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Original Studies |
Division of Cell Biology and Experimental Cancer Research (J.C.R., B.W., J.A.L.), Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland; and Department of Integrative Biology and Pharmacology (Q.L., A.S.), University of Texas Houston Medical School, Houston, Texas
Address correspondence and requests for reprints to: Jean Claude Reubi, M.D., Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, P.O. Box 62, CH-3010, Berne, Switzerland. E-mail: reubi{at}patho.unibe.ch
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Many studies have used in vitro receptor autoradiography, to show an often abundant somatostatin receptor expression in selected human tumors of nervous and neuroendocrine systems, such as small-cell lung carcinoma (11, 12), neuroblastoma (13, 14), medulloblastoma (15, 16, 17), and paragangliomas and pheochromocytomas (18, 19). However, these studies do not provide definitive information about the sst receptor subtype protein responsible for the binding activity. Moreover, if binding activity is not detected, these studies do not indicate whether the absence of binding is attributable to the lack of receptor protein or to desensitized or inactivated receptor. Numerous studies have also investigated the sst mRNA content of such tumors, by PCR or in situ hybridization, and have often found an abundance of sst2 mRNA (17, 18, 20, 21, 22). Because, however, recent reports have suggested a lack of parallelism between sst2 mRNA and receptor protein in the case of some human tumors (23), mRNA detection alone is unlikely to be sufficient to assess the presence of the receptor protein. It is the receptor protein and not the mRNA that is the molecular target for all presently available clinical applications of somatostatin in tumors (1, 24).
The means of identifying, in tumors, sst receptor subtypes based on protein rather than on mRNA detection has become available with the development of specific antibodies against the various sst subtypes (3, 25, 26, 27). Though there are reports on sst2 detection with immunohistochemistry in some neuroendocrine tumors, including primarily gastrointestinal neuroendocrine tumors (carcinoids and islet cell tumors) (25, 26, 28) and pheochromocytomas (28, 29), very little information exists for other neuroendocrine tumors. For instance, we lack information on sst2 receptor protein in such tumors as SCLC, medulloblastomas, neuroblastomas, and paragangliomas. Moreover, no studies have yet investigated, in detail, the subcellular distribution of sst2 and its regulation in human tumors.
Hence, the aim of the present study was to evaluate sst2A receptor protein in a representative number of SCLC, medulloblastomas, neuroblastomas, paragangliomas, and pheochromocytomas. We have determined the distribution of sst2A receptors, by immunohistochemistry on cryostat and formalin-fixed sections, and compared the results with 125I-[Tyr3]octreotide binding as quantitated by in vitro receptor autoradiography in subsequent sections. Moreover, we have studied the subcellular distribution of sst2A and searched for conditions favoring an internalized state vs. a membrane-bound state. Our results indicate that the approach described and validated here will be of diagnostic, therapeutic, and prognostic value for patients bearing these types of tumors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Two types of tumor samples were taken for this study: 1)
selected frozen samples from 68 different tumors, including 7
small-cell lung carcinomas, 11 medulloblastomas, 15 neuroblastomas, 15
paragangliomas, and 20 pheochromocytomas (Table 1
) (they were all characterized for their
somatostatin receptor content by receptor autoradiography using the
sst2-preferring
125I-[Tyr3]-octreotide;
moreover, 18 pheochromocytomas were tested for their content of
somatostatin mRNA); 2) unselected formalin-fixed, paraffin-embedded
archival material, including 50 tumors (namely 18 small-cell lung
carcinomas, 8 medulloblastomas, 6 neuroblastomas, and 18
pheochromocytomas). In addition, 2 frozen gastroenteropancreatic tumor
samples, one somatostatinoma, and 1 carcinoid were included for control
purposes.
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All frozen and formalin-fixed samples were evaluated immunohistochemically with R2–88. The R2–88 rabbit polyclonal antibody, generated against a unique sequence located in the C-terminal tail of the sst2A receptor, was used as primary antibody (30). Biochemical and immunohistochemical characterization of the antibody have been reported elsewhere (30, 31). R2–88 immunohistochemistry was essentially performed as described previously (26).
