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Tumor Biology |
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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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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GRP2 belongs to the family of bombesin-like peptides that includes the amphibian peptide bombesin as well as the mammalian counterparts GRP and neuromedin B (11) . These peptides have been shown to play a role in various tumor models and in human cancer. For instance, they were shown by the group of Rozengurt et al. (12) to be mitogenic in Swiss 3T3 cells. Moreover, Cuttitta et al. (13) showed that bombesin and GRP can stimulate small cell lung cancer growth and that this action is part of an autocrine feedback mechanism involving the expression of these peptides as well as their receptors in the tumor cells (14 , 15) . More recently, GRP and bombesin were shown to play a possible role in prostate cancers as well. For instance, it was shown that GRP can stimulate cell proliferation in the androgen-independent human prostatic carcinoma cell line PC3 and that antagonists of the GRP receptor inhibit the growth of a number of prostatic carcinoma models, either cancer cells in vitro or xenografts in syngeneic rats or nude mice (16, 17, 18, 19) .
GRP mediates its action through membrane-bound receptors. These receptors correspond to one of the subtypes of the bombesin-like peptide receptors, namely the GRP receptor, which is characterized by a high-affinity binding for GRP and bombesin and only a moderate affinity for neuromedin B. These receptors are members of the large superfamily of G-protein-coupled receptors with seven transmembrane domains. Bombesin-like peptide receptors seem to mediate the mitogenic action of bombesin-like peptides in neoplasias; therefore, the information about the presence of bombesin-like peptide receptors, in particular of GRP receptors, is crucial for the evaluation of the bombesin-like peptide action in tumors. GRP receptors have been detected in various types of tumor cell lines (20, 21, 22, 23) . To predict the potential implications of bombesin-like peptides in patients with prostatic cancers, it is mandatory to know the incidence and the density of GRP receptors in primary human tumor tissues. For such an evaluation, the method of choice is in vitro receptor autoradiography (24) . It allows the localization of peptide receptors in complex tumor samples obtained after surgical resection. In addition to prostatic carcinomas, such tissues usually contain normal prostate, hyperplastic prostate, and often PIN (25) . This morphological method, therefore, allows us to distinguish the receptor expression in the nonneoplastic prostate and its malignant counterparts in individual tissue samples.
The aim of the present study was the evaluation of the incidence and the density of GRP receptors in a large number of human prostatic samples containing normal prostate and various stages of prostatic neoplastic transformation. The method used was in vitro receptor autoradiography on tissue sections, using iodinated [Tyr4]-bombesin as radioligand.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In addition, seven samples of prostate cancer, metastatic to the bones and refractory to hormone treatment (androgen-independent), obtained previously from the University of Uppsala (26)
, were investigated. The diagnosis and grading were reviewed and formulated by use of cryostat as well as paraffin-embedded sections, according to the guidelines issued by Mostofi (WHO; Ref. 27
). All of the tumor samples were evaluated for their Gleason scores (28)
. The high-grade PIN stage was also evaluated in cryostat sections and defined as atypical prostatic intraepithelial proliferation containing basal cells identified immunohistochemically by the presence of high molecular weight cytokeratins (i.e., 34ßE12 antibody) to make a distinction from invasive cribriform carcinomas (29
, 30)
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The autoradiograms were quantified using a computer-assisted image processing system, as described previously. (31) . Tissue standards for iodinated compounds (Amersham) were used for this purpose. A tissue was defined as receptor-positive when the absorbance measured in the total binding section was at least twice that of the nonspecific binding section (in the presence of 10-6M bombesin).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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summarizes the GRP receptor status in prostate tissues. The data obtained by quantitative receptor autoradiography from the resected prostate samples of all 36 of the prostate cancer and the 14 bladder cancer patients are listed. Four types of tissues were investigated: (a) invasive prostatic carcinoma; (b) high-grade PIN; (c) prostatic hyperplasia; and (d) prostatic stroma; however, not all of the samples contained invasive prostatic carcinoma and/or high-grade PIN tissue. In a few samples resected at the border of the carcinoma and devoid of neoplastic tissue, GRP receptors were quantified only in the stroma and hyperplastic glands.
