[CANCER RESEARCH 47, 5758-5764, November 1, 1987]

Distribution and Biochemical Characterization of Somatostatin Receptors in

Tumors of the Human Central Nervous SystemJ. C. Reubi,1W. Lang, R. Maurer, J. W. Köper,and S. W. J. Lamberts

Sando: Research Institute, P. O. Box 2173, 3001 Berne, Switzerland [J. C. R., K. M.J; Department of Neuropathology, University Hospital, Zurich, Switzerland¡W.L.J; and Department of Medicine, Erasmus University, Rotterdam, The Netherlands [J. W. K., S. W. J,]

ABSTRACT

Fifty-two brain tumors, consisting of 17 astrocytomas, 4 oligodendrog-liomas. 20 glioblastomas, 3 neurinomas, 2 ependymomas, 1 neurofibroma,1 ganglioneuroblastoma, 1 medulloblastoma, 1 plexus papilloma, 1 tera-toma, and 1 germinonta, were tested for their content of specific soma-tostatin receptors using autoradiographic techniques or in vitro bindingassays with membrane homogenates. Somatostatin receptors were foundin most of the differentiated glia-derived tumors such as astrocytomasand oligodendrogliomas whereas the poorly differentiated glioblastomaswere usually free of receptors. Tumors originating from neuroblasts, i.e.,ganglioneuroblastoma and medulloblastoma, contained a high density ofSomatostatin receptors, whereas neurinomas and neurofibromas as wellas the ependymomas, one teratoma, and one plexus papilloma werelacking such receptors. In one germinoma, low amounts of Somatostatinreceptors were observed over the lymphocytic elements.

Receptor-positive tumors had saturable and high affinity receptorswith pharmacological specificity for Somatostatin and Somatostatin analogues resembling that of normal human central nervous system tissue.In most instances, they could be labeled with two different iodinatedradioligands, a Somatostatin octapeptide derivative (204-090) or a so-matostatin-28 analogue.

This is the first time that Somatostatin receptors have been shown toexist not only on neuronal structures of the central nervous system butalso on glial elements. The precise function of such Somatostatin receptorson glial cells, which may be different from neurotransmission, remainsto be determined.

INTRODUCTION

SS,2 a tetradecapeptide discovered by Brazeau et al. (1), has

potent inhibitory effects on various secretion processes in pituitary, pancreatic, or gastrointestinal tissue (2). In addition, itslocation within CNS neurons and its stimulus-evoked releasefrom nerve terminals suggests that it might be a neurotrans-mitter in the CNS (3). The various biological actions of SS,including those in the brain, seem to be mediated throughspecific high affinity receptors (4-7). In the rat and humanbrain, a specific and dense distribution in cortical and limbicareas of predominantly neuronally localized SS receptors (8, 9)would support indeed a neurotransmitter role of SS.

Not only normal target tissues for SS but also tumorallytransformed tissue of the same origin have SS receptors, as hasbeen shown for pituitary (10, 11) or pancreatic adenomas (12).They are probably the molecular basis for the clinical efficacyof SMS 201-995 therapy in such tumor patients. SS receptorslocated on the tumor itself may mediate the inhibition ofhormone secretion as well as perhaps additional intrinsic anti-proliferative effects (13-19).

Recently we reported that a group of human CNS tumors,the meningiomas, originating from a tissue not previously as-

Received12/31/86;revised5/28/87;accepted7/28/87.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

' To whom requests for reprints should be addressed.2The abbreviations used are: SS, Somatostatin; LTT-SS-28, [Leu'.o-

Trp",Tyr"]-somatostatin-28; LHRH, luteinizing hormone-releasing hormone;CNS, central nervous system; BSA, bovine serum albumin; Hepes, 4-(2-hydrox-yethyl)-1 -piperazine-ethanesulfonic acid.

sociated with SS, are bearing high densities of SS receptors(20). We have now extended the study to intracerebral tumors,mainly astrocytomas, oligodendrogliomas, and glioblastomasusing both in vitro receptor binding on homogenates and autoradiographic techniques. Such a study may help to furtherdefine on which cell types within the human CNS the SSreceptors are localized and to trigger future studies about themechanism of action of SS within this tissue.