Frozen tissues. Ten-micrometer-thick sections were cut on a cryostat (Leitz, Rockleigh, NJ). The sections were fixed for 10 min in acetone and postfixed for 10 min in 4% paraformaldehyde (diluted in PBS) and incubated for 20 min in 5% normal goat serum diluted in TBS. Then, the sections were incubated with the R2–88 antibody against the sst2A receptor overnight at room temperature. The antibody R2–88 was used at a 1:6000 dilution in TBS containing 1% BSA, 5% normal goat serum, and 0.1% NaN3. Sections were then incubated for 45 min at room temperature in a 1:200 dilution (same buffer as for primary antibody) of biotinylated goat-antirabbit Ig antiserum (DAKO Corp., Glostrup, Denmark) and thereafter for 45 min, at room temperature, with avidin-biotin-complex/horseradish peroxidase (1:120 in TBS; DAKO Corp.). Finally, sections were developed in 0.05% 3,3'-diaminobenzidine (Fluka Chemical Co., Buchs, Switzerland) and 0.006% H2O2 (Merck & Co., Inc., Rahway, NJ), weakly counterstained with hematoxylin, and mounted. A tissue was considered to be positive for R2–88 when the immunostaining was abolished after absorption of the antibody with the peptide antigen at 100 nM concentration (30 min at room temperature, with agitation before application of the antibody to the tissue). The tissue reaction was considered to be negative if the immunostaining was not suppressed in presence of the antigen.
Formalin-fixed, paraffin-embedded tissues. In all samples tested, the fixation time was 24–36 h. The fixed tissue was processed for conventional, approximately 5-µm-thick paraffin wax (Paraplast) sections. The sections were dewaxed, rehydrated, and boiled in 10 mM citrate buffer, pH 6.0, in a pressure cooker, as described previously (26). Sections were then (and after all subsequent steps) washed in TBS and incubated with the R2–88 polyclonal antibody against sst2A receptors used at a dilution of 1:2000 overnight at room temperature. All subsequent steps, including absorption of the antibody with the peptide antigen, were performed exactly as in the protocol for frozen tissue, and the same criteria were applied to distinguish between positive and negative tissues.
Receptor autoradiography with 125I-[Tyr3]-octreotide
Twenty-µm-thick cryostat sections, adjacent to those used for R2–88 immunohistochemistry, were used for in vitro receptor autoradiography with the sst2/sst5-preferring radioligand, 125I-[Tyr3]-octreotide, as described previously (32). Nonspecific binding was determined in the presence of 10-6 M octreotide. In all pheochromocytomas, a prewashing procedure was introduced to wash out excess endogenous somatostatin, as described previously (19).
Somatostatin mRNA in situ hybridization
Somatostatin mRNA in situ hybridization was performed in 18 frozen pheochromocytomas and 2 gastroenteropancreatic tumors (1 somatostatinoma and 1 carcinoid), as described in detail previously (33).
Immunoblots
Cell membranes from an sst2A-expressing rat growth hormone-producing pituitary cell line GH-R2 cells were prepared as previously described and were solubilized in SDS sample buffer (62.5 mM Tris-HCl, 2% sodium dodecylsulfate, 10% 2-mercaptoethanol (vol/vol), 6 M urea, and 20% glycerol, pH 6.8) (34). Membranes from frozen samples of two pheochromocytomas, one neuroblastoma, one paraganglioma, one somatostatinoma, and one carcinoid were prepared following published procedures (26). Tumor membrane proteins were solubilized for 60 min at 4 C in Lysis Buffer [150 mM NaCl, 20 mM Hepes, 5 mM EDTA, 3 mM EGTA (pH7.4), 4 mg/mL dodecyl-beta-maltoside with 1 mM PMSF, 10 µg/mL soybean trypsin inhibitor, 10 µg/mL leupeptin, and 50 µg/mL bacitracin]. The detergent lysates were clarified by centrifugation at 10,000 x g for 5 min, and the supernatants were incubated at 4 C for 90 min with 100 µL packed vol of wheat germ agglutinin-agarose. After centrifugation, the supernatant was aspirated, the pellet was washed vigorously with lysis buffer, and the absorbed glycoproteins were subsequently eluted with SDS sample buffer. Eluted proteins were separated by SDS-PAGE on a 12% polyacrylamide gel, transferred to polyvinylidene difluoride membrane, and immunoblotted with R2–88 antiserum (1:10,000 dilution), as described previously (34). Immunoreactive proteins were detected with the ECL enhanced chemiluminescent antibody detection system (Amersham Pharmacia Biotech, Arlington Heights, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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summarizes all immunohistochemical results in frozen and
formalin-fixed material. In addition, it compares, in frozen sections,
the immunohistochemical data with in vitro receptor
autoradiography data.
