluted 1:50 (Immunotech); no MIB-1 antibody was added to sections used as negative control samples. After rinsing, slides were incubated with rabbit biotinylated antimouse IgG (diluted 1:100) as secondary antibody for 30 min at room temperature and then exposed to streptavidin-biotin-peroxidase complex (Vector Laboratories, Inc., Burlingame, CA) for 30 min. After rinsing, sections were exposed in the dark for 5 min to the chromogen 3,3'-diaminobenzidine, which stains Ki-67-immunopositive nuclei with a dark brown color. Slides were lightly counterstained with hematoxylin, dehydrated, cleared, and mounted. Because MIB-1-positive cells may be unevenly distributed in biopsy samples, the Ki-67 LI was determined by counting a total of at least 1000 neoplastic nuclei subdivided in 10 randomly chosen fields at x400 magnification. Sections of human cecal appendix were used as positive control samples.
Determination of apoptosis
The TUNEL method was used after minor modifications, as previously described (23). Briefly, tissue sections of 4 µm were mounted on glass slides treated with poly-L-lisine, deparaffinized, hydrated, and treated for 10 min at 37 C with proteinase K (Roche, Mannheim, Germany; 20 µg/ml 10 mM Tris-HCl buffer, pH 7.4). Slides were rinsed twice with PBS. Then, 50 µl TUNEL reaction mixture (450 µl nucleotide mixture containing fluoresceinated deoxy-UTP in reaction buffer plus 50 µl enzyme terminal deoxynucleotidyl transferase from calf thymus) were added to samples. Slides were incubated in a humidified chamber for 60 min at 37 C. After rinsing, slides were incubated with antifluorescein antibody, Fab from sheep, conjugated to alkaline phosphatase for 30 min at room temperature (Roche). Then, on each slide, 50 µl substrate solution (blue tetrazolium) were added, and slides were incubated for 10 min at room temperature. Positive signal was defined as the presence of a distinct blue staining on nuclei of the neoplastic cells or on apoptotic bodies as morphologically defined. The apoptotic index was determined by counting a total of at least 1000 neoplastic nuclei subdivided into 10 randomly chosen fields at x400 magnification. Apoptotic cells were identified by TUNEL in conjunction with characteristic morphological changes, such as cell shrinkage, membrane blebbing, and chromatin condensation, to distinguish apoptotic cells and apoptotic bodies from necrotic cells. The latter were not considered apoptotic cells. Sections of human cecal appendix were used as positive controls.
All Ki-67 LI and apoptotic index determinations were performed by a single pathologist (F.M.), who was unaware of the clinical characteristics and treatment assignments of the patients.
Hormone assay
Serum GH levels were measured by commercially available immunofluorimetric assays (Tosoh, Tokio, Japan). Serum PRL levels were determined by a commercially available immunoenzymatic assay (Immuno 1, Bayer Corp., Divisione Diagnostici, Milan, Italy). Serum IGF-I was measured by a specific commercially available RIA after acid extraction (Bioclone, Marrickville, Australia).
Statistical analysis
All data are expressed as the mean ± SE.
Because the distributions of Ki-67 LI, apoptotic index, and GH levels
both at presentation and during octreotide treatment were markedly
skewed, we performed logarithmic transformation of the data; a value of
0% for apoptotic index was arbitrarily assigned to be 0.05%. However,
Ki-67 LI, apoptosis index, and GH levels are presented in the usual
decimal format in the text and figures. A t test for
unpaired or paired data, as appropriate, was used to compare continuous
variables among groups. Correlation between continuous variables was
calculated by the Spearman rank correlation coefficient method.
2 tabulation was used to compare binomial
proportions. A two-factor ANOVA was performed to evaluate the
interaction between selected tumor characteristics and treatment group
on the proliferation and apoptotic indexes. P < 0.05
was considered to indicate statistical significance. All calculations
were performed using the statistical package StatView 4.0 (Abacus
Concepts, Inc., Berkeley, CA).
Results
Patients’ characteristics
We analyzed the data from 78 acromegalic patients. All operations
were performed through the transsphenoidal approach. Clinical and
demographic characteristics of octreotide-treated and untreated
patients are summarized in Table 1
. As
expected, the two groups of patients, treated and untreated, were
similar with regard to sex distribution, mean age at surgery, tumor
size, tumor extension, and tumor invasiveness into the cavernous sinus.
