Chromogranin A and B and Secretogranin II in Medullary Carcinomas of the Thyroid

Schmid, K. W.; Fischer‐Colbrie, Reiner; Hagn, C.; Jasani, B M; Williams, E. D.; Winkler, Hans

doi:10.1097/00000478-198707000-00007

Cited by 59 publications

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“…Calcitonin may be present only in a few tumour cells [14,20,47] or may be completely lacking [14,41]. Usually the pattern of chromogranin A immunoreactivity resembles that of calcitonin reactivity [14,37]; however, some MTC show a greater proportion of chromogranin-A immunoreactive than of calcitoninimmunoreactive tumour cells [14]. Rare cases of chromogranin A-negative MTC have been described [29], but chromogranin A was detectable in all 142 MTC of the present series.…”

Section: Discussionmentioning

confidence: 44%

”Atypical" medullary thyroid carcinoma with little or no calcitonin expression

Schmid

Ensinger

1998

Virchows Archiv

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In a retrospective analysis of 142 medullary thyroid carcinomas, four sporadic cases with an unusual histological and immunohistochemical appearance were found. Three cases (two males, one female) had very few calcitonin-positive tumour cells, while the fourth case (male) completely lacked calcitonin immunoreactivity at both mRNA and protein levels, whereas a variety of neuroendocrine markers were positive in at least 50% of tumour cells. The four tumours were completely devoid of carcinoembryonic antigen expression and of amyloid. Differential diagnosis and histogenetic considerations are discussed.

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Section: Discussionmentioning

confidence: 44%

”Atypical" medullary thyroid carcinoma with little or no calcitonin expression

Schmid

Ensinger

1998

Virchows Archiv

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“…This happens because biotinylated MAb binds to the antigen and becomes, in its turn, the 'antigen' for the cold avidin and the radiotracer. Recently, a positive immunostaining for CgA in MTC has also been described: the staining for CgA correlates with the areas staining positively for calcitonin (Schmid et al, 1987). CgA is released by neuroendocrine tumours without physiological neuroendocrine stimuli and is present in a significant amount in the intracellular matrix of such tumours.…”

Section: Resultsmentioning

confidence: 92%

“…Thus ISG is very specific, but a relatively low tumour to background ratio and a high background activity can affect its sensitivity. Theoretically ISG can target different MTC-associated antigens, such as Ct, CEA and CgA (De Lellis et al, 1978;Talerman et al, 1979;Schmid-et al, 1987;Pacini et al, 1991). MTC often produces CEA, which is expressed both in the cytoplasm and on the cell membrane.…”

Section: Resultsmentioning

confidence: 99%

“…Positive immunohistochemical stains for Ct and CEA are characteristic of MTC (De Lellis et al, 1978;Talerman et al, 1979; Pacini et al, 1991). Recent immunohistochemical studies have established that MTC also stains positively for chromogranin A (CgA) (Schmid et al, 1987), a glycoprotein stored and released by exocytosis together with the resident hormones of electron-dense core secretory granules in apudomas.This paper reports the evaluation of pretargeted immunoscintigraphy (ISG) in the diagnosis of primary/metastatic and recurrent MTC. As antibodies, anti-CEA and anti-CgA (separately and as a cocktail) biotinylated MAbs were used in a three-step procedure.…”

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confidence: 99%

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Pretargeted immunoscintigraphy in patients with medullary thyroid carcinoma