For small-cell lung carcinoma, all 7 frozen samples showed a positive
R2–88 immunohistochemical staining, whereas 6/7 were positive on
autoradiography; the only negative small-cell lung carcinoma on
autoradiography was the one with the faintest staining with R2–88.
Fig. 1 (left) shows an example of the
concomitant positive R2–88 immunostain and positive receptor
autoradiography on a small-cell lung carcinoma frozen section. In the
archival material, 11/18 small-cell lung carcinomas (61%) were
positively stained for R2–88. Fig. 2
shows the predominant plasma membrane R2–88 staining of a
formalin-fixed archival small-cell lung carcinoma, at various
magnifications. It seems that almost all cancer cells are labeled.
Absorption with 100 nM peptide antigen abolishes
the staining.
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). Fig. 1 (right)
illustrates a strongly receptor-positive frozen sample of
medulloblastoma, both with R2–88 immunohistochemistry and receptor
autoradiography. Moreover, all 8 consecutive archival medulloblastomas
were positive for R2–88. Fig. 3 depicts
an R2–88-positive, formalin-fixed medulloblastoma with strong staining
of the tumor cell plasma membranes and abolishment of staining in the
presence of 100 nM peptide antigen.
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). One of
the R2–88-positive cases was negative with autoradiography, whereas
one case that was positive with autoradiography was negative for
R2–88. In archival, formalin-fixed material, 5/6 neuroblastomas were
stained with R2–88, sometimes in an heterogeneous manner and with
variable cytoplasmic and cell-surface staining. Fig. 4, A and B, shows an example of an
R2–88-positive heterogeneously stained neuroblastoma with strong
plasma membrane staining of neoplastic ganglion cells. Fig. 4, C and D,
illustrates (at high magnification) a different neuroblastoma with
mixed cytoplasmic and membranous staining.
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). For pheochromocytomas, 20/20 frozen cases were stained with
R2–88. They were all labeled with
125I-[Tyr3]-octreotide
(Table 1). As shown previously (19), a prewashing procedure was
necessary, in several cases, to markedly improve the
125I-[Tyr3]-octreotide
labeling. Because receptor occupancy probably occurs by the endogenous
somatostatin produced by pheochromocytomas (19, 35, 36), the wash
procedure presumably releases this prebound somatostatin. In
situ hybridization for somatostatin mRNA was performed in 18 of
the frozen pheochromocytoma samples. Seven of these samples were shown
to be positive for somatostatin mRNA, precisely those 7 which showed
improved labeling with
125I-[Tyr3]-octreotide
after the prewashing procedure. In formalin-fixed archival material,
16/18 pheochromocytomas were stained with R2–88 (Table 1). An example
of a formalin-fixed pheochromocytoma, positively stained at the tumor
cell plasma membranes for R2–88, is seen in Fig. 4, E and F. However,
the immunostaining of many of the pheochromocytomas was more
cytoplasmic than membranous. A comparable R2–88 immunostaining
pattern, showing both cytoplasmic and plasma membrane staining, could
also be observed in the frozen pheochromocytoma samples (see
below).
We next evaluated the relationship between the R2–88 immunostaining
pattern, receptor binding (as determined by autoradiography) and the
level of somatostatin gene expression (measured as mRNA) in frozen
material from pheochromocytomas. We then compared the results with
those obtained in a gastroenteropancreatic tumor with very high levels
of somatostatin mRNA (somatostatinoma) and a gastroenteropancreatic
tumor without somatostatin mRNA (carcinoid). As shown in Fig. 5, a pheochromocytoma (II) with abundant
somatostatin mRNA (middle) and one (I) without somatostatin
mRNA (left panels) both showed R2–88 staining as well as
125I-[Tyr3]-octreotide
binding. In contrast, the strongly somatostatin mRNA-positive
somatostatinoma (Fig. 5, right) was also R2–88-positive but
125I-[Tyr3]-octreotide-negative,
despite extensive prewashing. Details of the R2–88
immunohistochemistry of these cases, at higher magnification, in Fig. 6, reveal that the somatostatin
mRNA-negative pheochromocytoma I (A) had a more distinctly plasma
membrane staining pattern than the somatostatin mRNA-positive
pheochromocytoma II (B). Moreover, whereas the somatostatin
mRNA-positive somatostatinoma had mainly a cytoplasmic R2–88 staining
(D), the sst2A-positive carcinoid lacking somatostatin mRNA had a
strongly membranous R2–88 staining (C), as shown previously for this
type of tumor (26).
