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Molecular Oncology, Markers, Clinical Correlates |
Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: We investigated 161 human tumors for their bombesin receptor subtype expression using in vitro receptor autoradiography with the universal bombesin radioligand 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) in displacement experiments with unlabeled GRP, bombesin, NMB, and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14). The distinct rank order of potencies of these analogues for each receptor subtype allows us to identify the predominant subtype expressed by each tumor.
Results: Twelve of 12 prostate cancers, 41 of 57 breast cancers, and 5 of 5 gastrinomas expressed predominantly GRP receptors; 11 of 24 intestinal, 1 of 26 bronchial, and 1 of 1 thymic carcinoids had preferentially NMB receptors; 9 of 26 bronchial carcinoids, 1 large cell neuroendocrine lung carcinoma, and 4 of 9 small cell lung carcinomas had preferentially BB3 receptors, whereas 3 of 9 small cell lung carcinomas had GRP receptors. Renal cell carcinomas had GRP receptors in 6 of 16 cases and BB3 receptors in 4 of 16 cases. Finally, 2 of 10 Ewing sarcomas had BB3 receptors. In situ hybridization detected BB3 receptor mRNA in neuroendocrine tumors expressing the BB3 protein.
Conclusions: This is the first study detecting the proteins of BB3, NMB, and GRP receptors in a group of human tumors using differential binding techniques. Particularly relevant is the BB3 expression in lung carcinoids and other neuroendocrine lung tumors, whereas gastrointestinal carcinoids preferably express NMB receptors. These tumors may be targets for diagnostic and radiotherapeutic applications of subtype-selective bombesin analogues.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Bombesin and its human counterpart GRP2 belong to a family of brain-gut peptides, shown, in addition to physiological effects, to play also an important role in cancer (7 , 8) . It has been observed several years ago that cancer cell lines as well as primary human tumors can synthesize bombesin and GRP (9) . These peptides probably act in an autocrine fashion to stimulate the growth of the tumor cells they originate from, through bombesin receptors expressed on the membranes of these cells (7 , 10) . More recently, it has been shown that the GRP receptor proteins can be overexpressed in a large variety of human tumors, including prostate cancers, breast carcinomas, SCLCs, and non-SCLCs, as well as renal cell carcinomas (11, 12, 13, 14, 15) . Most of the studies up to now have been able to primarily identify the GRP receptor subtype, although it is known that the bombesin receptor family includes at least four different subtypes, namely the GRP receptor subtype (BB2), the NMB receptor subtype (BB1), and the BB3 and BB4 subtypes (16, 17, 18, 19) . Except for the GRP receptor, the other three subtypes have been poorly characterized, in particular in regard to their distribution and function in human tissues. Recently, a very potent ligand, the [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), shown to bind to all four of the bombesin receptors, has been developed by Mantey et al. (20) and Pradhan et al. (21) . This compound, iodinated at the D-Tyr6 residue, is a useful radioligand able to distinguish the various bombesin receptor subtypes on the basis of the rank order of their affinity for GRP, NMB, [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), or bombesin. Using this approach, we could recently detect specific BB3 receptor expression in human pancreatic islets (22) .
The aim of the present study was to evaluate in a selection of human tumors of different origins the expression of the various bombesin receptor subtypes using in vitro receptor autoradiography with 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) as a radioligand in displacement experiments with unlabeled GRP, bombesin, NMB, and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14). In all of the cases, we have compared the results obtained with 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) with those using [125I-Tyr4]bombesin, a ligand that preferentially identifies GRP receptors. In selected tumors, the corresponding receptor mRNA was measured with in situ hybridization techniques.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Receptor Autoradiography.
