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Departments of Biomedical Sciences and Human Oncology (M.P., P.C., M.V.), Pharmacology (G.M.), and Endocrinolgy (E.G.), University of Turin, I-10126 Turin, Italy; and Europeptides (R.D.), 95108 Argenteuil, France
Address all correspondence and requests for reprints to: Mauro Papotti, M.D., Department of Pathology, University of Turin, Via Santena 7, I-10126 Torino, Italy. E-mail: mauro.papotti{at}unito.it
Abstract
Ghrelin is a novel gastrointestinal hormone produced by about 20% of the rat and human gastric neuroendocrine cell population, which possesses strong GH-releasing activity, but also plays other central and peripheral roles, including influence on food intake, gastric motility, and acid secretion. The aim of the present study was to determine whether gastrointestinal endocrine hyperplastic and neoplastic lesions produce ghrelin, at both protein (immunohistochemistry) and mRNA (in situ hybridization and/or RT-PCR) levels, and express the GH secretagogue receptor mRNA by RT-PCR. Sixteen gastric and 20 intestinal carcinoids as well as normal gastrointestinal mucosa and atrophic gastritis-associated neuroendocrine cell hyperplasia were studied. The majority (12 of 16, 75%) of gastric carcinoids and only 5 of 18 (27%) of intestinal endocrine tumors were immunoreactive for ghrelin. In situ hybridization confirmed the immunohistochemical data, but also showed ghrelin mRNA in 1 gastric and 8 intestinal additional tumors. RT-PCR showed ghrelin mRNA in 14 of 14 cases, indicating a low level of ghrelin gene expression in all gastrointestinal endocrine tumors tested. Gastric neuroendocrine hyperplastic cells were also strongly positive for ghrelin. GH secretagogue receptor mRNA was absent in 3 gastric, but present in 7 of 11 intestinal carcinoids studied by RT-PCR. These findings demonstrate that most gastric carcinoids (and related neuroendocrine cell hyperplasias) and some intestinal carcinoids produce ghrelin. These hyperplastic/neoplastic conditions could represent the clinical model to clarify the existence and impact of ghrelin hypersecretion on endocrine and nonendocrine functions.
THE ENDOCRINE CELL population of the gastrointestinal tract may undergo proliferative phenomena that are both hyperplastic and neoplastic in nature. In the stomach, hyperplastic lesions include diffuse, linear, and nodular forms, usually occurring in the setting of chronic atrophic gastritis (CAG) (1, 2). A role of hypergastrinemia has been documented for endocrine cell growths of the oxyntic mucosa due to the stimulation of enterochromaffin-like (ECL) cells (3, 4, 5).
Neoplastic lesions include solitary (sporadic) or multiple, functioning or nonfunctioning endocrine tumors (carcinoids), according to the new WHO classification (6). Apart from the rare poorly differentiated endocrine carcinoma and the gastrin and enterochromaffin cell tumors, the majority of gastric carcinoids are ECL cell tumors. Three types of ECL tumors developing in the oxyntic mucosa were recognized (7). The first group includes multiple tumoral growths in the mucosa and submucosa usually associated with CAG and hyperplastic lesions of the neuroendocrine cells. Another group incorporates familial forms of endocrine tumors, either in the setting of MEN1 or Zollinger-Ellison syndromes, and the third group is represented by sporadic tumors (7).
Gastric carcinoids account for 0.3% of all gastric tumors (8). Functioning tumors are rare and may be associated with the carcinoid syndrome, but most cases are apparently symptomless and are discovered in the diagnostic work-up of atrophic gastritis or incidentally (8).
Ghrelin is a 28-amino acid acylated peptide that has recently been discovered in human and rat stomach (9, 10). It is produced by approximately 20% of rat and human neuroendocrine cell populations of the oxyntic glands, by cells different from ECL, enterochromaffin, or D cells and probably of the X-like type (10). Ghrelin has no homology with currently known biologically active peptides (9). However, recently Tomasetto and co-workers (11) isolated a novel gastric peptide, named motilin-related peptide, which shows a remarkable structural similarity to ghrelin (12, 13). Ghrelin displays a strong GH release activity (14, 15) and is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R), which had been shown to be specific for a family of synthetic, peptidyl, and nonpeptidyl GHS (9, 15, 16, 17, 18, 19). GHS-R have been demonstrated in the hypothalamus-pituitary unit (as expected) as well as in the human brain (20). In parallel, ghrelin and synthetic GHS recognize binding sites in the central nervous system as well as in peripheral, endocrine, and nonendocrine tissues in both normal (21) and neoplastic conditions (22, 23).
