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Effects of Neuromedin B and GRP-10 on Gastrin and Insulin Release from Cultured Tumor Cells of a Malignant Gastrinoma

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Effects of Neuromedin B and GRP-10 on Gastrin and Insulin Release from Cultured Tumor Cells of a Malignant Gastrinoma Endocrinol. Japon. 1990, 37 (6), 857-865 Effects of Neuromedin B and GRP-10 on Gastrin and Insulin Release from Cultured Tumor Cells of a Malignant Gastrinoma KOICHI KAWAI, HIDEHITO MUKAI1, KENJI YUZAWA2, SEIJI SUZUKI, NOBUAKI KUZUYA, KEIJI FUJII3, EISUKE MUNEKATA1 AND KAMEJIRO YAMASHITA Department of Internal Medicine, Department of Surgery2, Institute of Clinical Medicine, Department of Pathology3, Institute of Basic Medical Science, Institute of Applied Biochemistry1, University of Tsukuba Abstract A study relating to gastrin release from gastrinoma cells by neuromedin is and C-terminal decapeptide of gastrin releasing peptide (GRP-10) has not yet been reported. Therefore, we studied the effects of neuromedin B and GRP- 10 on gastrin release from cultured dispersed cells prepared from both the primary tumor in the pancreas and the metastatic tumor in the liver from a case of malignant Zollinger-Ellison syndrome. Both the primary and metastatic tumors obtained by a curative operation contained similar concentrations of gastrin and glucagon, whereas the primary tumor contained 10 times more insulin than the metastatic tumor. Gastrin release from cultured cells of both tumors was suppressed by 0.1 and 10nM neuromedin B and tended to be suppressed by 0.1-10nM GRP-10. However, insulin release from cultured cells of the pancreatic tumor was stimulated by GRP-10, but not by neuromedin B. These results might suggest that receptor function for the bombesin family peptides is abnormal in gastrinoma cells in both primary and metastatic tumors, and that a major source of insulin secretary cells is the contaminated normal islet cells in the primary tumor. Zollinger-Ellison syndrome is charac- Japan where only about 100 cases were terized by recurrent peptic ulceration, reported prior to 1982 (Kishimoto and marked gastric acid hypersecretion and islet Miyoshi, 1983). Gastrin release from this cell tumors secreting gastrin (Zollinger and tumor is abnormal; it is not suppressed Ellison, 1955; McGuigan and Trudeau, by secretin (Lamers and Van Tongeren, 1969). Its incidence is low, particularly in 1977; McGuigan and Wolfe, 1980), and is weakly stimulated by bombesin (Basso et Received June 22, 1990 al., 1981; Jansen and Lamers, 1982). Address for correspondence and reprint requests: Neuromedin B and C-terminal decapeptide KOICHI KAWAI, M. D. & Ph. D. Institute of Clinical Medicine, University of Tsukuba of gastrin releasing peptide (GRP-10) are Tsukuba, Tsukuba, Ibaraki-ken 305, Japan mammalian bombesin-like peptides (Mina- Endocrinol. Japon. 858 KAWAI et al. December 1990 mino et al., 1983; Okada et al., 1984;Reeve mission to the University Hospital. How- et al., 1983) which stimulate the release of ever, the duodenal ulcer recurred and a gastrin, insulin and glucagon in a similar high plasma gastrin level was found (1090 manner to bombesin (Spindel, 1986; Kawai pg/ml, normal value 40-20pg/ml). et al., 1988). However, no study relating The physician suspected Zollinger-Ellison to gastrin release from gastrinoma by these syndrome and referred her to the University peptides has yet been reported. Hospital. She had no family history of The effects of neuromedin B and GRP- peptic ulcer diseases. 10 on gastrin release from cultured dispersed The patient was 147 cm in height and cells, from both the primary tumor in the 54kg in weight, and seemed to be healthy. pancreas and the metastatic tumor in the Her blood pressure was 120/88mmHg. No liver obtained from a case of malignant abnormal findings were observed in the Zollinger-Ellison syndrome, are reported. physical examination except for an operation scar in her abdomen. The blood cell count on admission showed her to be Case Report slightly anemic; RBC was 350•~104/mm3, Hb, 10.0g/dl, and hematocrit, 39.9%. A 43-year-old woman had suffered from Urinalysis and blood chemistry yielded epigastric pain and diarrhea for 7 years. normal values ; serum total protein was A duodenal ulcer was diagnosed on the 7.0g/dl, albumin, 4.0g/dl, Ca++ 8.9mg/di, the basis of her symptoms and antiacids and inorganic phosphate 4.5 mg/dl. prescribed by a physician. The symptoms Endocrinological data on admission are sometimes relapsed and she received sub- shown in Table 1. The basal gastrin level total gastrectomy 9 months before her ad- was extremely high and it was not sup- Table 1. Endocrinological data on admission Gastrin: Secretin injection test; Mixed meal loading; Oral glucose tolerance test: Basal hormone levels in plasma: Thyroxine 8.2ƒÊg/dl, Triiodothyronine 93ng/dl, TSH 1.7ƒÊU/ml, Calcitonin 40pg/ml, Parathyroid hormone 0.3ng/ml (RIA with C-terminal-specific antibody), Growth hormone 3.6ng/ml, ACTH 35ƒÊg/ml, Prolactin 21ng/ml, Luteinizing hormone 15.0mIU/ml, Follicule- stimulating