PATIENTS AND METHODS

Samples

Fifty-two tumors originating from the human nervous system wereobtained at surgery from the University Hospital in Rotterdam andfrom the Neuropathology Division of the University Hospital in Zurich.One part was used for histológica!examination, all being diagnosed asCNS tumors and further classified into histological subtypes as shownin Table 1. The other part was processed as follows. The tissue wasimmediately put on ice and within a maximal delay of IS min frozenat -80°C. The storage time of the tumors at -80°C before autoradi

ographic processing ranged from 10 days to 4 months. Tumor samplesmeasured between 5 and 20 mm in diameter. Frozen material was cuton a cryostat for autoradiographic visualization of SS receptors and, insome cases, processed to obtain membrane homogenates for in vitro SSreceptor binding assays. Since contamination of the tumor sampleswith normal brain tissue, which contains a high concentration of SSreceptors (9), could not be excluded in advance, each sample was firstprocessed for autoradiography in order to identify the tissue bearingthe receptors. Only the receptor-positive samples containing exclusivelytumorous tissue at the autoradiographic level were used for furtherbiochemical characterization. All experiments were repeated two orthree times. As shown previously using post mortem human brains (9),the above mentioned sampling and storage procedure will not affectthe proteolytic stability of SS receptors.

None of the patients had been treated with SS or SS analogue priorto surgery.

SS Receptor Autoradiography. Visualization of SS receptors in CNStumors were performed as described previously (9, 21) for brain tissueusing '"1-204-090, a stable octapeptide SS analogue. 204-090 was

iodinated and purified according to the method of Reubi et al. (22, 23)and characterized in standard binding assays. For autoradiography, thetumors were cut on a cryostat (Leitz 1720) in 10-¿tmsections, mountedon precleaned microscope slides, and stored at -20°C for at least 3

days to improve adhesion of the tissue to the slide. Sections werepreincubated in 50 HIM Tris-HCl buffer (pH 7.4), containing 2 IHM("a('l: and 5 IHM KC1, for 10 min at ambient temperature and then

washed twice for 2 min in the same buffer without additional saltsadded. Incubation was carried out for 2 h at ambient temperature in170 mM Tris-HCl buffer (pH 7.4), containing bovine serum albumin(1%), bacitracin (40 Mg/ml), and MgClj (5 HIM),to inhibit endogenousproteases in the presence of iodinated ligand (0.16 x 10'' dpm/ml).Nonspecific binding was determined by adding unlabeled 204-090 at aconcentration of 1 u\i. In all SS receptor-positive tumors, nonspecificbinding was performed also using 10 M and 10" M concentrations ofSS or 204-090. Moreover, for specificity control, at least one sectionwas incubated with a 10~6M concentration of an unrelated peptide such

as LHRH or SS-28(1-12). Incubated sections were washed twice for 5min in cold incubation buffer containing 0.25% BSA. Prolonged washing times did not change the amount of specifically or nonspecifically

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SOMATOSTATIN RECEPTORS IN CNS TUMORS

Table 1 Individual data of 52 patients with CNS tumors and the result of receptor determinations

Case12345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152Age(yr)357330351710224425114123555405419594040285657685053586363666465733943546366644874241549646923562511SexMMMFFFMMMFMMMMMMFFMMFFMMMMFMMMMFFFMMFMMMFMFMMMFFFMMHistológica!diagnosisAstrocytomaAstrocytomaAstrocytomaAstrocytomaAstrocytomaAstrocytoma,

pilocyticAstrocytoma,pilocyticAstrocytoma,pilocyticAstrocytomaAstrocytomaAstrocytomaAstrocytoma,

pilocyticAstrocytomaAstrocytomaAstrocytomaAstrocytomaAstrocytomaOligodendroglioma,

anaplasticOligodendrogliomaOligodendrogliomaOligodendrogliomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaGlioblastomaPlexus

papillomaGanglioneuroblastomaMedulloblastomaNeurofibroma,

mediastinalNeurinomaNeurinomaNeurinomaEpendymomaEpendymomaMalignant

teratomaGerminomaWHOgradingII-IIImuniiiiiiniiiD-HIii-iiiininnunnIVIVIII-IVIVIVIVIVIVIVIVIVIVIVrvIVIVIII-IVIVIII-IVII-IIIIVIIIIIIIVSomatostatin

receptors*Mitoses"

'"1-204-090l25I-LTT-SS-28nt

++nt++nt

++++c—-1-++'—++————+++—+++

++++c———+—++——++nt

++++ent++nt

-+++nt-I-+++——nt

-—++++-++++nt

-nt++

——+——++

++ around necrosis+++——++——+——++——+——nt--++——+——++

——++

——++

——-1-+

——nt

-++——ntntnt

+++++nt++++++'nt

-nt_

_____++——nt++

——++ over lymphocytes——

overepithelialcellsCommentsKD

(nin); B„„(fmol/mgprotein)2.1;