Table 1
shows that neoplastic prostatic tissue expresses GRP receptors very frequently:
(a) All of the 30 cases with primary invasive prostatic carcinomas were found to express GRP receptors. In the majority (83%) of the cases, a high to very high density of receptors (>1000 dpm/mg tissue) was found (Table 1
, No. 1–21 and 37–40); in five cases (No. 12, 16, 19, 21, and 22) a heterogeneous distribution of the receptors within adjacent tumor regions was found. The only three available cases with high (i.e., 7–9) Gleason scores (No. 21, 24, and 26) were all associated with a very low density of GRP receptors. One case with the lowest levels of GRP receptors was identified as G3 grade with a Gleason score of 9; this patient did not have elevated levels of prostate-specific antigen in the serum (below 4 ng/ml), suggestive of a particularly poor differentiation or dedifferentiation of the tumor;
(b) All of the 26 tissue samples containing an area of PIN were GRP receptor-positive. All but one case (No. 45) had high to very high densities of GRP receptors. The PIN area quantified for GRP receptors consisted primarily of high-grade PIN, in particular PIN III, as a clearly identifiable stage (25) . PIN I, which is extremely difficult to distinguish from hyperplasia in cryostat sections (25) , may have been present in some of the cases but was not evaluated separately. In several cases, a heterogeneous distribution of GRP receptors was observed, with some PIN devoid of receptors located next to PIN with high receptor values (i.e., No. 44), possibly as a reflection of the different PIN stages (I, II, III) present in these samples.
In addition, Table 1
shows that nonneoplastic prostatic tissue only rarely expressed a measurable amount of GRP receptors, and normal prostatic glandular epithelium did not express GRP receptors; prostatic hyperplasia expressed GRP receptors in 23 of 50 cases; however, in all but two of these cases (No. 4 and 27), the density of the receptors was very low, <500 dpm/mg tissue. The prostatic stroma was GRP receptor-positive in 16 of 50 cases; however, in these positive cases, the prostatic stroma was only focally GRP receptor-positive, i.e., receptors were found in a restricted area of the whole prostatic stromal tissue; stromal values in Table 1
represent GRP receptor densities measured in stromal sites having the highest labeling found within a sample. Except for three cases (No. 13, 39, 44), the peak receptor density values obtained under these measurement conditions were below 1500 dpm/mg tissue.
Among the seven bone metastases of androgen-independent prostatic cancers [all of them of poor differentiation (G3)], four cases were GRP receptor-positive (respective values: 9402, 1226, 4800, and 600 dpm/mg tissue).
A comparison of the GRP receptor expression in malignant neoplastic prostatic tissue versus nonneoplastic prostatic tissue shows, as seen in Table 1
, that the receptor incidence is much higher in carcinoma tissue and high-grade PIN as compared with nodular hyperplastic prostate and stroma; also the receptor density, calculated as the mean of all of the values (Table 2)
, is much higher in prostate carcinoma and high-grade PIN as compared with prostatic hyperplasia. In every single case, the receptor density is usually considerably higher in the neoplastic GRP receptor-positive tissues than in the surrounding nonneoplastic GRP receptor-positive tissues.
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illustrates an example of a strongly GRP receptor-positive invasive prostatic carcinoma adjacent to a receptor-negative prostatic hyperplasia. Fig. 2
, A–C, illustrates a case consisting of an area of GRP receptor-positive high-grade PIN surrounded by receptor-negative normal prostate gland. Fig. 2 (D–F)
demonstrates high densities of GRP receptor expression in a high-grade PIN area with one adjacent PIN devoid of GRP receptors. Here, PIN is defined by the presence of basal cells positively immunostained for high molecular weight cytokeratins. Fig. 3
shows a GRP receptor-positive bone metastasis from an androgen-independent invasive prostatic carcinoma. Fig. 4
is an example of a focal area of GRP receptor-positive prostatic stroma surrounded by receptor-negative prostatic hyperplasia as well as additional receptor-negative stromal tissue.
