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Original Studies |
Departments of Internal Medicine III (D.F., M.P.v.H., P.M.v.K., D.M.M., E.G.R.L.-K., S.W.J.L., L.J.H.), Immunology (M.P.v.H.), and Nuclear Medicine (D.J.K.), Erasmus University, 3015 AD Rotterdam, The Netherlands; Department of Integrative Biology and Pharmacology, University of Texas (A.S.), Houston, Texas 77225; and Department of Molecular and Clinical Endocrinology and Oncology, Federico II University (D.F., A.C.), 80131 Naples, Italy
Address all correspondence and requests for reprints to: Dr. Leo J. Hofland, Department of Internal Medicine III, Room Bd 277, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: hofland{at}inw3.azr.nl
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Abstract |
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A high uptake of [111In-DTPA-D-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of [125I-Tyr11]SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 ± 2.5 pmol/L) with low maximum binding capacity (23.5 ± 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited [3H]thymidine incorporation by 40.6% and 43.2%, respectively.
The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a role in determining the uptake of [111In-DTPA-D-Phe1]octreotide by in vivo SS receptor scintigraphy.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The biological effects of SS, including the inhibition of hormone and exocrine secretion as well as the modulation of neurotransmission and cell proliferation, are mediated through five different G protein-coupled, high affinity, membrane receptor subtypes (sst1–5) (5, 6). SS receptors (SSR) have been demonstrated in normal tissues and in many tumors at the protein and messenger ribonucleic acid (mRNA) levels by receptor binding studies on tissue homogenates, by in vivo and in vitro SSR autoradiography, by in situ hybridization, as well as by RT-PCR (7, 8). Furthermore, SSR subtypes have been localized at the cellular level by immunohistochemistry using a specific antipeptide antibody in a series of human tumors and in normal human pancreas as well (9, 10, 11, 12, 13). Localization studies of SSR on specific cell types within SSR-positive tissues demonstrated heterogeneity of receptor distribution (14).
Octreotide, an octapeptide SS analog, binds with high affinity to sst2 and with a relatively lower affinity to sst3 and sst5 (15). Imaging techniques with [111In-DTPA-D-Phe1]octreotide have visualized SSR in various human neoplasms in vivo. In many cases, a positive scan predicts a good response to treatment with octreotide (16, 17).
We have recently characterized the SS and SSR subtype distribution pattern within the normal human thymus (18). SS and sst1, sst2A, and sst3 mRNAs were found in thymic tissue, whereas enriched cultured TEC selectively express sst1 and sst2A as well as SS mRNA (18). Moreover, successful treatments with octreotide have been reported in two patients with thymoma (19, 20). To unravel the functional significance of SSR in human thymomas, we investigated in the present study the expression and functional role of SS and SSR subtypes in a cortical thymoma. In vivo SSR scintigraphy was performed in a patient admitted for myasthenia gravis. SSR expression on the tumor tissue was investigated using in vitro SSR binding studies, RT-PCR, and immunohistochemistry. Moreover, the effects of SS and octreotide on cell proliferation were evaluated in a primary cell culture of the thymoma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Scintigraphy with
[111In-DTPA-D-Phe1]octreotide
was performed as previously reported (21). Briefly, planar and single
photon emission tomography (SPECT) images of the chest were obtained
24 h after the injection of 228 megabecquerels
[111In-DTPA-D-Phe1]octreotide
(Mallinkrodt, Inc., Petten, The Netherlands). Imaging
studies were performed using a two-headed 
-camera (Picker 2000,
Picker Instruments, Cleveland, OH) for planar imaging and a
three-headed -camera (Picker 3000) for SPECT studies, both equipped
with a medium energy collimator. Acquisition time for planar spot
images was 15 min.
Samples
The thymoma was surgically removed from a female patient (age, 55 yr). Samples from this tumor and from three normal thymuses (from children undergoing cardiac surgery) were used in the present study. The protocol was in accordance with the Helsinki Doctrine on Human Experimentation. Informed consent was obtained from the patients or their parents. Samples were taken directly at the operation, quickly frozen on dry ice, and stored at -80 C for autoradiographic and RT-PCR studies or fixed in 10% paraformaldehyde overnight for immunohistochemistry. An additional specimen of the tumor was used for the establishment of a primary culture.