1791.9;5050.2;

2771.09;

370Brain

tissue,+Brain

tissue,++Brain

tissue,++Necrosis,

-Brain

tissue,++Brain

tissue,++Braintissue,++Brain

tissue,+++Braintissue,+3.4;

2366Collagen

(leptomeninx), ++

" Mitoses: -, absence of mitoses; +, sparse mitoses; ++, numerous mitoses.* Receptor autoradiography: +, low; ++, moderate; +++, high density; -, absence of receptors; nt, not tested.' Tumor SS receptors have been characterized biochemically and pharmacologically.

bound tracer. After a brief dip in distilled water to remove excess salts,the sections were dried quickly, apposed to 3H-LKB films, and exposed

for 1 to 3 weeks in X-ray cassettes.

Additionally, autoradiography was performed on most tumors usinganother radioligand also labeling SS receptors in rat and human brain,the iodinated [Leu8,D-Trp22,Tyr"]-SS-28 (22). This ligand was prepared

as described previously (5), using the same methodology for autoradiography as described above.

Both '"1-204-090 and 125I-LTT-SS-28 radioligands were purified

with high pressure liquid chromatography to single peaks corresponding to the respective monoiodinated peptide, with an approximatespecific activity of 2000 Ci/mmol.

Hormone Receptor Assay. Selected tumors in which SS receptorswere visualized with autoradiographic methods were also characterizedbiochemically in homogenate binding assay when sufficient tumormaterial, not contaminated with normal brain tissue, was available.

SS binding assay with tumor homogenates was performed using '"!-

LTT-SS-28, purified as described previously (5). The membranes were

prepared from frozen pieces of each tumor according to the methoddescribed previously for pituitary adenomas (10). The thawed tumorswere homogenized in 5-20 volumes 10 mM Hepes buffer (Sigma

Chemical Co., St. Louis, MO), pH 7.6, on ice. The homogenate wascentrifugea once for 20 min at 47,000 x g at 4°Cand the resulting

pellet was resuspended in 5-10 volumes 10 mM Hepes buffer, pH 7.6.Aliquots of the homogenate were stored frozen at —30°C.

Binding studies were performed as described previously (5, 20, 23).Briefly, human tumor membranes (corresponding to about 20-50 >¡Kprotein) were incubated in triplicate in a total volume of 100 ;/l at 22°C

for 30 min with 40,000 to 60,000 cpm radioligand and increasingconcentrations of tinlabeled peptide in 10 mM Hepes buffer (pH 7.6)containing 0.5% BSA (Sigma). The incubation was terminated byaddition of 2 ml ice-cold saline followed by rapid filtration of themixture through GF/C filters (Whatman, Clifton, NJ) precoated for 2h in polyethylene-inline, which were then rinsed five times each with 2

ml saline. Filters were counted in an LKB counter (85% efficiency).Specific binding was taken to be total binding minus binding in the

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SOMATOSTATIN RECEPTORS IN CNS TUMORS

presence of 100 nsi SS-28. Protein was determined with the Bio-Rad(Richmond, CA) protein assay kit.

The dissociation constant (A,,) and number of binding sites (fim,x)were calculated from 5- to 7-point Scatchard plots of the data.

The following peptides were used: SS-28, SS-28(1-12), LHRH(Bachern, Marina del Rey, CA), SS, SMS 201-995[H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol)] and its Tyr3 analogue code-named 204-090 (synthesized by W. Bauer, Sandoz, Ltd.,Basel, Switzerland), and [Des-Trp*]-SS, a kind gift from Dr. J. Rivier

(The Salk Institute, San Diego, CA). The visualization of mitoses wasperformed using specific monoclonal antibodies against nuclear proteins (Ki 67) (24). Immunostaining against glial fibrillary protein wasperformed as described elsewhere (25).