Moreover, there were no significant differences between the two groups
in other characteristics that had not been used for matching, such as
year of surgery, mean basal GH and PRL levels at presentation, maximum
tumor diameter, history of previous dopaminergic therapy, and gonadal
status at surgery (Table 1). Dopamine agonist drugs were continued
until 3 months before surgery in eight patients (five
octreotide-treated and three untreated), whereas in the remaining six
patients dopaminergic treatment was stopped 3–36 months before
surgery. Exclusion of patients who received dopaminergic drugs within 3
months from surgery and their relative matches did not significantly
alter any results.
|
Ki-67 LI
The mean Ki-67 LI in both treated and untreated patients was
2.8 ± 0.4%, ranging from 0.1–18.8% (median, 1.6%).
Octreotide-treated patients showed a lower Ki-67 LI (1.8 ± 0.3%)
than untreated patients (3.8 ± 0.7%; P < 0.02;
Fig. 1). Overall, the mean Ki-67 LI of
treated patients was suppressed by 53% compared with that in untreated
patients.
|
), but there
was no significant interaction (F = 1.1; P =
0.30). Octreotide treatment and tumor invasiveness had an effect on
Ki-67 LI (F = 5.0; P < 0.03 and F = 5.4;
P < 0.03, respectively; Fig. 2), but again no
significant interaction was observed (F = 0.2; P =
0.70). These results indicate that the effects of octreotide on the
Ki-67 LI occurred independently of tumor extension and invasiveness.
Gonadal status at the time of surgery did not significantly affect the
Ki-67 LI values. Overall, the 44 hypogonadal patients had a Ki-67 LI
(2.8 ± 0.6%) similar to that of the 30 eugonadal patients
(2.9 ± 0.5%). A 2-way ANOVA did not detect any significant
interaction between octreotide treatment and gonadal status on the
Ki-67 LI.
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Apoptosis
Apoptosis could not be evaluated in 7 samples (4 from case patients and 3 from control patients) because of technical failure. In the following analyses we also excluded the respective matched untreated or octreotide-treated patients. Therefore, the data for apoptosis pertain to 32 pairs of patients.
The mean apoptotic index was 0.7 ± 0.2%, ranging from 0–8.7%
(median, 0.4%). Octreotide-treated and untreated patients showed
similar apoptotic indexes (0.6 ± 0.2% and 0.8 ± 0.3%,
respectively; Fig. 3). Sex, age, history
of previous dopaminergic therapy, year of surgery, extrasellar
extension of the tumor, preoperative GH level, and center did not
significantly affect the apoptotic index in the whole group of
patients. On the contrary, patients with tumor invading the cavernous
sinus had a higher apoptotic index (1.5 ± 0.6%) than patients
with noninvasive tumors (0.5 ± 0.1%; P < 0.05).
In the 32 pairs of evaluable patients, there was a positive correlation
between the Ki-67 LI and the apoptotic index (Spearman correlation
coefficient = 0.29; P < 0.03). Apoptotic index
was not influenced by the gonadal status (0.7 ± 0.2% in
hypogonadal patients vs. 0.9 ± 0.3% in eugonadal
patients). No significant interaction between octreotide treatment and
gonadal status on the apoptotic index was detected.
|
Discussion
Our study demonstrates that octreotide-treated patients have lower Ki-67 LI in the pituitary tumor than matched untreated patients, but no significant difference in the apoptotic index.
Besides the well known regulation of hormone secretion, somatostatin and its analogs exert an antiproliferative activity on various tumors and human cancer cell lines in vivo and in vitro (24, 25, 26, 27, 28). Upon activation of the somatostatin receptors, whose presence has been detected in endocrine and nonendocrine human cancer (27, 29), the antiproliferative effect of somatostatin has been ascribed to direct antagonism of epidermal growth factor action in pancreatic tumor cells (30) and to stimulation of a phosphotyrosine phosphatase activity that, in turn, inhibits tyrosine kinase activity in other cell types (31, 32).