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shows immunoblots of
glycosylated proteins purified by WGA affinity chromatography
from six R2–88-positive tumors, including some with plasma membrane
staining (carcinoid, paraganglioma, neuroblastoma, and pheochromocytoma
I) and some with intracellular staining (somatostatinoma and
pheochromocytoma II). In these experiments, GH-R2 cells provide a
positive control, because the sst2A receptor has been extensively
characterized in this cell line (34); the negative control is provided
by the addition of antigen peptide, which blocks immunodetection of the
receptor. Western blots revealed, in each tumor, a single broad band of
characteristic shape and appropriate size for the sst2A receptor (30, 34). In tissue sections of all six tumors, positive immunostaining with
R2–88 was observed. Therefore, both plasma membrane (as seen in the
carcinoid and pheochromocytoma I in Fig. 6) and intracellular (as seen
in the somatostatinoma and pheochromocytoma II in Fig. 6) staining
patterns are consistent with the presence of true sst2A receptors.
Moreover, in the case of tumors with large amounts of endogenous
somatostatin, as seen in the somatostatinoma, it is likely that the
great majority of the sst2A receptors have been internalized. These
intracellular receptors are not detected by ligand autoradiography,
although they are still recognized by the R2–88 antibody.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies, in which the sst2A receptor was labeled with a photoaffinity ligand, showed that this receptor migrated as a broad 70-kDa band and that the R2–88 antibody specifically recognized both the photoaffinity-labeled receptor protein and the unoccupied receptor protein (30). This antibody does not recognize any of the other sst receptor subtypes (30). The broad migration pattern of the sst2A receptor on SDS gels is caused by heterogeneous glycosylation, because treatment of the receptor with enzymes that remove asparagine-linked carbohydrates results in a decrease in the molecular size of the sst2A receptor, to about 40 kDa, and the generation of a much narrower band on SDS gels (37). Thus, the positive immunoblots that identify, in human tumors, the 70-kDa broad band characteristic of the glycosylated sst2A receptor (30) provide further confirmation that the correct protein is detected by the immunohistochemical staining. These results demonstrate that the R2–88 immunohistochemical staining is indeed highly specific for somatostatin receptors of the sst2A type and identify this receptor subtype as, at least partially, responsible for the 125I-[Tyr3]-octreotide binding.
For most tumors, the R2–88 immunostaining was concentrated mainly in the plasma membrane. This subcellular distribution was optimally observed in formalin-fixed tissues but could usually also be identified in cryostat sections, in particular when H + E counterstaining was omitted (26). Such cell-surface staining is compatible with the functional role of somatostatin receptors that are all G protein-coupled, membrane-bound proteins (3, 10).
In contrast to the plasma membrane staining in the majority of the tumors, the intracellular cytoplasmic R2–88 staining pattern, in several pheochromocytomas and neuroblastomas, required further investigation. It was possible that the preferentially cytoplasmic R2–88 staining was nonspecific and unrelated to somatostatin receptors, analogous to the nonspecific cytoplasmic HER-2 immunohistochemical staining seen in some tumors with the Herceptin test (38). However, two strong arguments favor the thesis that the cytoplasmic staining in pheochromocytomas and neuroblastomas represents true sst2A receptors. First, the usually excellent correlation with 125I-[Tyr3]-octreotide autoradiography indicates that active plasma membrane receptors are usually present in the same cells as the cytoplasmic, antibody-positive receptor. Second, the positive and specific immunoblots found with pheochromocytomas and neuroblastomas, which exhibit substantial cytoplasmic staining, indicate that staining results only from the correct protein. The cytoplasmic staining in these tumors may result in internalized receptors. It is known that ligand binding stimulates sst2A receptor internalization (34, 39). Further, in a recent, elegant study (40, 41), Beaudet et al. have shown that, in the rat brain, areas with high levels of local endogenous somatostatin have much more intracellular sst2A receptors than areas without endogenous somatostatin. These observations supported the conclusion that receptor occupancy by endogenous somatostatin increased the steady-state level of internalized sst2A receptor in rat brain. It is well known that pheochromocytomas and neuroblastomas can produce somatostatin (19, 35, 36, 42, 43, 44). We wanted to determine whether such chronic somatostatin production and release may act in an autocrine fashion to stimulate the internalization of tumoral sst2A receptors. Interestingly, we observed that pheochromocytomas with no somatostatin mRNA show plasma membrane staining, whereas pheochromocytomas with abundant somatostatin mRNA exhibit mainly cytoplasmic staining. Similar observations were made in two gastroenteropancreatic tumors. The somatostatin producing somatostatinoma shows a strong (mainly cytoplasmic) R2–88 staining. Presumably, in this type of tumor, which is characterized by extremely high somatostatin levels, the few remaining plasma membrane receptors do not suffice to yield a positive 125I-[Tyr3]-octreotide signal by autoradiography, despite a prewashing procedure to remove endogenously bound somatostatin from receptors. The other gastroenteropancreatic tumor, a nonsomatostatin-producing carcinoid, has mainly plasma membrane sst2A receptors and, accordingly, a positive receptor autoradiography, common for this type of tumors (26). Thus, our observations provide the first evidence to show that tumor-produced somatostatin can act in an autocrine fashion, that sst2A receptor internalization occurs in tumor tissue in vivo, and that internalized receptor protein may explain the absence of ligand binding.