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, there was high-affinity binding for GRP and bombesin and lower affinity for neuromedin B. Unrelated peptides like somatostatin were inactive. The same receptor subtype was also identified in the bone metastasis (Fig. 5)
and in the prostatic stromal tissue (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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High-grade PIN is defined as a moderate (PIN II) to severe (PIN III) intraductal dysplasia, containing numerous cells with large nucleoli identical to the cells found in prostatic carcinomas and characterized by the retention of the basal cells (25) . Present evidence from the literature supports the contention that high-grade PIN is a precursor of prostatic carcinoma. These lesions are highly associated with coexistent prostatic cancers and have similar DNA ploidy, antigenic composition, and kinetic potentialities (25) . It is recognized that detailed knowledge of PIN may have important impact on future patient care; therefore, a marker of this histological entity, such as GRP receptors, may be of considerable clinical interest.
The prostatic carcinomas examined in this study were mainly of a differentiated grade (G1 and G2 with Gleason scores of 3–6). There were only three poorly differentiated (G3 with Gleason scores of 7–9) prostatic carcinomas included in this study. Despite the uneven representation of the three differentiation grades G1, G2, and G3, it may be suggested, based on the low GRP receptor level in the few poorly differentiated prostatic carcinomas, that undifferentiated primary prostate carcinomas may not express or perhaps may have lost some of their GRP receptors. It is unclear yet whether the same general conclusion is valid for the androgen-independent bone metastases because they can sometimes express high levels of GRP receptors even though they are poorly differentiated. More G3 cases, both primary tumors and metastases, will be necessary for a more detailed evaluation of this aspect.
In a few cases a heterogeneous distribution of receptors was observed in histologically homogenous tumor areas. Heterogeneous receptor distribution was more often seen in tumors with a lower number of GRP receptors, reflecting possibly the presence of poorly differentiated tumor regions. It is also possible that the observed receptor heterogeneity is due to the presence of different tumor clones.
Several subtypes of the bombesin-like peptide receptors have been described: the neuromedin B receptor with high affinity for neuromedin B, the GRP receptor with high affinity for GRP but lower affinity for neuromedin B (33 , 34) , and the bombesin 3 receptor subtype, an orphan receptor for which no endogenous ligand has yet been found (35) . The pharmacological characterization of the receptor subtype in malignant neoplastic prostate tissues, as identified in the present study, points clearly toward the GRP receptor subtype, with very high affinity for GRP and bombesin and lower affinity for neuromedin B. This is in agreement with a recent in situ hybridization study evaluating the mRNAs for the three bombesin-like peptide receptor subtypes in prostatic tissues: only the GRP receptor subtype mRNA was detected both in nonmalignant and malignant prostate tissues (36) . The mRNA staining in cancerous tissue ranged widely from very intense to not detectable, whereas nonmalignant tissue displayed a low level of message (36) . These data may point toward an up-regulation of the GRP receptor expression in prostate neoplasia; gene up-regulations, for instance of the COSVIc gene, have recently been identified in prostate cancer, for which they may have diagnostic value (37) .
Although nonneoplastic prostatic tissues such as glandular hyperplasia and stroma were GRP receptor-negative in the majority of the cases, a few patients showed prostatic tissue or parts of prostatic tissue being weakly GRP receptor-positive. In those cases, the receptor density was usually several times lower in the nonneoplastic than in the neoplastic tissues. One possible explanation for the expression of a low density of receptors in prostatic hyperplasia may be the presence of an early phase of malignancy not readily detectable histologically in our cryostat sections. Alternatively, the GRP receptor expression seen in nonneoplastic prostate tissue in this study may be related to neuroendocrine elements known to be present in the normal prostate. Indeed, bombesin-like peptides and their receptors have been considered as markers of prostatic neuroendocrine tissues (38 , 39) . The very low level of receptors in hyperplastic glands could, therefore, represent GRP receptors located in the normal neuroendocrine cells of the glands (38 , 39) .