SS receptor autoradiography and RT-PCR
Receptor autoradiography was carried out on 10-micrometer thick
cryostat sections using
[125I-Tyr11]SS-14 and
[125I-Tyr3]octreotide as
radioligands (SA, 
2000 Ci/mmol) as previously described (18). RT-PCR
was performed as previously reported (18). The sizes of PCR products
were 318, 332, 651, 221, 323, 223, 349, and 762 bp, for
sst1, sst2A,
sst2B, sst3,
sst4, sst5, SS, and
ß-actin, respectively.
SS receptor binding studies
The method of membrane isolation and the reaction conditions were described previously (18). [125I-Tyr11]SS-14 and [125I-Tyr3]octreotide were used as radioligands.
Immunohistochemical localization of sst1, sst2A, and sst3 receptors
Paraffin-embedded sections (5 µm) were deparaffinized, rehydrated, exposed to microwave heating (in citric acid buffer) at 100 C for 15 min, rinsed in tap water followed by phosphate buffer solution, and subsequently incubated for 15 min in normal goat serum (1:10 dilution in phosphate buffer solution and 5% BSA). The sections were then incubated overnight at 4 C with the sst1 (R1–201) and sst2A (R2–88) antibodies (gifts from Dr. A. Schönbrunn) (22, 23) in a dilution of 1:500 (12) and with the sst3 antibodies (Biotrend, Cologne, Germany) in a dilution of 1:3000. Finally, a standard streptavidin-biotinylated alkaline phosphatase or peroxidase complex (ABC kit, Biogenix, San Ramon, CA) was used according to the manufacturer’s recommendations to visualize the bound antibodies. Negative controls for immunohistochemistry included 1) omission of the primary antibody, and 2) preabsorption of the antibodies with the respective immunizing receptor peptides (at a concentration of 100 nmol/L).
Cell dispersion and cell culture
Normal and neoplastic TEC were isolated as previously described (18). Briefly, the thymoma tissue was enzymatically dissociated with collagenase (Sigma, St. Louis, MO; 2 mg/mL) for 1 h at 37 C. The dispersed cells were precultured for 5–7 days in 15 mg/cm2 collagen type I (Collagen S, type I, Roche Molecular Biochemicals, Mannheim, Germany)-precoated 75-cm2 flasks (Costar, Cambridge, MA) at a density of 5 x 106 cells/flask in 10 mL culture medium. The culture medium, the same as that used during the experiments, was MEM D-valine (Life Technologies, Inc., Paisley, Scotland) supplemented with 10% FCS, penicillin (105 U/L), fungizone (0.5 mg/mL), and L-glutamine (2 mmol/L). The pH of the medium was adjusted to 7.4. The cells were cultured at 37 C in a humid CO2 incubator. After this period, cell viability detected by trypan blue exclusion was 90%, and the cells that had not attached to the flasks, mainly thymocytes, were harvested.
The isolation of epithelial cells was indirectly performed using sheep antimouse IgG-coated magnetic beads and an ASO2 antihuman fibroblast primary antibody kit (Dianova GmbH, Hamburg, Germany). This mouse monoclonal antibody reacts specifically with membrane-bound protein of human fibroblasts of different origins. The magnetic beads were coated with the specific primary antibody and mixed with the target cell suspension to form bead-rosetted cells (fibroblasts), which were collected at the tube wall and isolated using a magnetic separator rack. For a complete negative selection, the supernatant, containing the epithelial cells that were not bound to the beads was treated once again with the coated beads. This remaining suspension containing isolated epithelial cells was used for the experiments. The cells (20,000/well) were seeded in 1 mL culture medium in 24-well collagen type I-precoated plates (Costar) and allowed to attach for 24 h. Thereafter, test substances were added, and the cells were incubated for 72 h. Cell proliferation was measured by adding 1 µCi [methyl-3H]thymidine (91 Ci/mmol; Amersham Pharmacia Biotech, Houten, The Netherlands)/well during the last 24 h, as described in detail previously (18). For RT-PCR studies, neoplastic TEC were seeded in collagen-coated flasks (see above) and grown to confluence. Thereafter, the cells were harvested, and mRNA was isolated as described previously (18). For keratin staining, cells were cultured on collagen-coated glass coverslips. The cells were fixed for 10 min with methanol at the end of the incubation period. Cytokeratin staining was performed with a PAP Kit System (code K518, DAKO Corp., Glostrup, Denmark). Cultured thymocytes were collected and processed for mRNA analysis by RT-PCR as previously described (18).