Overall, the presented data clearly indicate that the presence of cytoplasmic staining by R2–88 does, at least in the case of somatostatin-producing tumors, represent specific sst2A receptors as reliably as the plasma membrane staining pattern (26). The main evidence for this assertion is the observation that both tumors with plasma membrane sst2A receptors (carcinoid, paraganglioma, neuroblastoma, pheochromocytoma) and tumors with cytoplasmic R2–88 staining (somatostatinoma, pheochromocytoma) show only the characteristic sst2A receptor band on Western blots. It does not mean, though, that cytoplasmic staining obtained with an antibody against sst receptors is always correlated with the presence of endogenous somatostatin, nor that it will always represent specific sst receptors (46).
Very few tumors tested for both R2–88 immunohistochemistry and receptor autoradiography with 125I[Tyr3]-octreotide gave discrepant results. One small-cell lung carcinoma and one neuroblastoma were R2–88-positive but were negative on autoradiography; one neuroblastoma was R2–88-negative but was positive on autoradiography. Numerous explanations can be given for such discrepancies, including technical reasons (inadequate sample preservation and processing), sensitivity differences between the detection methods, a predominance of low-affinity intracellular receptors, or the presence of non-sst2A receptors (e.g. sst2B or sst5) detectable by autoradiography.
The high incidence of sst2A receptors detected with R2–88 immunohistochemistry in archival material corresponds very well with previous measurements of somatostatin receptor abundance determined with other methods in frozen sections, such as receptor autoradiography; all medulloblastomas have somatostatin receptors (16, 17), a majority of pheochromocytomas have somatostatin receptors (18, 19), whereas small-cell lung carcinomas and neuroblastomas have somatostatin receptors in approximately 2/3 of the cases (11, 12, 13). However, with 125I[Tyr3]-octreotide autoradiography, the identity of the detected receptor cannot be known with certainty. In contrast, the results reported here unambiguously identify the sst2A receptor protein.
These data are not only of general interest, in terms of the biological characterization of the described tumors and their implication of a role for sst2A receptors in tumor regulation, they are also likely to have clinical applications. Because it was possible, in the present study, to identify sst2A in small biopsies of small-cell lung carcinomas, the described method may provide an immunohistochemical receptor test of sufficient accuracy and specificity, in small samples, for diagnostic use. This test would provide an additional discriminator for the differentiation of small-cell lung carcinomas from non-small-cell lung carcinomas, on the basis of the sst2A receptor content, because non-small-cell lung carcinomas usually do not have somatostatin receptors, at least when measured with 125I-[Tyr3]-octreotide binding (12, 45). The sst2A receptor may also be usefully identified in medulloblastomas by immunohistochemistry, and results from such an analysis could provide a rationale for the use of radiolabeled somatostatin analogs for diagnostic and/or radiotherapeutic purposes in sst2A-positive medulloblastomas. Differential diagnosis and follow-up, in particular the detection and therapy of recurrences, should be considered. Furthermore, immunohistochemical identification of sst2A in neuroblastomas may be of prognostic value, because we have shown, with receptor autoradiographical methods, that those neuroblastomas that express somatostatin receptors have a significantly better prognosis than neuroblastomas lacking such receptors (13). Finally, the observation of a predominant cytoplasmic localization of sst2A receptors in selected neuroendocrine tumors raises the question of whether these receptors will remain accessible in vivo to labeled or unlabeled somatostatin analogs and permit diagnostic and therapeutic applications; or whether, on the contrary, the lack of membrane-bound receptors in these tumors will prevent any useful application of somatostatin analogs in such tumors.
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Footnotes |
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Received December 22, 1999.
Revised April 15, 2000.
Accepted June 30, 2000.
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