The observation of GRP receptors located in prostatic stroma is intriguing. The relative low incidence of cases with stromal GRP receptors as well as the focal distribution of these receptors suggest that it is not a general phenomenon, as compared for instance with the ubiquitous expression of somatostatin receptors in the smooth muscle cells of most of the prostatic tissue (40) . The stromal GRP receptor expression may be simply a local reaction to cancer; alternatively, it could be part of the physiological stromal-epithelial interactions, known to play a role in the prostate development (40 , 41) .
Even if the exact biological role of GRP receptors in the normal and neoplastic prostate is not yet established, the present in vitro receptor data have a number of important therapeutic and diagnostic implications. The very high GRP receptor density in prostatic invasive carcinomas and high-grade PIN suggests that prostate neoplasia represents an adequate type of cancer to perform GRP-related early clinical trials:
(a) Over the last several years, potent and selective bombesin antagonists have been developed (17 , 34 , 42) . Several of these antagonists are compounds which have been shown in various animal tumor models to strongly inhibit tumor growth (17 , 43) . Other bombesin analogues have been designed as carriers for the radicals doxorubicin and 2-pyrrolinodoxorubicin to create hybrid cytotoxic drugs (44) ; they were also shown to inhibit the growth of cancer cell lines, including PC3 human prostate cancer cells (44) . Therefore, the application of these types of compounds as long-term treatment of human prostate cancer may be considered as a future goal.
(b) In analogy to the diagnosis of somatostatin receptor-expressing tumors in vivo with somatostatin receptor scintigraphy, in vivo GRP receptor scintigraphy may be a potentially valuable tool to visualize prostate neoplasia with a noninvasive method. A high tumor:background ratio may be expected on the basis of the high GRP receptor density in these neoplastic tissues as compared with nonneoplastic prostate. In addition to the detection of invasive prostatic carcinoma, the possibility of detection of high-grade PIN is extremely attractive because it would represent an early detection of the tumor, just as the in vivo detection of distant metastases could be extremely useful. Radioligands that would make in vivo GRP receptor scintigraphy technically possible have recently been synthesized: these include primarily Technetium-labeled bombesin analogues (45, 46, 47) .
(c) As a logical consequence and further development, a radiotherapy comparable to that using 90Yttrium-labeled octreotide (8) , aiming at the destruction of GRP receptor-positive tumors, could possibly be envisaged using adequate bombesin analogues linked to ß emitters such as Rhenium-labeled bombesin analogues (45, 46, 47) . Not only the treatment of prostatic invasive carcinomas but also that of early neoplastic stages, such as high-grade PIN, would be of great potential interest.
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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: 41-31-632-3242; Fax: 41-31-632-8399; E-mail: reubi{at}patho.unibe.ch 
2 The abbreviations used are: GRP, gastrin-releasing peptide; PIN, prostatic intraepithelial neoplasia.
Received 11/ 3/98. Accepted 1/ 4/99.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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M. Sumitomo, R. Shen, J. S. Goldberg, J. Dai, D. Navarro, and D. M. Nanus Neutral Endopeptidase Promotes Phorbol Ester-induced Apoptosis in Prostate Cancer Cells by Inhibiting Neuropeptide-induced Protein Kinase C {{delta}} Degradation Cancer Res., December 1, 2000; 60(23): 6590 - 6596. [Abstract] [Full Text]
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 R. E. Carroll, K. A. Matkowskyj, M. S. Tretiakova, J. F. Battey, and R. V. Benya Gastrin-releasing Peptide Is a Mitogen and a Morphogen in Murine Colon Cancer Cell Growth Differ., July 1, 2000; 11(7): 385 - 393. [Abstract] [Full Text]
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 M. Gugger and J. C. Reubi Gastrin-Releasing Peptide Receptors in Non-Neoplastic and Neoplastic Human Breast Am. J. Pathol., December 1, 1999; 155(6): 2067 - 2076. [Abstract] [Full Text] [PDF]
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), neuromedin B (
), and somatostatin (
). High-affinity displacement of the trace is found with bombesin and GRP, whereas neuromedin B shows lower affinity. Somatostatin has no effect. Nonspecific binding was subtracted from all of the values. The observed rank order of potencies of these analogues is characteristic for the GRP receptor subtype.