RESULTS

Table 1 summarizes the clinical and biochemical data from52 patients suffering from CNS tumors. From 17 astrocytomasinvestigated, a tumor originating from the astrocytic glial celltype, 14 were found to be SS receptor positive. The receptordensity varied among the tumors, possibly being dependent onthe degree of differentiation. The sometimes higher density ofreceptors in astrocytomas II or even III may be due to thehigher cellular density of these tumor types compared to typeI. Four of the tumors were characterized biochemically inaddition to autoradiographic visualization. The SS receptorswere shown to be saturable and of high affinity (KD = 1.9, 2.1,0.2, and 1.09 nM) and often of high density (5ma„= 505, 179,277, and 370 fmol/mg protein). Pharmacological specificity forsomatostatin was observed since SS, SS-28, and SMS 201-995displaced with high affinity the radioligand l25I-LTT-SS-28,whereas the biologically inactive SS-28(1-12) and the unrelatedpeptide LHRH (both at IO"6 M) did not displace the radioligand

in the astrocytoma membrane preparations (Fig. 1). Fig. 2visualizes SS receptors in two different cases of astrocytomas.

Among the 4 tested oligodendrogliomas, a tumor originatingfrom another glial cell type, the oligodendrocyte, 2 of themcontained also high amounts of SS receptors (Table 1; Fig. 3,A-D). These receptors were also of high affinity since IO"7 M204-090 totally and 10~8M 204-090 partially displaced the '"I-

204-090 ligand in autoradiographic sections. Moreover, inactive analogues such as SS-2S( I-l 2) did not displace the radioli

gand.A third group of tumor consisting of one ganglioneuroblas-

toma and one medulloblastoma, originating from primitiveneuronal cells, i.e., the neuroblast cells, were also rich in SSreceptors (Table 1; Fig. 4). Interestingly, whereas all tumoraltissue in the medulloblastoma contains SS receptors, only onepart of the ganglioneuroblastoma, the one with lower cellularity,was SS receptor positive. Biochemical characterization of themedulloblastoma receptors showed a very high density of highaffinity SS receptors in the in vitro binding assay (Fig. 1). Thedissociation constant (Kn) for SS was 3.4 nM and the totalnumber of sites (fimax) equivalent to 2366 fmol/mg protein.Biologically active analogues such as SS-28 or SMS 201-995were potent inhibitors of '"I-LTT-SS-28 binding whereas thebiologically inactive analogue SS-28(1-12) did not compete withthe radioligand. Moreover, SS was approximately equipotentwith SS-28. SMS 201-995 had a profile compatible with thatseen in rat cortical membranes (26, 27) and its binding affinitywas Na+- and Mg2+-dependent (28).

None of the 20 undifferentiated glioblastomas containedspecific SS receptors except for one, in which SS receptors werefound, but exclusively in a region surrounding a necrosis. Fig.3 (E-H) shows an example of an SS receptor-negative glioblas-

Somotostatin Receptors in Human Astrocytoma

10 100

Peptides (nM)

Somatostatin Receptors in Human Medulloblastoma

Fig. 1. Binding of ' "I-LTT-SS-28 to membranes from a human astrocytoma

(case 9) and a human medulloblastoma (case 44). Displacement of radioligand byincreasing concentrations of SS-28, SS, SMS 201-995, SS-28(1-12). and LHRH.Points, average of triplicate tubes. Insets, Scatchard plot of the inhibition curvewith SS-28. Astrocytoma: KD= 0.21 nM, B„„= 277 fmol/mg protein; medulloblastoma: KD= 3.4 HM,ß„„= 2366 fmol/mg protein. Membranes were incubatedfor 30 min at 22*C with 40,000 cpm radioligand. B/F, bound versus free.

toma, surrounded by normal brain tissue containing highamounts of SS receptors, as a positive control.

Neither neurinomas (n = 3) nor a neurofibroma were SSreceptor positive. A teratoma, a rare tumor derived from plu-ripotential cells, as well as two ependymomas and one plexuspapilloma, were also negative (Table 1). Interestingly, in onecase of germinoma (Fig. 5) accumulations of lymphocytic cellsappeared to be radiolabeled.

