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From the Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, 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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Bombesin-like peptides include the
amphibian peptide bombesin as well as the mammalian counterparts GRP
and neuromedin B.11
These peptides have been shown to be
mitogenic, causing growth of 3T3 murine fibroblasts12
and
normal bronchial epithelial cells13
in culture. They have
been implicated in the development of the fetal lung14
and
of diseases of the lung.15
Small-cell lung carcinoma cell
lines produce and secrete GRP and express high affinity receptors for
bombesin-like peptides, thus establishing an autocrine growth loop,
involved in the abnormal growth of these tumors,16
as
established also for several polypeptide growth factors, such as
transforming growth factor-
and insulin-like growth
factor.17
Likewise, GRP and bombesin may control growth in breast cancer cells as well.18 For instance, bombesin stimulates early signal transduction mechanisms (eg, activation of inositol phospholipid signaling and Ca2+ efflux) in human breast cancer cell line MCF-7.19 Human breast cancer cell lines were shown to bear GRP receptors by competitive binding of bombesin-like peptides.20
GRP mediates its action through specific membrane-bound receptors. The receptors correspond to one of the subtypes of the bombesin-like peptide receptors, namely the GRP receptor, which is characterized by high-affinity binding for GRP and bombesin and only moderate binding for neuromedin B. These receptors are members of the large superfamily of G protein-coupled receptors with seven transmembrane domains. If GRP receptors, as stated above, mediate the mitogenic action of GRP and bombesin-like peptides in neoplasias, the information about the presence of GRP receptors in primary human tumors is crucial for the understanding of GRP action in this tissue. Moreover, to evaluate the potential clinical implications of GRP and GRP receptor in patients with cancer, it is mandatory to know the incidence and the density of GRP receptors in human primary carcinoma tissue. The method of choice is in vitro receptor autoradiography performed on tissue sections,21 which allows localization in situ with high sensitivity of peptide receptors in tumor samples obtained after surgical resection. Such complex and heterogeneous tissue may contain, in addition to carcinoma tissue, contaminating tissues from the involved organs, vessels, nerves, and immune cells and needs to be analyzed morphologically. This in situ method, in comparison with methods using tissue homogenates,22 allows the distinguishing of the receptor expression in non-neoplastic tissue and of its malignant counterparts in each individual tissue sample.
The aim of this study was to evaluate, with in vitro receptor autoradiography on tissue sections, using [125I]Tyr4-bombesin, as well as [125I]D-Tyr6, ß Ala11, Phe13, Nle14-bombesin(6–14)23,24 as radioligands, the incidence and the density of GRP receptors in breast carcinoma samples containing various stages of neoplastic transformation as well as non-neoplastic breast.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breast tissue samples with primary breast neoplasias were obtained
from 56 patients, aged 36 to 84, who were operated on in several
institutions. Tissue samples were kept frozen at -80°C. Table 1
lists the histopathological types of
the investigated breast carcinomas. The diagnosis was reviewed and
formulated by use of cryostat sections, according to the WHO guidelines
stated by Tavassoli.25
Of 56 patients, 46 (82%) showed an
invasive ductal carcinoma, representing almost the natural incidence of
this carcinoma type.25
Histological evaluation identified
23 cases with intermediate (G2), 18 cases with low (G1), and 5 cases
with high (G3) grade, according to a modified Bloom-Richardson grading
method.25
There were four invasive lobular carcinomas and
four ductal carcinomas in situ, as well as one tubular and
one mucinous carcinoma. Of the tissue samples with invasive ductal
carcinoma, 13 contained concomitant ductal carcinoma in
situ, and 2 with invasive lobular carcinoma contained concomitant
lobular carcinoma in situ. In 7 patients, we could
investigate tissue samples obtained from the primary tumor and from all
its axillary metastases; carcinoma type, age, tumor size, and
progesterone and estrogen receptor status at the time of diagnosis are
listed below. We investigated the non-neoplastic breast tissue adjacent
to carcinoma tissue in 22 tissue samples and the breast tissue sample
of a patient operated on for suspicion of carcinoma but with a final
diagnosis of breast fibrosis. Those breast tissues were all found to be
histopathologically inconspicuous.
