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Releasing Peptide, in a Human Medullary Thyroid Carcinoma1

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Releasing Peptide, in a Human Medullary Thyroid Carcinoma1 [CANCER RESEARCH 48, 2412-2416, May 1, 1988] Molecular Forms of Katacalcin, Calcitonin Gene-related Peptide and Gastrin- releasing Peptide, in a Human Medullary Thyroid Carcinoma1 J. Michael Gonion,2 Gerard P. McGregor, GöranWallin, Lars Grimelius, and Lars Thim Clinical Research Group for Gastrointestinal Endocrinology of the Max-Planck-Gesellschaft at the University of Gòttingen, D-3400 Göttingen,Federal Republic of Germany [J. M. C., G. P. M.]; Department of Surgery, Karolinska Hospital, Stockholm, Sweden [G. W.]; Department of Pathology, University Hospital, Uppsala, Sweden [L. G.J; and Novo Research Institute, Bagsvaerd, Denmark [L. T.] ABSTRACT amination of a fine needle biopsy showed medullary thyroid carcinoma. Subsequent examination of the patient revealed extensive métastases Peptides synthesized by a human medullary thyroid carcinoma were purified to homogeneity by reverse-phase high performance liquid chro- in lymph nodes, in the neck, right supraclavicular fossa, mediastinum, and lungs. Total thyroidectomy was performed and a large tumor mass matography and structurally characterized by determination of amino growing upwards into the neck was removed. The patient had a serum acid composition, amino acid sequence, and fast atom bombardment mass calcitonin concentration of 40.8 ng/ml before operation and 20.8 ng/ spectra. The katacalcin-related material in the tumor extract was heter ml after tumor resection (healthy subjects, 8-40 pg/ml). There were no ogeneous. Katacalcin (1-21) represented the predominant molecular form obvious signs of thyroid disease or other endocrine disorders in the but metabolites, identified as katacalcin (1-20), (1-19), (1-15) and (1- patient's nearest relatives. 13), were also identified in high concentration. Calcitonin gene-related peptide-I was isolated from the tumor but calcitonin gene-related pept ¡de Tumor Histopathology. Light microscopy showed an argyrophil tu ll was absent. A minor component of calcitonin gene-related peptide-like mor with polyglonal cells and a mixed growth pattern (solid and trabecular arrangement). Moderate nuclear atypia was seen. Mitoses immunoreactivity was of higher molecular weight and may represent an were fairly frequent. Immunostaining using the peroxidase-antiperoxi- incompletely processed form of the prohormone. Gastrin-releasing pep- tide (1-27) and gastrin-releasing peptide (18-27) (neuromedin C) were dase technique showed that the majority of tumor cells displayed isolated from the tumor but gastrin-releasing peptide (14-27) and bom- calcitonin and chromogranin A immunoreactivity. Groups of cells showing GRP, somatostatin, and neurotensin immunoreactivity were besin were absent. observed. An antiserum that reacts with bombesin but not GRP did not immunostain any tumor cells. Full details of the antisera used in INTRODUCTION ¡ninninoliistochemistry are provided in Ref. 12. Medullary carcinomas of the thyroid are derived from para- Extraction of Tumor Tissue. The tumor was immersed in liquid follicular ("-cells and are frequently associated with the produc nitrogen immediately after resection and stored at —70°Cuntiltime of tion of multiple regulatory peptide products. Immunohisto- extraction. The tissue (2.81 g) was homogenized while still frozen with chemical and radioimmunoassay studies have identified calci ethanol/0.7 M HC1 (3:1 vol/vol; 25 ml) using an Ultraturrax blender. tonin (1), katacalcin (2), CGRP3 (3), gastrin-releasing peptide The homogenate was stirred at 4"C for 16 h and centrifuged (20,000 x (GRP) (4), somatostatin (5), pancreatic polypeptide (6), and g for 1 h). Ethanol was removed from the supernatant under reduced adrenocorticotropic hormone (7). Calcitonin (and its COOH- pressure and peptides were isolated using Sep-pak CIS cartridges terminal flanking peptide, katacalcin) and CGRP-I are products (Waters Associates, Milford, MA) as described (13). Bound material was eluted with acetonitrile (80% vol/vol) and lyophilized. Synthetic of the same gene but they arise from different mRNAs by katacalcin (1-21) (40 nmol) and gastrin-releasing peptide (20 nmol) alternative RNA processing events (8). More recently, a second were incubated with the original extract (0.5 ml) for 16 h at 4°Cand human gene has been identified that encodes the precursor of the peptides were isolated using a Sep-pak cartridge. CGRP-II (9). The human CGRP-II sequence differs from the Purification of Peptides. The tumor extract, after partial purification CGRP-I sequence by three amino acid residues and the peptide on Sep-pak cartridges, was redissolved in 0.1% vol/vol trifluoroacetic has been detected in nervous tissue and medullary thyroid acid (2 ml) and injected onto a reverse-phase Supelcosil LC-18-DB column (250 x 10 mm; Supelco Inc., Belief«mte, PA) equilibrated with carcinoma (10). A single gene encoding the sequence of human 0.1 % trifluoroacetic acid. The column was eluted at 30°Cand at a flow GRP directs the synthesis of three distinct mRNAs resulting in the production of three preproGRP peptides (11). These pre rate of 2 ml/min. The acetonitrile concentration in the eluting solvent cursors differ in structure in the region of the COOH-terminal was raised to 21% vol/vol over 10 min followed by a raise to 49% vol/ extension peptide and all contain the full sequence of GRP (I- vol over 80 min. Absorbance was measured at 214 and 280 nm and individual peaks were collected by hand. 27). In this study, peptides derived from procalcitonin, pro- Peaks 1-5 (Fig. 1) representing katacalcin and related metabolites CGRP, and proGRP were isolated in pure form from an extract were purified to homogeneity on a Supelcosil LC-3DP column (250 x of a human medullary thyroid carcinoma. Structural character 4.6 mm) equilibrated with 0.1% trifluoroacetic acid. The column was ization of these peptides has provided insight into the pathways eluted at 30°Cand at a flow rate of 1.5 ml/min. The concentration of of posttranslational processing of the prohormones in the tumor acetonitrile in the eluting solvent was raised to 21% vol/vol over 30 cells. min. Peak 6 (Fig. 1), representing GRP (18-27), was purified to homo MATERIALS AND METHODS geneity on a Supelcosil LC-18-DB column (250 x 4.6 mm) equilibrated with 0.1% trifluoroacetic acid. The column was eluted at 30°Cand at Patient Details. The patient, a 41-year-old male, was admitted to hospital because of a progressive growth of a goiter. Cytological ex- a flow rate of 1.5 ml/min. The concentration of acetonitrile was raised from 14-35% vol/vol over 60 min. Received6/2/87; revised 10/30/87; accepted2/8/88. Peak 7 (Fig. 1), representing GRP (1-27), was purified under the The costs of publication of this article were defrayed in part by the payment same conditions as peak 6 except that the acetonitrile concentration of page charges. This article must therefore be hereby marked advertisement in was raised from 17.5-38.5% vol/vol over 60 min. The peptide was accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported by the Stiftung Volkswagenwerk and the Swedish purified to homogeneity on a Supelcosil LC-3DP column (250 x 4.6 Medical Research Council (Project 102). mm) equilibrated with 0.1 % trifluoroacetic acid. The column was eluted 2To whom requests for reprints should be addressed, at Klinische Arbeits at 30°Cand at a flow rate of 1.5 ml/min. The concentration of gruppe der MPC, Gosslerstrasse 10D, D-3400 Göttingen, Federal Republic of acetonitrile was raised from 17.5-38.5% vol/vol over 60 min. Germany. 3The abbreviations used are: CGRP, calcitonin gene-related peptide; GRP, Peak 8 (Fig. 1), representing CGRP-1, was purified to homogeneity gastrin-releasing peptide; cDNA, complementary DNA. on a Vydac 218TP54 column (250 x 4.6 mm; The Separations Group, 2412 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1988 American Association for Cancer Research. REGULATORY PEPTIDES FROM MEDULLARY THYROID CARCINOMA AB GRP CORP 05 30 20 CD < 70 80 Time (min) 5 Fig. 1. Reverse phase high performance liquid chromatography on a semipre parative CIS column of an extract of a medullary thyroid carcinoma. Details of the elution conditions are given in the text. Arrows,retention times of neuromedin C (NMC) identical to GRP (18-27), GRP (14-27), bombesin (B), GRP (1-27), and human CGRP-I. O. fractions with CGRP-like immunoreactivity. The follow ing peptides were isolated: peak 1, katacalcin (1-13); peak 2, katacalcin (1-15); 20 30 40 50 peak 3, katacalcin (1-21); peak 4, katacalcin (1-19); peak 5, katacalcin (1-20); Time (min) peak 6, GRP (18-27); peak 7, GRP (1-27); peak «,CGRP-I; peak 9, a high molecular weight form of CGRP. AHSi,,, absorbance at 214 nm. Fig. 2. Purification of tumor katacalcin (1-21) (peak 3 in Fig. 1) by reverse- phase high performance liquid chromatography on an analytical column. , concentration of acetonitrile in the eluting solvent. Peak A represents katacalcin Hesperia, CA) equilibrated with 0.1% trifluoroacetic acid. The column (1-21) and peak B was not part of the procalcitonin sequence. AUS.,,,, absorbance was eluted at 30*C and at a flow rate of 1.5 ml/min. The concentration at 214 nm. of acetonitrile was raised from 21-48% vol/vol over 60 min. Structural Analysis. Amino acid compositions were determined using peptides were katacalcin (1-13) (peak 1) 4.7 nmol; katacalcin a Durrum DSOOautomatic analyzer as previously described (13). Tryp- (1-15) (peak 2) 3.9 nmol; katacalcin (1-19) (peak 4) 13.1 nmol, tophan and cysteine residues were not determined. Primary structures katacalcin (1-20) (peak 5) 5.8 nmol; katacalcin (1-21) (peak 3) were determined by automated Edman degradation using an Applied 27.6 nmol.
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