Sections of most CNS tumors were also incubated in separateautoradiographic experiments with ' "I-LTT-SS-28 radioli

gand. As seen in Table 1 all tumors in which SS receptors weremeasured with the '"1-204-090 ligand were also shown to bereceptor positive with the '"I-LTT-SS-28 tracer. Interestingly,

in some tumors, an apparent higher density of receptors wasobserved with the ' "I-LTT-SS-28 ligand. This may be relatedto the fact that '"204-090 labels only a subpopulation of SS

receptors in some brain regions (22, 23). A comparative quantification of the SS receptors with each tumor has not beenperformed, due to the heterogeneity of the tumor material fromone section to the next, as well as to the different degradationproperties of the tracers. In two astrocytomas (cases 11 and12), SS receptors were detected only with ' "I-LTT-SS-28,

suggesting that only one subpopulation of receptors, namelythe SS2 type, was present there. Some brain regions, i.e., sub-

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SOMATOSTATIN RECEPTORS IN CNS TUMORS

A —

H

m s.

i ..•«.

ftv ¡*

Fig. 2. Localization of SS receptors in two astrocytomas. (case 9, A-I>, andcase 5. E-H). A and E, hematoxylin-stained tissue sections; B and F, autoradiograms showing total binding: C and G, nonspecific binding. Radioligand, '"I-204-090. Inset D from tissue section A represents a differentiated, grade IIastrocytoma. Insel H from tissue section E represents a low grade (I), welldifferentiated astrocytoma with microcystic changes in the neuropil. 'H-LKBUltrofilms. exposure time 1 week. Bar. \ mm.

stantia nigra of the human brain, are known to contain onlySS2 receptors (22).

The sex or the age of the patients was not related to thepresence or absence of receptors in any discernible way.

DISCUSSION

The main result of this study is the demonstration of specifichigh affinity receptors for SS on well differentiated CNS tumorsoriginating either from glial cells, the astrocytomas and theoligodendrogliomas, or from primitive neuronal neuroblasts. Incontrast, undifferentiated glial tumors, the glioblastomas, didnot possess SS receptors. Although we have shown recently (9)

*•*.«*««

Fig. 3. SS receptors in an oligodendroglioma (case 20, .!-!>) and a glioblas-toma (case 24,1. ID. A and /•..hematoxylin-stained tissue sections; B, C, F, andG, autoradiograms showing total (B + F) or nonspecific binding (C + G). InsetD from the tissue section A represents a well differentiated oligodendrogliomawith moderate cellularity. Absence of SS receptors in the glioblastoma 24 (F) isrepresentative for most glioblastomas. Notice the sharp transition between glioblastoma tissue with high cellularity (upper pan) and brain tissue (lower part),shown in detail in Inset H. Only brain tissue is labeled (F). Radioligand, '"1-204-090. Exposure time. I week. Bars, I mm.

that the human brain contains high numbers of SS receptors,it could usually not be clearly determined whether such receptors were localized on neuronal or glial membranes. Directevidence solely for a neuronal localization of SS receptors inthe hippocampus was obtained from lesion experiments in the

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SOMATOSTATIN RECEPTORS IN CNS TUMORS

Fig. 4. Localization of SS receptors in aganglioneuroblastoma (Ai', case 43) and a

medulloblastoma (F-l, case 44). A and F, he-matoxylin-stained tissue sections. //. C, G, and//, autoradiograms showing total (B + G) ornonspecific (C + H) binding. Radioligand. '"I-204-090. In the ganglioneuroblastoma I I).only the right part, characterized by low cellu-larity and trabecular structures (Inset E),shows SS receptors whereas the cell-dense leftpart (Inset D) is virtually free of SS receptors.Inset I, detail from the medulloblasloma in /.Exposure time, I week. Bars, I mm.

rat hippocampus (8) and from the description of a vascularlesion in a human hippocampus (9). The present results nowclearly support a glial localization of some SS receptors inaddition to a neuronal location, if we assume that the SSreceptors measured in the present study are not simply newlyexpressed material due to tumorous transformation (29). Thiswould imply that in normal brain both astrocytes and oligoden-drocytes may bear SS receptors. The role of such SS receptorson glial cells is for the moment largely unknown. Nevertheless,there is evidence that some glial cells in the rat brain aresensitive to SS, as shown by the effects of SS on cyclic AMPproduction or on the modulation of some glia-mediated neu-rotransmitter actions (30-33). Moreover, it could be speculatedthat, in analogy to the endocrine system, SS may inhibit therelease of some glial (growth) factors or have a trophic function0,2).

The absence of SS receptors in undifferentiated glial tumorssuch as glioblastomas may indicate that SS receptors are markers for the differentiation grade of CNS tumors.

Among other positive results are the numerous SS receptorsfound in tumors originating from primitive neuroblasts. There,however, they can be easily explained, considering the wide andvery strong distribution of SS receptors within the human CNS

in general. It is not clear whether the high receptor density inthe medulloblastoma is a particularity of this type of tumor,since only one case could be analyzed. However, it should beremembered that high variability in SS receptor density hasbeen observed in tumors and that for instance 10-fold differences in SS receptor number has been observed in pituitaryadenomas (10).