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Twenty-µm-thick cryostat sections of the tissue samples were processed for GRP receptor autoradiography as described in detail previously for other peptide receptors.26 One radioligand used was [125I]Tyr4-bombesin, known to specifically label GRP receptors.4,27 The other radioligand used was [125I]D-Tyr6, ß Ala11, Phe13, Nle14-bombesin(6–14) known to label all four bombesin receptor subtypes.23,24 For autoradiography, tissue sections were mounted on precleaned microscope slides and stored at -20°C for at least 3 days to improve adhesion of the tissue to the slide. Sections were then processed according to Vigna et al.27 They were first preincubated in 10 mmol/L N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.4, for 5 minutes at room temperature. They were then incubated in 10 mmol/L N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, 130 mmol/L NaCl, 4.7 mmol/L KCl, 5 mmol/L MgCl2, 1 mmol/L ethylene glycol-bis (ß-aminoethylether)-N-N'-tetraacetic acid, 0.1% bovine serum albumin, 100 µg/ml bacitracin (pH 7.4), and approximately 100 pmol/L [125I]Tyr4-bombesin (2000 Ci/mmol; Anawa, Wangen, Switzerland) in the presence or absence of 10-6 mol/L bombesin for 1 hour at room temperature. Additional sections were incubated in the presence of increasing amounts of nonradioactive bombesin, GRP, neuromedin B, or somatostatin to generate competitive inhibition curves. After incubation, the sections were washed four times for 2 minutes each in 10 mmol/L N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid with 0. 1% bovine serum albumin (pH 7.4) at 4°C. Finally, the slides were rinsed twice for 5 seconds 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 3H-Hyperfilms (Amersham, Aylesbury, UK) and exposed for 4 to 7 days to X-ray cassettes. All cases tested with [125I]Tyr4-bombesin were also evaluated with [125I]D-Tyr6, ß Ala11, Phe13, Nle14-bombesin(6–14) as ligand, using the same methodology, except that 20 pmol/L of this radioligand (2000 Ci/mmol; Anawa, Wangen, Switzerland) was given in the incubation solution.
The autoradiograms were quantified using a computer-assisted image processing system, as described previously.4,26 Tissue standards for iodinated compounds (Amersham) were used for this purpose. A tissue was defined as receptor-positive when the optical density measured in the total binding section was at least twice that of the nonspecific binding section (in the presence of 10-6 mol/L bombesin).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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summarizes the GRP receptor incidence in breast carcinoma
tissue. GRP receptors were expressed in a total of 29 of the 46
invasive ductal carcinomas. Furthermore, there was a limited number of
tested cases of invasive lobular carcinoma and tubular and mucinous
carcinomas, also often expressing GRP receptors (Table 1)
. Finally,
carcinomas in situ, both ductal and lobular, expressed GRP
receptors in 12 of 19 cases. The receptor distribution in the tumor
samples was heterogeneous in more than half of the cases. As shown in
Figure 1
, the density of the receptors
varied very much from one case to another and encompassed low (417
dpm/mg of tissue) to very high (19,126 dpm/mg of tissue) values. Even
within a single tumor, large variations of GRP receptor density were
observed in different areas. Figure 1
also compares the GRP receptor
density values of the tumors with that of non-neoplastic breast tissues
(n = 23), most of them adjacent to the tumor
tissue samples, and illustrates the same broad range of density levels
in both tissues. Interestingly, non-neoplastic breast tissues showed,
without exception, a heterogeneous distribution of the GRP receptors.
Figure 2
illustrates two typical cases of
invasive ductal carcinoma samples, one receptor-positive (Figure 2, A–C)
and one receptor-negative (Figure 2, D–F)
, both, however, with
receptor-positive adjacent breast tissue. Figure 3
shows a GRP receptor-positive invasive
lobular carcinoma sample, with the tumor distributed diffusely in the
breast stroma, showing characteristic lines of a few carcinoma cells
between collagenous fibers, so called Indian files (Figure 3D)
. This
typical distribution of tumor cells is also reflected in the
radioactivity pattern of the autoradiogram (Figure 3B)
as small dots.
The apparent lower receptor density in this lobular carcinoma may be
due partly to the lower tumor cellularity that is frequent in this type
of tumor.
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, Figure 1
). In the present
series, 15 of the samples contained concomitant carcinomas and
carcinomas in situ (13 invasive ductal and 2 invasive
lobular). In most cases, the GRP receptor expression was comparable in
both carcinoma and carcinoma in situ (11 invasive ductal and
1 invasive lobular).
In seven patients with metastatic breast cancer, we have investigated
the tissue samples containing the primary tumor and all of its axillary
metastases. The summarized clinical data, including patient age,
carcinoma type, tumor size, and steroid receptor status, show these
patients to be a representative group with invasive mammary carcinomas.