In the GH3 rat pituitary tumor cell line, a
frequently used cell model of GH-secreting tumors, octreotide induces a
cytostatic block by inhibiting the entry of quiescent cells into the
pool of replicating cells (33). Using the same cell
system, another study demonstrated that octreotide prevented the
irreversible passage of cells into S phase of the cell cycle by
inhibiting either the expression of the early response gene
c-fos or DNA binding of the heterodimeric transcription
factor complex (34). Despite this experimental background,
the antiproliferative effect of somatostatin and its analogs on
GH-secreting adenomas has not been thoroughly investigated to date. In
an uncontrolled study, the Ki-67 LI of 16 octreotide-treated
acromegalics was half the value in 36 previously untreated patients
(18). However, it was not clear whether the 2 groups of
patients were comparable in terms of age, tumor size, tumor
invasiveness, and pretreatment GH value. Thapar and co-workers
(19) studied a subgroup of 32 acromegalic patients
included in a multicenter randomized controlled trial of presurgical
octreotide therapy. Octreotide treatment for 4 months before surgery
was associated with a mean Ki-67 LI that was 83% than that in surgical
controls, independently of the densely or sparsely granulated nature of
the tumors (19). Unfortunately, no information was
available regarding the other clinical and hormonal characteristics.
Our study confirms and extends these results. Despite the diverse
nature of the studies (Refs. 18 and 19 and
the present study), it is reassuring that the estimate of the
antiproliferative effect of octreotide was reasonably similar in all 3
series (50%, 83%, and 53%, respectively). We used very stringent
matching criteria to ensure that the 2 groups of patients differed only
in the variable of interest, namely the presence or absence of
octreotide pretreatment. The similarity of other characteristics, such
as history of dopaminergic therapy, maximum tumor diameter, gonadal
status at the time of surgery, and basal GH and PRL levels, which were
not used as matching criteria, confirms that the 2 groups of patients
were quite comparable. In the univariate analysis we found that tumor
extension, defined as intrasellar vs. extrasellar extending
tumors, and tumor invasiveness into the cavernous sinus affected the
Ki-67 LI. Our data show that the effect of octreotide pretreatment on
Ki-67 LI occurred independently of either tumor extension or
invasiveness. Together with the aforementioned effectiveness in both
densely and sparsely granulated tumors (19), these results
suggest that the antiproliferative effect of octreotide should occur in
most GH-secreting adenomas. The possible influences of gonadal status
on cell cycle characteristics are largely unknown. Our data, showing
similar Ki-67 LI values in hypogonadal and eugonadal subjects and no
interaction between gonadal status and octreotide treatment, suggest
that the antiproliferative effect of the drug in acromegaly is
virtually independent of patients’ gonadal status. The principal
potential bias of our study is the nonrandomized nature of octreotide
treatment, which was usually decided by the referring endocrinologist,
as well as the variability of the dose and the duration of medical
treatment before surgery. The lack of a significant association between
the Ki-67 LI and the total octreotide dose and duration of therapy
seems to exclude an important confounding effect of the latter
variables on our main results. The percentage of patients showing a
marked reduction (
50%) of GH levels during octreotide therapy in our
study (64%) is not much different from that in previous reports
(7, 35, 36), suggesting that our case patients should not
represent a particular subgroup of acromegalic patients. The
proliferation index was significantly lower in the group of patients
who reached an optimal level of GH suppression (basal GH, <2.5
µg/liter) during octreotide treatment compared with patients with
incomplete GH suppression, suggesting that the antiproliferative effect
of octreotide in GH-secreting adenomas is more evident when GH
secretion is almost completely suppressed. However, the relationship
between the antiproliferative and antisecretory activities of
octreotide is likely to be much more complex, as suggested by the lack
of a significant difference in Ki-67 LI when patients were classified
according to the criterion of a 50% reduction of GH levels. The time
interval from the pretreatment MRI scan and that during octreotide
therapy varied in our study population. Despite this possible caveat,
we identified a reduction of the maximum tumor diameter in 5 of 25
evaluable patients (20%), a percentage slightly lower than that
reported in other series (7, 8, 9). Interestingly, the Ki-67
LI was significantly lower in patients with shrinking adenoma compared
with that in patients with no modification of tumor size. However, the
low number of patients available for these analyses mandates caution in
interpreting the relationship between the responsiveness to octreotide
therapy and the antiproliferative effect of the drug.