It has been shown recently that certain regions of the rat andof the human brain contain two different populations of SSreceptors. This conclusion is based on the differentiated affinityof a reduced-size SS analogue, SMS 201-995 (22, 26, 27). Wewere able to show recently (22) that different regions of thehuman brain possess different proportions of each of thesereceptor subtypes. The present study does not suggest that oneof these SS receptor types is glia cell specific, since one wouldthen expect that astrocytomas and oligodendrogliomas expressonly one of both subtypes. However, the fact that the tumoralSS receptors can be labeled by the reduced-size SS analogue'"1-204-090 as well as or by the iodinated SS-28 analogue

suggests that both types of SS receptors may be present onmost of the investigated tumor cells, reflecting the variabilityin subtype ratio seen in the normal brain. As seen from thepharmacological specificity of SMS 201-995 in most tumors of

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SOMATOSTATIN RECEPTORS IN CNS TUMORS

.,. . . . , . .. .»*Ä# -g» •

",••„;'.- •.•'•r ••'.."•TI" : -•••••-7í--,.: ••••.•.,..•;.•-•.''r-w1•- ••-.

i•

- .''.'•' '•.'.•. '

.-" •••:••

•\ •l- ~•.,. : • V'X

•

Fig. S. SS receptor distribution in one case of germinoma (case 52). Thistumor (stained tissue section in A, inset magnified in C) consists of large cells(arrow) and lymphocytic elements. As seen in the autoradiogram in B, theradioligand is selectively localized over the lymphocytic elements. D, nonspecificbinding. Radioligand, '"1-204-090. Exposure time, 1 week. Bars, 1 mm.

the present study, there is no significant difference in thisrespect between the tumors and brain regions containing bothtypes of SS receptors such as cortex. In most cases, SMS 201-995 does displace the radioligand '"I-LTT-SS-28 in the high

affinity range (26, 27), however, not always completely.Germinoma is a rare tumor originating from primitive stem

cells, consisting of large epithelial human chrionic gonadotro-pin-producing cells on one hand and lymphocytes on the otherhand (34). The lymphocytes in our case seem to bear a lowdensity of SS receptors. This finding would support an earlierreport suggesting the presence of SS receptors in monocytesand lymphocytes (35). Moreover, a potential role for SS in suchcells as inhibitor of proliferation has been demonstrated (36,37).

The elucidation of the potential functional role of the highdensity of SS receptors in brain tumors, such as glial tumors ormeningiomas, is of particular importance. Since very little isknown from physiological studies in healthy brain tissues, thequestion may be approached with tumor material directly. Inpreliminary studies, where SS receptor-bearing meningiomasare grown in cell culture, only a minimal effect of SS or SMS201-995 is observed on growth parameters such as [3H]thymi-dine incorporation.3 Although such studies suggest that the

main functional role of SS is not growth regulation, it is stillpossible that optimal testing conditions have not yet been found.Indeed, evidence that SS may have an antiproliferative role insome tumor types has been reported; in gerbil fibroma andHeLa cells, SS is able to inhibit the epidermal growth factor-induced DNA synthesis and cell replication (38). Preliminaryresults in our laboratory suggest that the molecular basis forsuch an interaction is given in meningiomas also, since thesetumors bear a high number of both epidermal growth factorreceptors and SS receptors.4 Although the identification of SS

receptors in selective brain tumors is of basic interest, moreinformation will be necessary before the therapeutic potentialof SS in brain tumors can be conclusively evaluated. Moreover,it should be considered that all the tumors investigated in thisreport are localized within the blood-brain barrier. Althoughthis barrier may no longer be completely intact in the tumorregion (39), it is probable that the low brain permeability ofperipherally applied peptides currently used such as somato-statin and their analogues will partly hinder such compoundsto reach their targets within the brain easily.

ACKNOWLEDGMENTS

We thank U. Horisberger, B. Thomi, and D. Huebener for theirexcellent technical assistance.

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SOMATOSTATIN RECEPTORS IN CNS TUMORS

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1987;47:5758-5764. Cancer Res   J. C. Reubi, W. Lang, R. Maurer, et al.   Receptors in Tumors of the Human Central Nervous SystemDistribution and Biochemical Characterization of Somatostatin

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