Figure 4
depicts that four of the seven
primaries were GRP receptor-positive and that metastases of
receptor-positive primary carcinomas were all positive, with usually a
comparable range in GRP receptor density levels in primary tumors and
in metastases. Most of these metastases had a homogeneous GRP receptor
distribution, even those arising from heterogeneously positive primary
carcinomas. In this series, GRP receptor-negative primary carcinomas
had only receptor-negative metastases. Figure 5
illustrates a case with a GRP
receptor-positive primary tumor and a positive axillary metastasis of
the same patient. The primary tumor represents an example of a GRP
receptor-positive invasive ductal carcinoma next to a receptor-positive
ductal carcinoma in situ, as reported above. The lymph node
metastasis is homogeneously positive, with receptor-negative adjacent
lymphatic tissue.
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, cancer-bearing breast; and Figure 6D
,
non-cancer-bearing breast). The receptor distribution was ubiquitously
heterogeneous with lobules and ducts strongly GRP receptor-positive
while others were completely negative (Figure 6)
. The number of the
identified receptor-positive ducts and lobules varied between 20% and
more than 80% of the total number detected in a section, based on
estimates by visual inspection. The range of density values of the
positive tissues varied from moderate (1144 dpm/mg of tissue) to very
high (20,282 dpm/mg of tissue) values (Figure 1)
. The presence of GRP
receptors in the non-neoplastic breast did not correlate with the
degree of GRP receptor expression of the adjacent carcinoma (Figure 2)
or with the distance of the investigated breast tissue from the
carcinoma tissue.
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, there was a high-affinity binding in
the nanomolar range for GRP and bombesin and a lower-affinity one for
neuromedin B, characteristic for the GRP receptor subtype.
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illustrates a typical case with
similar labeling of non-neoplastic and neoplastic breast tissue with
both radioligands.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The GRP receptors in the primary carcinomas are often heterogeneously distributed. It is well established that breast carcinomas may contain different tumor clones with distinct biological parameters. These clones may have different GRP receptor expression. A highly heterogeneous distribution has been reported previously in breast carcinoma for other receptors, ie, somatostatin, estrogen, and progesterone receptors.28,29 Interestingly, this study shows that the metastases of the receptor-positive primary tumors have mostly a homogeneous receptor distribution. One may speculate that, if there are different tumor clones with distinct GRP receptor expression, the receptor-positive clones would metastasize easier than negative ones.
Although GRP receptors were previously detected in cell lines of breast carcinoma by receptor-binding techniques,20,22 this is the first morphological study of GRP receptor in breast cancer by autoradiography. Compared with binding studies in cell lines or tissue homogenates, in which a 33% incidence of GRP receptor-positive breast carcinomas was found,22 a significantly higher incidence of receptor-positive cases could be identified, however. The different incidence numbers may be due to methodological differences. Different assay conditions may be responsible for different sensitivities of detection. Moreover, the autoradiographic technique, as a morphological method, can assign the identified receptors to the various tissue compartments of the whole sample, ie, to the tumor tissue as well as to parenchyma, stroma, adipose tissue, vessels, or nerves. The use in this study of two different radioligands specific for bombesin receptors and giving identical results is a strong argument in favor of the specificity of the reported findings.
Another main result of this study is the demonstration of GRP receptors in non-neoplastic breast glands in all investigated tissue samples. Both lobules and ductules express receptors, ranging from moderate- to very high-density values. It is interesting that, in all tissues, the receptor distribution is heterogeneous, namely with groups of receptor-positive lobules or ducts adjacent to receptor-negative ones. The high incidence of GRP receptors found in the breast in this study contrasts with the much lower incidence of hormone receptors such as estrogen and progesterone receptors in normal human breast tissue. In the mean, 7% of mammary epithelial cells or even less expressed estrogen receptors,30,31 and 12% expressed progesterone receptors.30 The distribution pattern of these receptors has also been described to be heterogeneous in ductules and lobules,32 as it is found for GRP receptors. The reason for such a GRP receptor heterogeneity in normal tissue is not clear and needs further investigations. Because in our study the sample size containing non-neoplastic breast tissue was often small, the percentage of receptor heterogeneity may not be representative for the whole breast. The observed heterogeneity could be related to a heterogeneous innervation pattern of the glands and lobules, assuming that GRP plays a neurotransmitter role in the breast, as it does in the gastrointestinal tract.14
The pharmacological characterization by competition experiments reveals the GRP receptor as the main bombesin receptor subtype involved in non-neoplastic and malignant breast tissue. Bombesin and GRP show a very high affinity, and neuromedin B a lower one, as expected for this receptor subtype;33 unrelated peptides like somatostatin show no affinity. The use of picomolar concentrations of radioligand (as low as 20 pmol/L) that can be fully displaced by nanomolar amounts of unlabeled bombesin and GRP is a strong argument of the very high affinity of these binding sites. The receptor subtyping is important information considering the large number of synthetic analogs having a high affinity for precisely this GRP receptor subtype.
