gastrin-releasing-peptide and Carcinoid-Tumor

A 40-year-old male was referred to our hospital because of a nodular shadow detected in the left lower lobe with the tendency to increase gently. Because fluoro-2-deoxy-D-glucose (FDG) uptake was extremely low on a FDG positron emission tomography (PET-CT), the tumor was highly suspected of the benign tumor. Five years later, a follow-up computed tomography (CT) showed the shadow to be enlarged. FDG uptake was changed to be high, and serum level of pro-gastrin-releasing peptide (Pro-GRP) was extremely elevated. Surgical treatment was chosen under suspicious diagnosis of neuroendocrine tumor, such as small cell carcinoma, large cell neuroendocrine carcinoma, and carcinoid. By the intraoperative aspiration cytology, a small cell carcinoma or a carcinoid was suspected and left lower lobectomy with systemic lymph node dissection was performed. The final histological diagnosis was a typical carcinoid. The elevated serum ProGRP immediately decreased to normal postoperatively.

Topics: Adult; Biomarkers, Tumor; Carcinoid Tumor; Diagnosis, Differential; Fluorodeoxyglucose F18; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Male; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals

To establish whether gastrin releasing peptide (GRP) and the GRP receptor (GRPR) are expressed together in gastrointestinal carcinoid tumours.. Twenty six carcinoid tumours from the stomach, small intestine, appendix, and colorectum were investigated by immunohistochemistry for GRP and GRPR.. GRP was detected in nine of 19 tumours and GRPR in 22 of 26. Coexpression of both the ligand and receptor was seen in six of 19 cases. GRPR but not GRP was more strongly expressed in appendix and colonic tumours.. GRP and GRPR are produced by a large number of gastrointestinal carcinoid tumours. An autocrine/paracrine pathway may exist for GRP stimulated cell proliferation in some of these neoplasms, analogous to that seen in small cell anaplastic carcinoma of the lung.

Topics: Appendiceal Neoplasms; Carcinoid Tumor; Colonic Neoplasms; Gastrin-Releasing Peptide; Gastrointestinal Neoplasms; Humans; Neoplasm Proteins; Receptors, Bombesin; Stomach Neoplasms

Patterns of elevated serum peptides may reveal additional markers and permit better classification of tumors based on (secondary) peptide secretion.. Fasting peptide profiles were obtained from 31 carcinoid patients. vasoactive intestinal peptide (VIP), pancreatic polypeptide (PP), neurotensin, substance P, gastrin-releasing polypeptide (GRP), calcitonin, gastrin, and pancreastatin were measured. Peptide elevation patterns were correlated with disease sites, syndrome, and survival.. Elevations in patients were as follows: VIP 0%, PP 13%, neurotensin 10%, substance P 20%, GRP 3%, calcitonin 10%, and gastrin 3%. There were no consistent patterns of elevated peptides with regard to site or syndrome. Pancreastatin was elevated in 81% of profiles and was the only abnormal peptide in 57% of patients.. Peptide profile results do not permit improved classification, predict syndrome development, or correlate with survival. In contrast, pancreastatin is elevated in most cases and may be utilized to monitor disease progression and evaluate response to therapy.

Topics: Biomarkers, Tumor; Calcitonin; Carcinoid Tumor; Chromogranin A; Disease Progression; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Male; Neurotensin; Pancreatic Hormones; Pancreatic Polypeptide; Peptides; Predictive Value of Tests; Substance P; Vasoactive Intestinal Peptide

Previously, GRP receptors were characterized in small cell lung cancer cells and here non-small cell lung cancer (NSCLC) cells were investigated: (125I-Tyr4) bombesin (BN) or 125I-GRP bound with high affinity to NCI-H720 (lung carcinoid) and NCI-H1299 (large cell carcinoma) cells. Binding was specific, time dependent, and saturable. Specific (125I-Tyr4)BN binding to NCI-H1299 cells was inhibited with high affinity by GRP, BN, GRP14-27, (D-Phe6)BN6-13methyl ester, moderate affinity by NMB, and low affinity by GRP1-16. BN (10 nM) transiently elevated cytosolic calcium in a dose dependent manner. BN caused translocation of protein kinase C from the cytosol to the membrane and the translocation caused by BN was reversed by (D-Phe6)BN6-13methylester. BN stimulated arachidonic acid release and the increase caused by BN was reversed by (D-Phe6)BN6-13methylester. Using a clonogenic assay, BN stimulated the growth of NCI-H720 cells, and the number of colonies was reduced using (D-Phe6)BN6-13methylester. These data suggest that GRP receptors that are present in lung carcinoid and NSCLC cells may regulate proliferation.