Test substances
SS-14 (Bachem, Hannover, Germany) and octreotide (Novartis, Basel, Switzerland) were used at a concentration of 10 nmol/L.
Statistical analysis
Data are expressed as the mean ± SEM. Binding experiments were performed at least twice, and the data shown for the displacement study are derived from triplicate values. In functional studies, there were four wells per treatment group. The data were analyzed by ANOVA to determine overall differences between treatment groups. When significant differences were found, a comparison between treatment groups was made using the Newman-Keuls test. SSR binding data were analyzed by the method of Scatchard.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A high uptake of
[111In-DTPA-D-Phe1]octreotide
was detected after 24 h in the mediastinum (Fig. 1
, A and B). Computed tomographic
scanning of the chest confirmed the diagnosis of thymic enlargement
(Fig. 1C).
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At autoradiography, no specific binding of
[125I-Tyr11]SS-14 or
[125I-Tyr3]octreotide was
found in the thymoma (data not shown). However, Scatchard analysis of
[125I-Tyr11]SS-14 binding
on an enriched membrane preparation of the thymoma tissue revealed high
affinity binding sites with an apparent Kd of
47.5 ± 2.5 pmol/L and a low maximum binding capacity
(Bmax) of 23.5 ± 2.5 fmol/mg membrane
protein. Figure 2A shows a representative
experiment. No specific binding was detectable on the tumor-derived
cultured thymocytes. In addition, octreotide (100 nm) displaced
[125I-Tyr11]SS-14 binding
on membrane preparations of the thymoma tissue significantly less
compared with SS-14 (49.5% vs. 90.8%, respectively; Fig. 2B). On normal human thymus membranes high affinity binding sites for
[125I-Tyr3]octreotide
were detected [Kd, 200 ± 70 pmol/L;
Bmax, 4.7 ± 0.3 fmol/mg membrane protein
(mean ± SEM)].
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).
Conversely, mRNAs encoding for SS, sst2B,
sst4, and sst5 were absent
(Table 1). In the cultured neoplastic TEC, RT-PCR analysis showed the
presence of sst3 mRNA only (Table 1). In cultured
thymocytes only mRNA for ß-actin was detected (Table 1). As
previously described (18), the normal thymus expressed SS,
sst1, sst2A, and
sst3 mRNAs, whereas cultured TEC expressed SS,
sst1, and sst2A mRNAs
(Table 1). By immunohistochemistry, a high immunoreactivity for
sst3 receptors and a very weak immunostaining for
sst1, but not for sst2A,
receptors was observed on the tumor cells (Fig. 3, A and C). sst2A
was weakly expressed in the stroma, mainly on endothelium of few small
intratumoral vessels (Fig. 3B). In all cases the immunostaining could
be completely abolished by preabsorption with 100 nmol/L of the
respective antigen peptides (Fig. 3, D, E, and F).