Cryostat sections (20-µ thick) of the tissue samples were processed for receptor autoradiography as described in detail previously for other peptide receptors (23)
. The radioligands used were [125I-Tyr4]bombesin, known to preferentially label GRP receptors (24)
, and the newly developed radioligand 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14] bombesin(6–14), which has been reported to be an outstanding ligand identifying all four of the bombesin receptor subtypes (21
, 22)
. For autoradiography, tissue sections were mounted on precleaned microscope slides and stored at -20°C for at least 3 days to improve adhesion of tissue to the slide. The sections were then processed as described previously (13
, 24)
. They were first preincubated in 10 mM HEPES (pH 7.4) for 5 min at room temperature. They were then incubated in 10 mM HEPES, 130 mM NaCl, 4.7 mM KCI, 5 mM MgCl2, 1 mM ethylenglycol-bis (ß-aminoethylether)-N-N'-tetraacetic acid, 0.1% BSA, 100 µg/ml bacitracin (pH 7.4), and 
100 pM [125I-Tyr4]-bombesin (2000 Ci/mmol; Anawa, Wangen, Switzerland) or 20 pM 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14; 2000 Ci/mmol; Anawa) in the presence or absence of 1 µM bombesin or [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) for 1 h at room temperature. Because each of the bombesin receptor subtypes is characterized by a specific rank order of potencies of GRP, bombesin, NMB, and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), the use of these four peptides as unlabeled competitors in displacement experiments allows us to identify the receptor subtypes predominantly expressed in tissues (20
, 21
, 25)
. Therefore, sections from selected tumors, labeled with 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), were incubated in the presence of increasing amounts of nonradioactive bombesin, GRP, NMB (Bachem, Bubendorf, Switzerland), and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) to generate competitive inhibition curves. These displacement experiments showed that a 50 nM concentration of each of the four competitors {bombesin, GRP, NMB, and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14)} given in successive tumor sections labeled with 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) was adequate to discriminate between the four receptor subtypes. This procedure was performed in all of the tumors in duplicate. After incubation, the sections were washed four times for 2 min each in 10 mM HEPES with 0.1% BSA (pH 7.4) at 4°C. Finally, the slides were rinsed twice for 5 s each at 4°C in distilled water. The slides were then dried at 4°C under a stream of cold air. The slides were placed in apposition to [3
H]hyperfilms (Amersham, Aylesbury, United Kingdom) and exposed for 7 days in X-ray cassettes. The autoradiograms were quantified using a computer-assisted image processing system, as described previously (13
, 14
, 23)
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In Situ Hybridization Histochemistry.
BB3 receptor mRNA was identified in selected tumors with in situ hybridization histochemistry on cryostat sections as described in detail previously (26)
. BB3-specific oligonucleotides that do not span the very conserved transmembrane domains of the human BB3 receptor gene (27)
were selected. The following oligonucleotide probes were used for in situ hybridization: BRS3-S5 acc aat tct tcc gaa cag cca tcc ttc tgc aag gta gtg agt tgc (nucleotides 313–357 from atg) and BRS3-S9 ggt cac act aat ttc aga cat ctg tat gct ccc agt gcc cgg gac (nucleotides 1111–1155 from atg). Sequence similarity searches were performed using all four of the oligonucleotide sequences against the GenBank database at National Center for Biotechnology Information, Bethesda, MD,3
with the BlastN program to detect possible homologies to other sequences (28)
. No strong homologies to human sequences were detected. The probes were synthesized and purified on a 20% polyacrylamide-8 M urea sequencing gel (Microsynth, Balgach, Switzerland). They were labeled at the 3'-end by using [
-32P]dATP (>3000 Ci/mmol; NEN, Life Science Products, Boston, MA) and terminal deoxynucleotidyltransferase (Roche Diagnostics, Mannheim, Germany) to specific activities of 0.9–2.0 x 104 Ci/mmol. Control experiments were carried out as reported previously (26)
to determine the specificity of the hybridization signal obtained.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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summarizes the results of the bombesin receptor subtype expression in 161 human tumors. From the 12 prostatic carcinomas tested, all expressed GRP receptors, whereas they were devoid of the other bombesin receptor subtypes. Similarly, 41 of 57 ductal breast carcinomas expressed GRP receptors, whereas no other subtype was found in significant amount. The results of the neuroendocrine gastroenteropancreatic tumors could be divided as follows: all 5 gastrinomas had preferentially GRP receptors, whereas 11 of 24 intestinal carcinoids preferentially expressed NMB receptors. Also 1 thymic and 1 bronchial carcinoid had preferentially NMB receptors. Interestingly, the neuroendocrine lung tumors much more frequently expressed BB3 receptors: 9 of 26 bronchial carcinoids and 1 of 1 large cell neuroendocrine carcinoma had preferentially BB3 receptors; furthermore, 7 of 9 SCLCs expressed bombesin receptors, 4 of them having BB3 receptors and 3 others having GRP receptors. Also renal cell carcinomas expressed bombesin receptors (8 of 16), either BB3 receptors alone (2 of 16), GRP receptors alone (4 of 16), or both subtypes together (2 of 16). Finally, 2 of the 10 tested Ewing sarcomas expressed BB3 receptors (Table 1)
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in a GRP receptor-expressing prostate carcinoma. Table 2
shows the IC50s for the different ligands measured in a series of GRP receptor-expressing tumors. Conversely, the tumors with a predominant expression of NMB receptors were characterized by a very high affinity for NMB and for [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), a moderate affinity for bombesin, but a very low affinity for GRP. An example of a displacement curve using a NMB receptor-expressing ileal carcinoid is shown in Fig. 1
. Table 2
summarizes the IC50 values for the four peptides, as measured in several NMB receptor-expressing tumors. Furthermore, all of the tumors expressing predominantly BB3 receptors were characterized by a very high affinity for [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) only, whereas NMB had a low affinity, and GRP and bombesin an even lower affinity. An example of a displacement experiment in a BB3 receptor-expressing bronchial carcinoid is shown in Fig. 1
. IC50 values calculated in six bronchial carcinoids are shown in Table 2
for the corresponding analogue peptides. In this study, we have not seen tumors having a pattern of rank order of potencies for peptides corresponding to BB4 receptors. Such a BB4 profile would retain a very high affinity for [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) but also a high affinity for NMB and bombesin, and a high to moderate affinity for GRP (25)
; a BB4-selective analogue is presently lacking that would allow us to assess more specifically the presence of BB4 receptors.