Indeed, the functions of this new hormone are not specifically related to GH secretion. Besides potent GH-releasing activity (9, 24, 25), ghrelin (and synthetic GHS) also has stimulatory effects on lactotroph and corticotroph secretion, stimulates food intake, and modulates sleep (26, 27, 28, 29, 30, 31). In agreement with the presence of specific GHS-R in peripheral tissues, ghrelin and synthetic GHS have been demonstrated to exert cardiovascular actions as well as an antiproliferative effect in neoplastic tissues (23, 32, 33). More recently, it has been reported that ghrelin markedly stimulates cholinergic-mediated gastric contractility and acid secretion in rats (34).
Although ghrelin has been isolated and purified from the rat and human oxyntic mucosa of the stomach, it is also produced in other tissues, including the small intestine, but not the colon or rectum (10), the arcuate nucleus of the hypothalamus (9), the kidney (35), or the placenta (36). No data exist on the expression of ghrelin by gastrointestinal tumors.
Based on the foregoing, in the present study we aimed to verify the expression of ghrelin and the GHS-R in a series of gastrointestinal carcinoids by means of immunohistochemistry, RT-PCR, and in situ hybridization. Herein, we show that the majority of nonantral gastric carcinoids and some intestinal carcinoids are ghrelin-producing endocrine tumors. These findings demonstrate the frequent existence of ghrelin-producing gastric carcinoids and might have important clinical implications related to the multifaceted and still not fully understood ghrelin functions.
Materials and Methods
Tumors
Thirty-six gastrointestinal carcinoids were collected from the pathology file of the University of Turin during the period 1986–2000. All cases were surgical samples, except for 1 biopsy case and one autoptic case. All were reviewed and histologically confirmed by positive chromogranin A immunostaining. These included 16 gastric and 20 intestinal endocrine tumors. In the gastric carcinoid group, 14 cases were surgically resected, and the remaining 2 were a recent gastric biopsy specimen and an autopsy case. The latter was also studied in parallel, with the corresponding gastric biopsy performed shortly before death. All tumors were located in the gastric body. Eleven cases were small carcinoids associated with chronic atrophic gastritis. Eight of these tumors were multiple, and in 9 cases neuroendocrine (NE) cell hyperplasia was observed in the peritumoral mucosa. Five cases were solitary (sporadic) tumors. In the intestinal carcinoid group, 4 cases developed in the duodenum (3 of which were gastrin-producing), 8 in the small intestine, 3 in the appendix, and 5 in the colon-rectum. Three samples each of normal stomach (antrum and body), duodenum, small intestine, and colon as well as 3 cases each of adenocarcinoma of the stomach and of the colon served as controls. All patients gave their informed consent for the research use on their tissues, and the study project was approved by an independent ethical committee.
Immunohistochemistry
Ghrelin immunostaining was performed on formalin-fixed and paraffin-embedded cases. The primary antibody was a polyclonal serum antihuman ghrelin (amino acids 13–28; Phoenix Pharmaceuticals, Inc., Belmont, CA), diluted 1:600 and incubated for 1 h at room temperature. A standard manual immunoperoxidase procedure with streptavidin-peroxidase and diaminobenzidine as the final reaction product was used. No antigen retrieval or amplification procedures were used throughout this study. Control experiments included the immunoperoxidase reaction in serial sections by either omitting the primary antibody or using the primary antibody preabsorbed with a 100-fold excess of the antigen. Neuroendocrine cells of the peritumoral oxyntic gastric mucosa served as a positive (internal) control.
In situ hybridization
All cases were studied in parallel sections by a nonradioactive in situ hybridization (ISH) procedure. Both tumor areas and peritumoral normal or atrophic mucosa were analyzed. Two 45-nucleotide antisense probes (9), corresponding to positions 90–134 and 421–465 of the prepro-ghrelin sequence were synthesized and digoxigenin-labeled with the Roche labeling kit (Mannheim, Germany) following the manufacturer’s instructions. The equimolar mixture of the two probes was applied overnight at a working dilution of 33 nM for each probe per slide. Prehybridization treatments included a microwave passage (5 min at 800 watts in citrate buffer, pH 6.0) and proteinase K digestion (1 µg/ml) for 4 min. The hybrids were revealed with the GenPoint kit (DAKO Corp., Glostrup, Denmark) as described previously (37) with minor modifications, including 1:5 dilution of the tyramide kit solution and washings at high temperature after the tyramide incubation (38). The peritumoral oxyntic mucosa of the stomach served as a positive internal control. Negative controls included ISH reactions of serial sections with an unrelated probe or without any probe, as well as ribonuclease digestion before hybridization.