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SS-14 (10 nm) and the SS analog octreotide (10 nm) significantly
inhibited [3H]thymidine incorporation by 40.6%
and 43.2%, respectively, in the cultured tumor cells (Fig. 4). The epithelial origin of the cultured
tumor cells was confirmed by immunocytochemical staining for
cytokeratin that revealed a 100% pure epithelial cell culture.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A high in vivo uptake of [111In-DTPA-D-Phe1]octreotide has been detected in patients bearing thymoma or thymic carcinoid, whereas the normal or hyperplastic thymus is not visualized (20, 26). Moreover, successful treatments with octreotide and prednisone and with octreotide alone have been reported in two patients with thymoma (19, 20). In one case the treatment resulted in both tumor size reduction and an improvement in the autoimmune-related disease (19). The precise mechanisms involved in this effect are unclear, however. In a previous study, using in vitro SSR autoradiography, Reubi et al. did not find SS-binding sites in four thymomas of undefined histological subtype, whereas SSR receptors were detectable in the normal thymus (27). The lack of in vitro detection of SSR in human thymoma seems in contrast with the compelling evidence that tumors originating from SSR-positive tissues generally express SSR (8, 28).
We have recently characterized SSR subtype expression in the normal human thymus (18). sst1 and sst2A mRNAs were expressed in the thymic tissue and isolated TEC, whereas sst3 mRNA was detectable in thymic tissue only and not on enriched cultured TEC or cultured thymocytes (18). As several different subsets of epithelial cells and thymocytes have been described within the human thymus, the sst3 receptor might be expressed on another cell subset or might undergo rapid down-regulation during culturing. In fact, it is well known that the expression of neuropeptide receptors on immune cells is dynamically regulated and depends on the traffic of these cells through and within lymphoid compartments and homing in the tissues (29, 30). Moreover, preliminary data show sst2A immunoreactivity on stromal cells in the medullary compartment of normal human thymus (31). All of these findings are in agreement with the evidence of a strong compartmentalization of neuroendocrine peptide receptors in lymphoid tissue (32).
In the present report we found a high uptake of [111In-DTPA-D-Phe1]octreotide in a patient with cortical thymoma and, in agreement with the study by Reubi et al. (27), a lack of SSR-binding sites by autoradiography performed on cryostat sections from the tumor tissue. However, we were able to detect a very low density of specific high affinity binding sites of [125I-Tyr11]SS-14 on an enriched membrane preparation from the thymoma tissue. By RT-PCR, we found mRNAs encoding for sst1, sst2A, and sst3 in the thymoma tissue, whereas mRNA encoding for sst3 was detectable in primary cultured neoplastic cells. Conversely, no binding was detectable, and no mRNAs encoding for SSR subtypes were found on the tumor-derived cultured thymocytes. Consonant with the presence of sst1 mRNA and the low affinity of octreotide for sst3 receptors, we found that octreotide only partially displaced [125I-Tyr11]SS-14 binding on cell membrane from this tumor. To further characterize the heterogeneous expression of SSR subtypes in this tumor, we used three recently developed polyclonal SSR antibodies, highly specific for sst1, sst2A, and sst3 receptors (11, 22, 23). By immunohistochemistry, we observed a high immunoreactivity for sst3 receptors and a very weak expression of sst1 receptors on the tumor tissue. Conversely, the tumor cells did not express sst2A receptors, whereas sst2A immunoreactivity was localized in the stroma, mainly on the endothelium of scattered small intratumoral vessels. These findings confirm the predominant presence of sst3 in this tumor. In fact, the mRNA encoding for this protein has been detected by RT-PCR on both tumor tissue and cultured tumor cells, and our hypothesis is that this cortical thymoma might have arisen from a subset of thymic sst3-expressing cells. However, the diffuse immunoreactivity for sst3 in the tumor tissue suggests the presence of this SSR subtype on reactive thymocytes as well. Although mRNA encoding for sst3 was undetectable in cultured thymocytes from both thymoma and normal thymus, our recent observation showed the presence of SS-binding sites on freshly isolated thymocytes (31). This finding might explain the diffuse immunoreactivity for sst3 in the thymoma and confirm the evidence that neuropeptide receptor expression in lymphoid tissues might rapidly change in conditions different from those in the natural microenvironment (33).
sst3 receptors have been shown to display the highest amount of agonist-dependent receptor internalization compared to the other SSR subtypes (34). Although the affinity of octapeptide SS analogs for sst3 is lower compared with that for sst2, the high internalization of sst3 receptors might be the possible mechanism regulating the in vivo uptake of [111In-DTPA-D-Phe1]octreotide within thymomas. Indeed, the present study demonstrates that sst3 is the subtype predominantly expressed in this tumor, displaying a significant in vivo uptake of [111In-DTPA-D-Phe1]octreotide. Another suggestive hypothesis, which can not be completely excluded, is the presence of a novel unidentified SSR involved in determining the in vivo uptake of the radiotracer.