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Fig. 2
is an autoradiographic illustration of the receptor status in three different tumors predominantly expressing GRP receptors, NMB receptors, or BB3 receptors. The GRP receptor-expressing prostate carcinoma shows a very strong binding in the tumor area of 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), which is completely displaced by 50 nM of bombesin, GRP, or [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), whereas it is virtually not displaced by 50 nM of NMB. Conversely, the NMB receptor-expressing intestinal carcinoid is strongly labeled by 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), and it is fully displaced by 50 nM NMB or 50 nM of the universal bombesin ligand [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14); moreover, it is displaced to a large extent by 50 nM bombesin but only poorly by 50 nM GRP. Finally, the BB3 receptor-expressing SCLC is also strongly labeled by 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) but is fully displaced by 50 nM of unlabeled [D-Tyr6, ß-Ala11, Phe13, Nle14] bombesin(6–14) only and not by 50 nM bombesin, GRP, or NMB.
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reports the mean density for the various bombesin receptor subtypes identified in several types of tumors. Prostate carcinomas and gastrinomas are usually characterized by a very high density of GRP receptors, whereas SCLCs have only a low density. Ileal carcinoids express a high density of NMB receptors. Neuroendocrine lung tumors have a high density of BB3 receptors, especially the bronchial carcinoids, whereas renal cell cancers and Ewing sarcomas have a low density only.
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is an example of a bronchial carcinoid containing abundant BB3 mRNA detected with in situ hybridization using the BRS3-S5 probe. This tumor was also strongly BB3 receptor-positive on receptor autoradiography.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The mRNAs of the various bombesin receptor subtypes have been detected previously in several human tumors, in particular mRNA for GRP receptors in prostate cancers, ovarian cancers, renal cancers, and colorectal cancers (11 , 15 , 29 , 30) , whereas mRNAs for NMB or BB3 were found less frequently or were even absent in these tumors (11 , 29 , 30) . The GRP receptor proteins have also been frequently found overexpressed in tumors such as prostate cancers, breast cancers, renal cell carcinomas, and lung cancers (12, 13, 14, 15 , 31) . However, the BB3 receptor proteins have never been detected in primary human tumors before. The NMB receptor proteins have only been identified in tumor cell lines; Moody et al. (32) have reported recently that functional NMB receptor proteins were present on several SCLC cell lines. The present study identifies NMB receptors in primary human cancers, predominantly in carcinoids originating from the gastrointestinal tract. We also show that there is a preferential expression of BB3 receptors in primary lung tumors having a neuroendocrine origin, namely bronchial carcinoids, SCLCs, and a large cell neuroendocrine carcinoma. These data suggest that carcinoids of bronchial and gut origin may be distinguished on the basis of their bombesin receptor subtypes. Because various types of neuroendocrine lung tumors (carcinoids, SCLCs, and large cell neuroendocrine carcinoma) can express BB3, it is conceivable that the neuroendocrine cells from which these tumors originate may express BB3 receptors. Evidence that BB3 receptors can be expressed in certain human neuroendocrine cells has been given recently, with the finding of BB3 receptors in human pancreatic islets (22) . Furthermore, BB3 receptors are also found in low density in two other distinct neoplastic entities, namely in some of the renal cell carcinomas and in a few Ewing sarcomas.