RT-PCR for ghrelin and GHS-R
In three gastric carcinoids (no. 1–3) and in 11 intestinal endocrine tumors (no. 17, 21–26, 29, 30, 32, and 36) frozen material was available. Total RNA extraction and cDNA transcription were performed as described previously (37). PCRs for ghrelin and GHS-R were performed following the procedure described by Gualillo et al. (36) for ghrelin mRNA amplification. The primers for ghrelin were synthesized according to the method of Gualillo et al. (36), and the sequences were 5'-TGAGCCCTGAACACCAGAGAG-3' for the forward primer and 5'-AAAGCCAGATGAGCGCTTCTA-3' for the reverse primer. Those for GHS-R Ia and Ib were synthesized according to the following sequences reported by Korbonits et al. (39): 5'-TCGTGGGTGCCTCGCT-3' as forward primer for both GHS-R 1a and GHS-R 1b, 5'-CACCACTACAGCCAGCATTTTC-3' for GHS-R 1a reverse primer, and 5'-GCTGAGACCCACCCAGCA-3' for GHS-R 1b reverse primer. The expected sizes of the amplicons were 327, 65, and 66 bp for ghrelin, GHS-R 1a, and GHS-R 1b, respectively. ß2-Microglobulin amplification served as a control of the RNA quality (see details in Ref. 37).
Correlations
The data for ghrelin expression were correlated with
clinico-pathological parameters of each tumor. Statistical analysis was
carried out using the 
2 (Yates-corrected)
test.
Results
Ghrelin expression in gastrointestinal carcinoids
As summarized in Table 1
, 12
of 16 (75%) gastric and 5 of 18 (27%) intestinal carcinoids were
immunoreactive for ghrelin in a variable percentage of tumor
cells.
|
10% of tumor cells) immunostaining, but all other cases
were diffusely expressing the hormone (Fig. 1), including a small lymph node
metastasis (case 2). The cellular pattern of ghrelin reactivity was
diffuse, finely granular cytoplasmic staining, in general as strong as
(or slightly weaker than) that of peritumoral gastric endocrine cells
(see below). No staining was observed in intratumoral stromal or
inflammatory cells. No difference in reactivity was detected in
CAG-associated tumors compared with sporadic tumors. In the
intestinal carcinoid group, two cases were diffusely positive
(Fig. 2A) and three had a focal (in
10% of tumor cells) immunoreactivity. The pattern of ghrelin
distribution was similar to that reported for gastric tumors, although
the immunostaining was much weaker than that of either gastric tumors
or the scant normal endocrine cells found in the peritumoral intestinal
mucosa. No immunoreactivity was found in parallel sections stained
omitting the primary antibody or using ghrelin antiserum preabsorbed
with full-length (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) ghrelin (Europeptides,
Argenteuil, France).
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and 3). One gastric and 8 intestinal
endocrine tumors that were negative by immunohistochemistry had mRNA
expression detected by ISH. In the other cases an overlapping
percentage of ghrelin-positive tumor cells was observed using
immunohistochemistry and ISH in parallel sections. ISH omitting the
specific probe, using an unrelated probe (Fig. 3B), or ribonuclease pretreatment was
negative.
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) or intestinal
location.
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In the peritumoral oxyntic mucosa of the stomach, a population of
ghrelin-positive cells was present in all cases, although with a
remarkable variability. Sporadic endocrine tumors and some of the
atrophic gastritis-associated carcinoids had only scattered, small,
oval, or polygonal, immunoreactive cells, basally located in the deep
glands and never in the foveolae. In other cases (no. 1, 4, 6, 7, and
8), an extensive ghrelin-producing cell population was found throughout
the mucosa. This finding was associated with NE cell hyperplasia in the
context of CAG (Fig. 5).
Ghrelin-producing cells were larger than their normal counterpart,
polygonal or flask-shaped, and occurred in the diffuse, linear, or
nodular forms of hyperplasia (Fig. 5B). In parallel sections stained
with the antiserum preabsorbed with ghrelin, no immunoreactivity was
observed (Fig. 5C). ISH for ghrelin mRNA was positive in hyperplastic
NE cells with a pattern similar to that of ghrelin immunostaining.
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RT-PCR to reveal GHS-R type Ia and Ib mRNAs was performed in the
same 14 cases tested for ghrelin. None of the three gastric carcinoids
was positive (Fig. 4), as opposed to 7 of 11 (63%) intestinal
endocrine tumors that had a positive signal for either type of
GHS-R.