Cell subsets containing neuropeptide hormones are present in the cortical areas of normal thymus as well as in thymoma (35). The identification of SS and its receptors in the normal thymus strongly supports the paracrine actions of the peptide in modulating the immuno- and/or neuroendocrine functions in this organ (18, 27). The pattern of distribution of SS-binding sites observed in normal thymus seems to be still preserved in thymic hyperplasia associated with myasthenia gravis, but seems to be lost in thymoma (27). Furthermore, in the present case, SS mRNA was not detectable in either thymoma tissue or the primary cultured tumor cells, whereas it was detected in normal human thymic tissue and in normal cultured TEC (18). This finding suggests that the loss of local SS production might be implicated in the uncontrolled cell growth and/or the tumor autoimmune-related diseases and possible tumor pathogenesis. In support of this hypothesis, we found that the in vitro administration of SS-14 and the SS analog octreotide at high concentration (10 nmol/L) significantly inhibited [3H]thymidine incorporation in the cultured tumor cells. Both compounds displayed a comparable ability in inhibiting [3H]thymidine incorporation by cultured cells. As SS-14 binds sst3 with higher affinity than octreotide, a difference in the percentage of inhibition should have been observed. However, taking into consideration that we measured the uptake of [3H]thymidine after 72 h, we might have underestimated the true inhibition degree by SS-14 due to a lower stability of the latter compound. The inhibition of cell proliferation by SS-14 and octreotide, and the predominant expression of sst3 in the thymoma are in line with emerging data regarding signal transduction pathways linked to SSR that show a cell cycle-dependent induction of apoptosis by octreotide (36). Octreotide-induced apoptosis seems signaled through the sst3 and associated with dephosphorylation-dependent conformational change in wild-type p53 (37). Although controversial data about alterations of p53 expression have been reported in thymic epithelial tumors (38, 39), SS-induced apoptosis might represent an additional mechanism involved in the regulation of cell proliferation in human thymus. Furthermore, this finding may form the basis for the inhibition of tumor growth in patients with thymoma treated with octreotide. As octreotide binds to sst2A, sst3, and sst5, but not to sst1, and considering that in the present case sst2A and sst5 are not expressed in the tumor cells, the in vitro effect of SS and octreotide seems to be mediated directly by sst3.
In conclusion, although further investigations are required, the loss of SS production in combination with a predominant expression of sst3 receptor in this thymoma might be implicated in uncontrolled cell growth and tumor pathogenesis. These data support the physiological paracrine/autocrine role of SS in the human thymic microenvironment and indicate that a disturbance in this system might be involved in the pathogenesis of thymic neoplasms. Furthermore, SSRs are localized in different complementary cell compartments in the normal and neoplastic human thymus. At least three SSR subtypes seem to control neuroendocrine function as well as the cell growth in this organ. Moreover, the sst3 subtype may play an important role in determining the uptake of [111In-DTPA-D-Phe1]octreotide during in vivo SSR scintigraphy. The inhibition of cell proliferation by octreotide through sst3 may explain the reported successful treatment of thymoma with this SS analog. Finally, SSR scintigraphy and SS analog treatment of thymomas may represent a new diagnostic and therapeutic approach to these tumors.
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Acknowledgments |
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Received June 28, 1999.
Revised December 3, 1999.
Accepted January 6, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), nonspecific (
), and specific (•) binding of
[125I-Tyr11]SS-14. Inset,
Scatchard analysis of [125I-Tyr11]SS-14
binding to thymoma tissue membranes (Kd, 50 pmol/L;
Bmax, 21 fmol/mg membrane protein). B, Displacement of
[125I-Tyr11]SS-14 binding by SS-14 (100 nm;
) and octreotide (100 nm; 