Topics: Arachidonic Acid; Bombesin; Calcium; Carcinoid Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Neoplasm Proteins; Peptides; Receptors, Bombesin

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Gastrin-releasing peptide (GRP; mammalian bombesin) is present in the neuroendocrine cells of human fetal lung and in small cell lung carcinomas (SCLCs), where it may act as a growth factor. Considering the potential importance of GRP as a tumor marker, we have conducted a retrospective immunohistochemical analysis of 176 lung tumors for markers of GRP gene expression, as well as several other markers of neuroendocrine cell differentiation: chromogranin A, neuron-specific enolase, and calcitonin. The majority of carcinoids contained mature GRP, in contrast to only a minority of SCLCs and large cell lung carcinomas (LCLCs). However, a majority of SCLCs and LCLCs contained proGRP immunoreactivity. In situ hybridization did not add any information beyond what was obtained using proGRP antisera. In spite of sharing these neuroendocrine cell markers, SCLCs are associated with a graver prognosis than LCLCs. No prognostic significance was associated with immunostaining for GRP or several other markers of neuroendocrine cell differentiation.

Topics: Adult; Aged; Biomarkers; Carcinoid Tumor; Carcinoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Gastrin-Releasing Peptide; Gene Expression; Humans; Immunoenzyme Techniques; In Situ Hybridization; Lung Neoplasms; Male; Middle Aged; Peptides; Retrospective Studies; RNA, Messenger; RNA, Neoplasm; Survival Analysis

Levels of gastrin-releasing peptide (GRP) were determined by radioimmunoassay in human normal main and lobar bronchus and parenchymal lung tissue extracts. It was found that the level of GRP differed significantly between all 3 areas. The concentration of GRP was statistically higher in main bronchus (median 6.74 ng/g) compared to both lobar bronchus (median 4.79 ng/g) and parenchymal lung (median 1.73 ng/g), and also statistically higher in lobar bronchus compared to parenchymal lung. Chromatographically, GRP-immunoreactivity in both main and lobar bronchial extracts corresponded to GRP1-27 and GRP18-27, while in lung tissue only one major species was identified which corresponded in retention time to GRP18-27. No significant difference was detected when the levels of GRP in normal lobar bronchus and normal lung tissue were compared to the levels in lobar bronchus and lung taken from patients with lung carcinoma, at a site adjacent to the carcinoma. However, a significant difference was observed between the GRP content of normal main bronchus compared to main bronchus from patients with carcinoma. GRP was measured in 26/56 lung carcinomas examined. The levels ranged from 42,000 ng/g in a carcinoid tumour to 0.18 ng/g in a squamous-cell carcinoma, though only in 6 tumours were the levels outside the range determined for normal pulmonary tissue. Chromatography of selected tumour extracts of different histopathologies showed that there were differences in the GRP products present.

Topics: Adenocarcinoma; Adult; Aged; Carcinoid Tumor; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Female; Gastrin-Releasing Peptide; Gastrointestinal Hormones; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Peptides; Radioimmunoassay

A carcinoid tumour presenting as Cushing's syndrome is reported. Although no tumour mass could be initially identified the patient returned with first a liver and subsequently a cerebellar mass both of which were resected. Only at post-mortem was the lung primary discovered. ACTH, gastrin-releasing peptide (GRP) and calcitonin gene-related peptide were elevated in plasma before resection of the hepatic tumour. These peptides were demonstrated in both the hepatic and cerebellar tumours by immunocytochemistry and radioimmunoassay. This case illustrates the occasional tendency of primary lung carcinoids to remain small and clinically undetectable while generating secondary tumours which are symptomatic. It is suggested that immunological demonstration of GRP may be diagnostically helpful in directing attention to the lung as a primary site in neuroendocrine tumours which present in this fashion.

Topics: Adrenocorticotropic Hormone; Bombesin; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoid Tumor; Cerebellar Neoplasms; Chromatography, Gel; Gastrin-Releasing Peptide; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neuropeptides; Peptides; Radioimmunoassay

A selected group of 263 pulmonary neuroendocrine tumours comprised 156 small cell carcinomas, five combined cell carcinomas, nine atypical carcinoid/small cell carcinomas, 32 atypical carcinoids, ten large cell/small cell carcinomas, and 51 carcinoid tumours. These were compared with a group of 109 non-small cell carcinomas, using four markers of neuroendocrine differentiation to determine differences in reactivity between the two groups and among the variants of neuroendocrine tumour. The antibodies used were neuron-specific enolase (NSE), protein gene product (PGP) 9.5, human bombesin, and the C-terminal flanking peptide of human bombesin (CTP). Most small cell carcinomas, carcinoid tumours, and atypical carcinoid variants showed immunoreactivity for both NSE and PGP 9.5 but a significant number of non-small cell carcinomas, mainly squamous cell carcinomas, were also positive (11 and 35 per cent, respectively). Bombesin was specific for neuroendocrine tumours, being demonstrable in 35 per cent carcinoids and 24 per cent small cell carcinomas, but staining was focal and often confined to scattered cells. Diffuse strongly positive immunoreactivity for CTP was seen in the majority of malignant neuroendocrine tumours, but only 12 per cent of carcinoid tumours were positive and non-small cell carcinomas were negative. CTP is therefore of potential value as a specific marker of malignant neuroendocrine tumours, particularly if the amount of biopsy material is limited and the tumour is an unusual variant, such as atypical carcinoid or large cell-small cell carcinoma.