hormone 11.2mIU/ml, Cortisol 9.1ƒÊg/dl, Aldosterone 15.0ng/dl. Vol.37, No.6 GASTRINOMA AND NEUROMEDIN B, GRP-10 859 pressed to normal by injecting secretin sound of the neck were normal. (2 U/kg Secrepan(R), Eisai, Tokyo, Japan). From these results, the diagnosis of The response of gastrin release to a mixed Zollinger-Ellison syndrome was established meal was low. A 75g oral glucose loading with a primary tumor in the pancreas and test revealed an abnormal increase in plasma multiple metastatic tumors in the liver. No glucose level, the so called "oxyhyper- positive data for multiple endocrine neo- glycemia" type, probably due to subtotal plasia were found. She received a resection gastrectomy. Plasma insulin increased with of the body and tail of the pancreas a pattern of delayed response from its high together with the spleen and residual fasting level (normal value 3-18 pU/ml). stomach, and a partial resection of the Basal levels of thyroid, parathyroid, pitui- liver and an enucleation of hepatic metastatic tary and adrenal hormone were normal. tumors. Urinary excretion of epinephrine, norepine- The primary tumor nodule was a phrine, metanephrine and normetanephrine solitary, solid and yellowish mass; 55mm were normal at 8.1, 77.4, 40 and 100ƒÊg/ in size at its largest diameter and weighing day, respectively. 69 gr. Fig. 1 shows the microscopic find- Basal acid output was 35.2mEq/hr and ings for the primary and metastatic tumors. the maximum acid output in response to tetra- Histologically, the arrangement of the gastrin (4ƒÊg/kg Gastpsin(R), Nihonkayaku, primary tumor cells exhibited combinations Tokyo, Japan) was 39.6mEq/hr. Abdominal of a trabecular pattern, solid nests and a ultrasound, CT scanning and angiograms gyriform pattern. The tumor cells varied revealed a tumor in the pancreatic body in shape, i. e. ovoid to polygonal, and the and multiple metastatic tumors in the liver. tumor cells were larger than normal islet CT scanning of the pituitary and ultra- cells. Cytoplasm of the tumor cells was Fig. 1 A Fig. 1. Histological observation of the primary tumor in the pancreas (A), capsular margin of the primary tumor (B), and the me- tastatic tumor in the liver (C). Hema- toxin-eosin staining (•~100). Primary tumor (A): Solid Endocrinol. Japon. 860 KAWAI et al. December 1990 Fig. 1 B B Fig. 1 C C tumor growth with scanty stroma. Note the polygonal shaped cells and the round nuclei. Capsular margin of the primary tumor (B): The compressed remaining Langerhans' islets are seen at the right hand side of the photo. Liver metastasis (C): The tumor with thin fibrous capsule exhibiting a solid pattern and scanty stroma. Vol.37, No.6 GASTRINOMA AND NEUROMEDIN B, GRP-10 861 abundant, and the staining characteristics fetal calf serum and gentamicin (40ƒÊg/ml) in were granular and acidophilic. The nuclei humidified, 95% air and 5% CO2 at 37•Ž for were often giant hyperchromatic. Mitotic 3 days. figures were rarely seen. In the primary Hormone release from cultured cells nodule, capsular invasion was prominent, After 3 days' culture, the medium was and the tumor cells protruded in the pan- aspirated and the wells were washed twice with creatic duct, obstructing the lumen. 1ml DMEM supplemented with 10% fetal calf After the operation, her plasma gastrin serum and gentamicin (40ƒÊg/mi). The cells level fell to 50pg/ml and she was dis- were then incubated in 1ml of the above charged. medium at 37•Ž for 24 hr to determine the basal hormone release. The viability of the cells was > 90% by trypan blue exclusion. After incubation, the medium was collected and Materials and Methods washed twice with the same medium. The cells were then incubated in 1 ml of the same medium Materials containing neuromedin B or GRP-10 at 37•Ž Neuromedin B and GRP-10 used in this for 1h. After the incubation, the medium was study were synthesized by the solid phase collected and the cells were again incubated in method (Mukai et al., 1987). They were purified 1ml of the medium containing the same dose by gel filtration and reverse phase high- of neuromedin B or GRP-10 at 37•Ž for 1 hr. performance liquid chromatography described The medium was collected and stored at 40•Ž previously (Mukai et al., 1987), and proved to until the hormone assaay. be at least 98% pure. Hormone assay Extraction of hormone from tumors The gastrin level was determined with a commercial kit (Gastrin-RIA kite, Dainabot 0.3g each of primary pancreatic tumor and hepatic metastatic tumor were placed into 3ml Radioisotope, Tokyo, Japan). The antiserum of boiling 0.1 N acetic acid for 10 min and in this immunoassay is directed against the C- homogenized with a Polytron (Brinkman). The terminal residues of gastrin. Insulin and homogenate was centrifuged for 30 min at glucagon levels were measured by RIAs accord- 100,000•~g at 4•Ž. The supernatant was ing to the method of Herbert et al.(1965), and lyophylized and dissolved in 0.2M glycine Faloona and Unger (1974) with E-7 antibody buffer pH 8.8 containing 0.25% human serum (kindly donated by Dr.
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