Control tissues
The normal mucosa of the gastrointestinal tract showed a decreasing ghrelin immunoreactivity of NE cells from the gastric oxyntic mucosa (several ghrelin-producing cells, accounting for approximately 20% of the NE cell population), through the antrum and small intestine (rare ghrelin-positive cells), toward the colon-rectum (no ghrelin-producing cells). The myoenteric nerve plexus of small and large intestines was weakly positive for ghrelin (by immunohistochemistry or ISH) in both ganglion cells and nerve fibers. Immunostaining with preabsorbed ghrelin antiserum was negative in all of the above tissues. The six control (nonendocrine) gastric and colorectal adenocarcinomas lacked any ghrelin immunoreactivity.
Clinico-pathological correlations
The ghrelin-producing cells in both gastrointestinal carcinoids
and gastric NE cell hyperplastic lesions were neuroendocrine cells, as
confirmed by chromogranin A coexpression by the same cells.
Chromogranin A-positive neuroendocrine cells largely outnumbered those
ghrelin-reactive in the normal gastric mucosa and in some carcinoid
tumors, but not in NE cell hyperplastic lesions of the stomach. In the
latter the number of ghrelin-positive cells was much higher (compared
with that in normal mucosa), although not as high as that in
chromogranin A-reactive cells (Fig. 6).
In gastric carcinoids, ghrelin expression was observed in 75% of cases
by immunohistochemistry and in 81% of cases by ISH. The concordance
between the two procedures was 94% (all but one cases). In intestinal
carcinoids, ghrelin immunoreactivity was found in 27% of cases only, a
statistically significant difference from gastric carcinoids
(P = 0.016). Ghrelin mRNA was detected in 72% of cases
by ISH and in 100% of cases by RT-PCR. The discrepancies are probably
related to the different thresholds of detectability of the various
methods, but also to the amount of stored protein in the cells of
intestinal tumors.
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Discussion
In this study we have demonstrated that the majority of gastric carcinoids and a fraction of intestinal endocrine tumors show immunoreactivity for ghrelin, a novel gastrointestinal hormone recently isolated from the rat and human stomach (9). Ghrelin was also intensely expressed in atrophic gastritis-associated neuroendocrine cell hyperplasia.
In the stomach, endocrine tumors include rare familial cases associated with MEN1 or Zollinger-Ellison syndrome, multiple ECL cell carcinoids of the atrophic body (oxyntic) mucosa, and sporadic cases. The latter 2 groups were analyzed in the current study and found to diffusely produce ghrelin in most cases (75%). Ghrelin immunoreactivity was paralleled by ghrelin mRNA expression by the same tumor cells in both neoplastic and hyperplastic conditions. This indicates that the ghrelin-producing cell population is actively transcribing the mRNA and subsequently synthesizing the protein. All but 1 of the ghrelin-negative cases by immunostaining were also negative in terms of mRNA expression. A partially similar profile was observed in the intestinal carcinoid group, which expressed immunoreactive ghrelin in 5 of 18 cases only, but had mRNA transcripts detected in the majority of cases by ISH. This finding was confirmed by a 100% positive signal for ghrelin mRNA by the highly sensitive RT-PCR technique. As care was taken to select a small tumor fragment for RT-PCR, avoiding normal peritumoral mucosa, the results of RT-PCR analysis probably indicate that a low level of ghrelin mRNA transcription is present in most (or all?) gastrointestinal endocrine tumors. The extent of such transcription is probably below the threshold of sensitivity of either ISH or immunohistochemistry, and the latter techniques therefore fail to detect ghrelin mRNA or protein in single tumor cells.
The antibody and probes employed in this study recognize both octanoylated and des-octanoylated forms of ghrelin (40). Only the former is reported to have GH release activity (9), but other biological activities, such as antiproliferative effects (23), are also associated with des-octanoylated (originally considered biologically inactive) forms of ghrelin. Ghrelin-producing tumors should therefore to be added to the list of hormone-producing gastrointestinal endocrine tumors, with special reference to gastric carcinoids. ECL cell carcinoids are the most common endocrine tumors of the corpus/fundus mucosa and are usually the consequence of hypergastrinemic conditions associated with CAG (7). Ghrelin was not identified in normal ECL cells and was proposed to be the product of X-like cells (10). X-Like cell carcinoids have not been documented to date, and endocrine tumor growths of the atrophic body mucosa are known to be ECL cell carcinoids (41). Whether ghrelin is coproduced by neoplastic ECL cells or is the product of a peculiar neoplastic cell population remains to be clarified by further immunoelectron microscopy studies.