Topics: Biomarkers, Tumor; Bombesin; Carcinoid Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Humans; Immunoenzyme Techniques; Lung Neoplasms; Neuropeptides; Peptide Fragments; Peptides; Phosphopyruvate Hydratase; Ubiquitin Thiolesterase

We have described a case of MEN-I in association with a benign pulmonary carcinoid tumor. Two other members of our patient's family also had MEN-I and benign carcinoid or adenomatous lung tumors. Hormonal assays of our patient's carcinoid lesion showed the production of gastrin, gastrin-releasing peptide, neurotensin, and somatostatin, but not serotonin, a hormonal profile distinct from those previously reported in carcinoid lung tumors unassociated with MEN-I.

Topics: Carcinoid Tumor; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Middle Aged; Multiple Endocrine Neoplasia; Neurotensin; Pedigree; Peptides; Somatostatin

Topics: Bombesin; Bronchial Neoplasms; Carcinoid Tumor; Carcinoma, Small Cell; Chorionic Gonadotropin; Diagnosis, Differential; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Immunoenzyme Techniques; Lung Neoplasms; Middle Aged; Peptides; Phosphopyruvate Hydratase

Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours.

Topics: Adenoma; Adrenal Gland Neoplasms; Amino Acid Sequence; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Humans; Intestinal Neoplasms; Lung Neoplasms; Neoplasms; Neurosecretory Systems; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Pituitary Neoplasms; Thyroid Neoplasms

Several reports have indicated that the amphibian peptide bombesin is present in oat-cell carcinoma of the human lung. The recent observation that gastrin-releasing peptide (GRP), a 27-amino acid peptide isolated from porcine intestine, may be the mammalian analog of bombesin led the authors to look for this peptide in human pulmonary tumors. Examination of 36 human lung tumors (8 carcinoids, 8 oat-cell carcinomas, and 20 non-oat-cell carcinomas) by immunohistochemistry and radioimmunoassay demonstrated the presence of high, although variable, levels of GRP in neuroendocrine tumors, and not in other histologic types. These findings indicate that bombesin immunoreactivity in human lung tumors should be attributed to GRP or GRP-like molecules and that GRP may be a useful marker of neuroendocrine differentiation.

Topics: Animals; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immunoenzyme Techniques; Lung Neoplasms; Neurosecretory Systems; Peptides; Rabbits; Radioimmunoassay

We have prepared and cloned cDNAs derived from poly(A)+ RNA from a human pulmonary carcinoid tumor rich in immunoreactivity to gastrin-releasing peptide, a peptide closely related in structure to amphibian bombesin. Mixtures of synthetic oligodeoxyribonucleotides corresponding to amphibian bombesin were used as hybridization probes to screen a cDNA library prepared from the tumor RNA. Sequencing of the recombinant plasmids shows that human gastrin-releasing peptide (hGRP) mRNA encodes a precursor of 148 amino acids containing a typical signal sequence, hGRP consisting of 27 or 28 amino acids, and a carboxyl-terminal extension peptide. hGRP is flanked at its carboxyl terminus by two basic amino acids, following a glycine used for amidation of the carboxyl-terminal methionine. RNA blot analyses of tumor RNA show a major mRNA of 900 bases and a minor mRNA of 850 bases. Blot hybridization analyses using human genomic DNA are consistent with a single hGRP-encoding gene. The presence of two mRNAs encoding the hGRP precursor protein in the face of a single hGRP gene raises the possibility of alternative processing of the single RNA transcript.