The method used in the present study, based on the binding of a universal radioligand to all bombesin receptor subtypes and its displacement by subtype-selective competitors, allows us to clearly identify the receptor subtypes that are predominantly expressed in a tumor; however, the method will not identify small amounts of additional bombesin receptor subtypes present in a low proportion in the same tumor, because those would be masked by the strong binding to the predominantly expressed receptor type (33) . Moreover, one should be aware that measuring bombesin receptors with binding techniques is notoriously problematic in certain tumors (15) because of the presence of high amounts of membrane-bound endopeptidases that are able to rapidly degrade bombesin (34) . This was reported in particular for gastrointestinal tumors (34) . Therefore, it cannot be completely excluded that the reported incidence of GRP, NMB, and BB3 receptor-expressing tumors is somewhat underestimated because of a false-negative receptor status in some of the tested tumors (15) . Nevertheless, the present data confirm the high incidence and high density of GRP receptors in prostate and breast carcinomas reported previously (13 , 14 , 31) and indicate that only a very low density, if any, of the other bombesin receptor subtypes may be present in theses tumors. This is in accordance with a recent mRNA study by Sun et al. (11) performed in prostate cancers showing that the majority of the tumors had GRP receptor mRNA, whereas only very few had mRNA for NMB receptors or for BB3 receptors. We can also confirm the presence of GRP receptors in renal cell carcinomas, reported recently by Pansky et al. (15) with binding assays and PCR methods. We could not only detect GRP receptors in some of the tested renal cell carcinomas but identify the presence of BB3 receptors in some of them as well.
Little information is available about the role and function of the NMB and BB3 receptors in cancer (35) ; however, a recent report by Weber et al. (36) gives first indications that the BB3 activation may cause cancer cell proliferation, since the analogue [D-Phe6, ß-Ala11, Phe13, Nle14]bombesin(6–14) caused increased nuclear oncogene expression, mitogen-activated protein kinase phosphorylation, and ELK.1 activation in lung cancer cells. The presence of these receptor subtypes in selected human tumors may allow us to investigate in more detail the function of these receptors in these tumors to identify new applications of bombesin analogues in the clinic.
The discovery of BB3 and NMB receptor expression in human tumors may suggest several clinical applications. For instance, the development of BB3- or NMB-selective analogues suitable for clinical applications may be of interest to visualize and treat selected tumors. A BB3-selective analogue has been recently developed by Mantey et al. (37) ; it should be possible to attach a chelator (diethylenetriaminepentaacetic acid or 1,4,7,10-tetra-azacylododecane N,N',N'',N'''-tetraacetic acid) to this analogue to have a radiopharmaceutical suitable for in vivo clinical investigations. Clinical applications of such compounds may include tumor targeting for the visualization of receptor-positive tumors and their metastases as well as for the radiotherapy of such tumors (38, 39, 40) . Linear bombesin analogues are known to be susceptible to degradation by proteases including the BB3-selective analogue [D-Phe6, ß-Ala11, Phe13, Nle14]bombesin(6–14) that has a half-life of <1 h. It is presently unclear to which extent this proteolytic effect may represent a problem for targeting. However, it has been shown that tumors are usually labeled within a few minutes after radiopeptide tracer injection (41) , suggesting that most of the radioligand uptake occurs during the first passage, i.e., before most of it is degraded. Highly encouraging in this regard is the successful visualization of GRP receptor-expressing prostate and breast cancers reported recently by Van de Wiele et al. (40) with a 99mTc-labeled linear GRP analogue. Moreover, the distinct bombesin receptor subtype expression in bronchial and gut carcinoids may permit us to distinguish the bronchial from the gastrointestinal origin of liver metastases of a carcinoid with unknown primary location, by identifying its BB3 or NMB receptor expression, respectively, in vitro in needle biopsies of liver metastases. An additional clinical application could be the use of subtype-selective analogues linked to cytotoxic drugs, in analogy to the bombesin analogues linked to doxorubicin developed previously by Nagy et al. (42) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, CH-3010 Berne, Switzerland. Phone: 41-31-63-23-24-2; Fax: 41-31-63-28-99-9; E-mail: reubi{at}patho.unibe.ch 
2 The abbreviations used are: GRP, gastrin-releasing peptide; SCLC, small cell lung carcinoma; NMB, neuromedin B.
3 Internet address: http://www.ncbi.nlm.nih.gov/.
Received 9/21/01; revised 12/28/01; accepted 1/ 7/02.
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REFERENCES |
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), GRP (
), NMB (
),[D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14; •), and 1000 nM of somatostatin (
). The GRP receptors in the tumor in the top graph are characterized by a high affinity for GRP, bombesin, and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) but a very low affinity for NMB and no affinity for somatostatin. The NMB receptors in the tumor in the middle graph are characterized by a high affinity for NMB and [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14), moderate affinity for bombesin, and very low affinity for GRP. The BB3 receptors in the tumor in the bottom graph are characterized by high affinity for [D-Tyr6, ß-Ala11, Phe13, Nle14]bombesin(6–14) but a low affinity for NMB and an even lower affinity for bombesin, GRP, and somatostatin.