The other possible mechanism by which octreotide might control the growth of GH-secreting adenomas is induction of apoptosis (16). It has been demonstrated in transfected CHO-K1 cells expressing the five known somatostatin receptors that octreotide in nanomolar concentrations can induce apoptosis by up-regulating p53 expression (37). However, only the somatostatin receptor subtype 3 seemed involved in signaling apoptosis (37). In another experimental model employing the murine ACTH-secreting adenoma cell line AtT-20, octreotide inhibited cell growth by inducing apoptosis during the G2 phase of the mitotic cycle (38). The increase in the apoptotic index was about 5-fold after an incubation period of 24 h with the drug (38). Interestingly, similar results were found in MCF-7 breast cancer cells treated in an analogous manner (39). High doses of lanreotide, another long-acting somatostatin analog, induced apoptosis in neuroendocrine gastrointestinal tumors, especially in those patients who showed a good clinical response to the drug (40). However, few data are available on the direct assessment of apoptosis in GH-secreting adenomas (20, 21, 41, 42). Our results, showing no significant difference in apoptotic index among octreotide-treated and untreated patients, are in keeping with data from other published reports (20, 21). In particular, Saitoh and co-workers (20) observed that the apoptotic index in 11 patients treated with 0.3 mg octreotide, sc, for 2–5 wk before surgery (0.40 ± 0.60%) was similar to that in 11 untreated patients (0.81 ± 0.79%). The absence of consistent morphological features among octreotide-treated tumors (10, 14) further supports the conclusion that the induction of apoptosis is not the principal mechanism by which the drug exerts its antiproliferative activity in GH-secreting adenomas. We did not find any significant association between the apoptotic index and several clinical characteristics of the patients. However, invasive tumors, in addition to a higher Ki-67 LI (see above), showed a higher apoptotic index than noninvasive tumors. It seems likely that the high apoptotic index of invasive adenomas is secondary to the increased proliferative activity of such tumors. This hypothesis is supported by the weak, but significant, correlation between apoptotic index and Ki-67 LI. Interestingly, a similar relationship between Ki-67 LI and apoptotic index was detected in a group of ACTH-secreting micro- and macroadenomas (23) and in malignant neoplasms at large (43, 44). It has been hypothesized that an increase in the proliferation activity within a cell population leads to exhaustion of factors that promote cell multiplication and inhibit apoptosis. Moreover, comparing normal and hyperplastic pituitaries, pituitary adenomas, and carcinomas, Kulig and co-workers (21) also detected a positive correlation between proliferative and apoptotic indexes, which seems to be a general rule in hormone-dependent epithelial tumors (45). GH and tumor responsiveness to octreotide, total dose, and duration of drug therapy did not affect the apoptotic index. However, we need caution in interpreting this result, as some of the associations were near the significance level. Because, as noted previously, different subtypes of somatostatin receptors may be involved in the regulation of the cell response, it is possible that somatostatin analogs with another binding profile, i.e. a higher affinity for somatostatin receptor subtype 3, will be shown to induce apoptosis in GH-secreting adenomas.
In conclusion, our study demonstrates that chronic octreotide administration has an antiproliferative effect on GH-secreting adenomas that is mainly mediated by a lower percentage of replicating cells, rather than stimulation of cell loss by apoptosis. From a clinical perspective, as treatment with somatostatin analogs needs to be lifelong to maintain adequate control of GH secretion, the antiproliferative effect of octreotide on GH-secreting adenomas, demonstrated in this and previous studies (18, 19), should reassure about the long-term control of tumor growth in treated patients.
Acknowledgments
We are grateful to Prof. A. Liuzzi, Istituto Auxologico Italiano (Verbania, Italy), and Dr. U. Pagotto, Max Planck Institute (Munich, Germany), for critical reading and discussion of the manuscript. We thank Dr. G. Calori, Medical Statistic Unit, Istituto de Ricovero e Cura a Carattere Scientifico San Raffaele, for statistical advice.
Footnotes
This work was performed in cooperation with the Study Group on Acromegaly of the Italian Society of Endocrinology and was partially supported by grants from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica, Rome, and an educational grant from Novartis Pharmaceuticals.
Abbreviations: LI, Labeling index; MRI, magnetic resonance imaging; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling.
Received January 22, 2001.
Accepted July 23, 2001.
References
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