The autoradiographic method allows also to investigate peritumoral vessels and other tumor-surrounding tissues.34 It is important to note that the lymphatic tissues surrounding the lymph node metastases were always GRP receptor-negative. Moreover, in breast cancer, peritumoral vessels and stromal tissues were not expressing GRP receptors at difference to what is seen with somatostatin receptors in several tumor types.34,35 Therefore, in the resected tissue samples and with the methodology used, only breast tissue, non-neoplastic or neoplastic, is massively GRP receptor-positive.
Although a possible physiological action of GRP in normal breast tissue is so far unknown, the strong GRP receptor expression in non-neoplastic human breast tissues suggests a specific GRP action in this tissue. For such an in vivo action, not only a functional receptor is required but also the presence of the corresponding endogenous ligand in the immediate surroundings. GRP has not been detected in normal human breast tissue so far.36 However bombesin-like immunoreactivity was shown in human breast cyst fluids37 and in human milk.38 The concentration of bombesin-like immunoreactivity in human breast milk was threefold greater than the corresponding plasma concentration.39 Moreover, patients with benign breast disease showed a significantly higher bombesin-like immunoreactivity concentration in the blood than did healthy patients.40 Moreover, in other species, for instance the cow, GRP could be identified in the mammary glands.15 These data may represent indirect evidence of an endogenous source of bombesin-like peptides in normal breast tissue or, at least, that the endogenous peptide may be reaching the breast tissue.
The presence of endogenous bombesin-like peptides in breast carcinomas is more extensively documented and may support the proposal of a functionality of GRP receptors. Bombesin-like peptides in breast carcinoma tissues have been detected by immunological methods,41 by Northern blot analysis for GRP-mRNA,42 and, in the blood of breast carcinoma patients, by immunoassays.40 Moreover, there is evidence for a role of bombesin-like peptides in the growth of breast cancer cells.18 An autocrine growth-stimulatory effect of bombesin has been shown in small-cell lung carcinoma in vivo.16 Such a mechanism of action was also proposed for breast carcinomas.42 Our study, therefore, by showing clearly the presence of an essential constituent of this regulatory feedback loop, namely the GRP receptors, in breast carcinomas, supports such a proposal.
The expression of GRP receptors in breast carcinomas may have clinical implications. For diagnostic purposes, the identification of a high expression of tumoral GRP receptors with GRP receptor scintigraphy may be a potentially valuable tool to visualize breast tumors, in particular their axillary lymph node metastases. The high receptor density and homogeneous distribution in axillary lymph node metastases compared with the lack of GRP receptors in surrounding lymphoreticular tissue (high tumor to background ratio) may represent a crucial argument for optimal diagnosis of metastases. From a therapeutic point of view, it should be noticed that, over the last few years, potent and selective bombesin antagonists have been developed.43-45 These compounds show, in animal tumor models and human cell lines, a strong inhibition of breast cancer growth.18,46 Further, bombesin analogs have been designed as carriers for cytotoxic drugs, which were also shown to inhibit the growth of cancer cell lines.47 Therefore, the application of this type of compound as a long-term treatment of breast cancer may be considered as a future therapeutic goal. In addition to a possible cytotoxic drug therapy, the recent synthesis of bombesin analogs linked to ß-emitters may permit their use for radiotherapy48 to destroy GRP receptor-positive tumors, comparable with the use of 90Y-labeled octreotide to destroy somatostatin receptor-positive tumors.8
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Footnotes |
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Accepted for publication August 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-melanotropin immunoreactants in human milk. Regul Pept 1985, 10:99-105[Medline]
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)
or heterogeneous (
)
GRP receptor distribution. Axillary metastases are with either
homogeneous (
) or
heterogeneous (
) GRP
receptor distribution.
).
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 analogs is characteristic for the GRP
receptor subtype.