Topics: Amino Acid Sequence; Base Sequence; Bombesin; Carcinoid Tumor; Cloning, Molecular; DNA; DNA Restriction Enzymes; Gastrin-Releasing Peptide; Humans; Liver Neoplasms; Nucleic Acid Hybridization; Peptides; Poly A; RNA; RNA, Messenger

Human neuroendocrine tumors are known to demonstrate immunoreactivity to the amphibian peptide bombesin. The recent observation that gastrin-releasing peptide (GRP), a 27 amino acid peptide first isolated from porcine intestine, may be the mammalian analog of bombesin led us to look for this peptide in intestinal carcinoid tumors. Formalin-fixed tissues from 20 of these tumors were examined by the immunoperoxidase technic, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense diffuse cytoplasmic immunoreactivity was observed in carcinoids from the small intestine (7/10), appendix (4/5), and colon (1/5). In each positive case, the pattern of staining for GRP (1-16) and GRP (1-27) was identical. These findings indicate that bombesin-like immunoreactivity in human intestinal carcinoid tumors is attributable to GRP-like molecules and that GRP is a useful marker for neuroendocrine differentiation.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immunochemistry; Intestinal Neoplasms; Male; Middle Aged; Nerve Fibers; Peptides

Bronchial endocrine cells containing gastrin-releasing peptide (GRP), a mammalian analog of bombesin, and adrenocorticotropic hormone (ACTH) were immunohistochemically localized in paraffin sections of normal and pathologic human lungs. GRP-containing cells were present in fetal bronchi at the 12th gestational week and in "neuroepithelial bodies" about the time of delivery. In normal adult lungs, a few isolated GRP-containing cells were present in bronchial and bronchiolar mucosa. In bronchiectatic or fibrotic lungs, small clusters of GRP-containing cells were occasionally noted in basal bronchial mucosa. Pronounced GRP cell hyperplasia often was observed in ectatic bronchioles of lungs with tumorlet. Cells of pulmonary tumorlets mostly showed GRP immunoreactivity. Two bronchial carcinoids exhibited a moderate number of GRP-containing cells. Three of four small cell carcinomas, intermediate cell type could be designated "GRPomas" from the number of GRP-containing cells present. In four of 11 small cell carcinomas, oat cell type, GRP immunoreactivity was infrequently recognized. Immunoabsorption tests indicated that GRP immunoreactivity in lungs would mainly fall under the C-terminal fragment rather than the whole sequence of GRP. Bombesin immunoreactivity in human lungs should be attributed to GRP or GRP-like molecules, since no bombesin immunoreactants were identified with bombesin antiserum which shows no cross-reactivity to porcine GRP. ACTH-containing cells, also reactive to beta-endorphin antiserum, were absent from normal fetal or adult lungs but did accompany GRP-containing cells occasionally in ectatic non-neoplastic bronchioles, always in tumorlet cells, and often in endocrine lung tumors, although the cells containing GRP and ACTH were not identical. The significance of GRP in the physiology and pathophysiology of the lung is discussed, and the necessity of reevaluation of "ectopic" ACTH production in lung neoplasms is proposed.

Topics: Adrenocorticotropic Hormone; Adult; Antibodies; Bombesin; Bronchi; Carcinoid Tumor; Carcinoma, Small Cell; Fetus; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immune Sera; Immunochemistry; Immunoenzyme Techniques; Infant; Infant, Newborn; Lung; Lung Neoplasms; Peptides; Pulmonary Fibrosis; Substance P

Recent immunohistochemical findings have indicated the presence of gastrin-releasing peptide in normal and pathological human lungs. Gastrin-releasing peptide is a 27-amino acid peptide isolated from porcine gut which bears considerable carboxyterminal homology with bombesin. We have characterized the gastrin-releasing peptide-like peptides present in a human malignant lung carcinoid tumor by gel chromatography and reverse-phase high-performance liquid chromatography. Our results show that this tumor did not contain bombesin; however, this tumor expressed a gastrin-releasing peptide-like compound, several amino-terminal fragments, and a carboxy-terminal fragment of gastrin-releasing peptide.

Topics: Amino Acid Sequence; Carcinoid Tumor; Chromatography, High Pressure Liquid; Female; Gastrin-Releasing Peptide; Gastrointestinal Hormones; Humans; Lung Neoplasms; Microscopy, Electron; Middle Aged; Peptides

A carcinoid tumor of the peripheral lung producing gastrin-releasing peptide (GRP), a peptide hormone known to be present in the endocrine cells of fetal bronchial epithelium, is reported. Brain-gut peptide hormones in this tumor were assayed by radioimmunoassays, localized by immunohistochemistry and characterized by gel filtration. Electron microscopic study revealed that tumor cells resembled P-cells of normal human fetal bronchial epithelium. While GRP-containing cells were predominant in this tumor, calcitonin-containing cells were also found in some areas. Difference in distribution of hormones according to histologic features was noted in the tumor. A greater portion of the tumor showed spindled cells that predominantly contained GRP, and a smaller portion of the tumor showed cells arranged in tubular or trabecular patterns that mainly contained calcitonin. The gel-filtration pattern of the tumor extracts consisted of two peaks, one of these corresponded to the synthetic replicate of porcine GRP, and another was considered to correspond to C-terminal fragments of the peptide.

Topics: Adult; Carcinoid Tumor; Chromatography, Gel; Female; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Lung Neoplasms; Peptides; Radioimmunoassay