In the current study the fraction of ghrelin-producing cells in diffuse, linear, or nodular neuroendocrine cell hyperplasia (1, 2, 4) was much higher than that in normal oxyntic mucosa. Therefore, its expression probably increased not only within the specific cell type normally producing ghrelin, but also in neuroendocrine cell types other than X-like cells. Hypergastrinemic conditions leading to the proliferation of ECL and/or other cell types could determine hyperplastic and neoplastic endocrine cell growths that could involve the ghrelin-producing cell compartment and/or activate ghrelin overproduction.
Although gastric carcinoids are rare and generally benign conditions, we observed two aggressive cases and an additional low grade tumor with a lymph node metastasis. Ghrelin was produced by two of these tumors, and therefore its expression seems to be independent from the biological aggressiveness of the tumor. The same holds true for intestinal carcinoids, which had ghrelin expression (at both protein and mRNA levels) in either benign tumors or invasive and metastasizing cases.
Regardless of having identified a new separate ghrelin-producing tumor or of having described an additional hormonal product within ordinary gastrointestinal carcinoids, a clinical interest may derive from the possible existence of functioning ghrelin-producing endocrine tumors, especially in the gastric body, from which ghrelin has been isolated. Although the whole spectrum of ghrelin functions is still incompletely defined, no reports exist in the literature on functioning gastric carcinoids having symptoms possibly related to GH release. One single case of multiple gastric carcinoids associated with a GH-producing pituitary adenoma, possibly related to hypergastrinemia-induced GHRH release, has been described (42). However, as GH release-related symptoms and others related to central nervous activities may be subtle, patients affected by gastric carcinoids need to be reevaluated from this point of view before excluding the possibility of functioning, ghrelin-producing, endocrine tumors.
In addition, the newly discovered ghrelin-producing endocrine tumors may represent an in vivo experimental model for better understanding currently unknown ghrelin functions at both central nervous and metabolic levels. This may better define the role of ghrelin and its synthetic agonist and antagonist counterparts (GHS) in the treatment of several human diseases. In fact, receptors for ghrelin and GHS have been identified in several human peripheral tissues (9, 10, 21). Using a specific antibody, GHS-R was also found in the rat stomach (43). In addition, there is evidence that GHS-R are present in neuroendocrine tumors and pituitary adenomas (39, 44), and we found GHS (Tyr-Ala-hexarelin)-binding sites, by means of RRAs, in breast and thyroid carcinomas (22, 23) and in bronchial and pancreatic endocrine tumors (unpublished observation).
In the current study GHS-R (types Ia and Ib) mRNA was absent in the few gastric carcinoids available for RT-PCR analysis, but was present in 63% of intestinal carcinoids. Whether negative cases truly lack the GHS-R or possess a different, currently unknown, receptor subtype is not clear. In any case a fraction of gastrointestinal endocrine tumors exists that have concurrent expression of GHS-R and its ligand ghrelin. The complete mapping of ghrelin-producing cells or tumors and ghrelin receptor-positive cells or tumors will shed further light on the complex ligand-receptor interactions at the single organ level.
In conclusion, the present study reports on ghrelin-producing gastrointestinal endocrine tumors as well as on a remarkable ghrelin expression in gastric neuroendocrine cell hyperplasias. Although Korbonits et al. (44) reported on ghrelin expression in neuroendocrine tumors, their data were restricted to three cases of pancreatic insulinomas and one pancreatic gastrinoma. Our findings therefore provide the first detailed evidence of ghrelin-producing neuroendocrine neoplasms of the stomach and intestine. These findings suggest that screening of circulating ghrelin levels may be useful in the diagnostic work-up of atrophic gastritis and associated neuroendocrine cell growths as well as of gastrointestinal tumors of suspected neuroendocrine nature. This investigation possibly defines a clinical scenario of gastric (and possibly intestinal) endocrine cell diseases that may include biologically active ghrelinomas.
Acknowledgments
We thank Profs. G. Bussolati and F. Camanni (University of Turin) for their suggestions. We are grateful to Dr. E. Allia, Dr. P. Gugliotta, Dr. C. Pecchioni, S. Chiappone, and A. Grua (University of Turin) for their skillful assistance.
Footnotes
This work was supported by grants from the Italian Association for Cancer Research (Milan, Italy), the Italian Ministry of University (Rome; Grant ex-40% to G.M. and E.G.), Europeptides (Argenteuil, France), and the Studio delle Malattie Endocrine e Metaboliche Foundation (Turin, Italy).
Abbreviations: CAG, Chronic atrophic gastritis; ECL, enterochromaffin-like; GHS, GH secretagogue; GHS-R, GH secretagogue receptor; ISH, in situ hybridization; NE, neuroendocrine.
Received April 30, 2001.
Accepted June 15, 2001.
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