Magnani

Paganelli²,

Songini³

et al. 1996

Br J Cancer

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Summary To evaluate the use of pretargeted immunoscintigraphy (ISG) in the diagnosis and follow-up of patients with medullary thyroid carcinoma (MTC), we studied 25 patients with histologically proven disease; ISG was repeated after surgery in two patients. The antibody, either an anticarcinoembryonic antigen (CEA) or an antichromogranin A (CgA) biotinylated monoclonal antibody (MAb) or a cocktail of the two biotinylated MAbs was first injected. After 24 h, avidin was administrated i.v., followed by "'In-labelled biotin 24 h later. Fifty-two lesions were visualised. Six primary tumours, diagnosed by increased calcitonin levels, were all correctly diagnosed; 47 recurrences, also suspected by blood tumour markers, were detected and confirmed by cytology or histology. In one case, single photon emission tomography allowed the detection of small lymph nodes with a diameter of 4 -7 mm. These lesions, not judged neoplastic by ultrasound, were confirmed to be neoplastic by fine needle aspiration. Pretargeted ISG correctly localises primary tumours and recurrences in MTC patients, when the only marker of relapse is serum elevation of calcitonin. With this three-step pretargeting method, cocktails of potentially useful MAbs can be used, avoiding false-negative studies that may occur when CEA or CgA are not expressed.Keywords: medullary thyroid carcinoma; monoclonal antibody; avidin-biotin Medullary thyroid carcinoma (MTC) arises from calcitoninsecreting parafollicular cells in the thyroid. Both the sporadic and the familial form are treated by surgery (Chong et al., 1975;Rossi et al., 1980), as the efficacy of radiotherapy is limited (Samaan et al., 1988) and chemotherapy is ineffective (Rougier et al., 1983;Brunt and Wells, 1987). Early diagnosis of recurrence or metastasis and accurate localisation of recurrent disease are very important prerequisites for successful surgical excision.Elevated serum calcitonin (Ct) is considered to be a marker for MTC. High serum levels of Ct and carcinoembryonic antigen (CEA) can often be found in patients with recurrent disease several years before it becomes clinically apparent, but, at present, no efficient and specific method is available for the localisation of recurrences.Morphological imaging techniques (ultrasonography, US; computerised tomography, CT; magnetic resonance imaging, MRI) are routinely used to confirm and localise a biologically detected recurrence but are not always adequate because of topographic polymorphism and the small size of tumour recurrences at an early stage of development (Schwerk et al., 1985;Frank et al., 1987;Crow et al., 1989).Several methods based on tumour avidity of non-specific radiopharmaceuticals such as [99"Tc](V)DMSA, '3I11231-MIBG and 20'T1 have also been designed for this purpose, with variable results (Arnstein et al., 1986;Hilditch et al., 1986;Baulieu et al., 1987;Clarke et al., 1987;Hilditch, 1987; Clarke et al., 1988;Hoefnagel et al., 1988;Guerra et al., 1989;Adams et al., 1990;Charkes et al., 1990;Udelsman et al., 1993).In the attem...

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“…However, further studies, in particular Secretion of G A W K by a h u m a n medullary thyroid carcinoma cell line 507 microsequencing, are needed to elucidate the precise nature of 10.6 K G A W K -L I . I n human MCT, the presence of C g A and C g C in addition to C g B was also demonstrated immunohistochemically (5). CgA, C g C o r their processing products could be secreted by h u m a n M C T .…”

Section: Fig 2 Effects Of A23187 (Lo-' M) Alone and A23187mentioning

confidence: 85%

Secretion of GAWK, a Presumed Product of Chromogranin B Processing, by a Human Medullary Thyroid Carcinoma Cell Line: Effect of Phorbol Ester, Forskolin and Calcium‐lonophore

Iguchi

Kameya

Kadoya

et al. 1990

J Neuroendocrinology

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GAWK was isolated from human pituitary glands and presumed to be a processing product of human chromogranin 6. In the present studies, we investigated effects of phorbol ester (TPA), forskolin and Ca2+-ionophore (A23187) on GAWK secretion using a human medullary thyroid carcinoma-derived cell line (TT-cell). A dose-responsive stimulation of GAWK-like immunoreactivity (LI) secretion was found in the presence of TPA as well as forskolin. A23187 caused an increase of GAWK-LI secretion and addition of TPA together with A23187 revealed an additive effect on the GAWK-LI secretion. These findings indicate that GAWK-LI is a secretory peptide in the TT-cells and suggest that A and C kinase, and possibly CaZ+-calmodulin transduction systems are involved in the GAWK-LI secretion by the TT-cells. TT-cells may provide a good model for the investigation of regulation of chromogranin secretion.GAWK was initially isolated from human pituitary glands and sequenced in 1985 (I). GAWK is composed of 74 amino-acids and this sequence is entirely homologous to the amino-acid residues 420-493 of human chromogranin B (CgB) deduced from cDNA (2, 3). A GAWK sequence is located between the regions composed of two and four basic amino-acids in the human CgB GAWK could originate from CgB after proteolytic cleavage.CgB is distributed mainly in the neuroendocrine tissues in humans (4) and the presence of CgB in medullary carcinoma of the thyroid (MCT) was demonstrated immunohistochemically (5). However, CgB secretion by various tissues has not been demonstrated except bovine chromaffin cells (6) and rat PC12 cells (7). The present studies were undertaken to investigate secretion of GAWK-like immunoreactivity (LI) using a human MCT-derived cell line (TT-cell) (8). Gel permeation chromatography was also performed to characterize GAWK-LIs released and/or present in the cells. molecule (Lys418-Arg419 and 1 (2). Results Cell contents of GA WK-LI and calcitonin ( C T )Cell contents (mean SD of four determinations) of GAWK-LI and CT were 54+6 pmol/rng protein and 373k54 pmol/mg protein, respectively.Effect of 12-0-tetradecanoyl phorboll3-acetate ( T P A ) , CaZ'-ionophore (A23187) and forskolin on the secretion of GA WK-LI by TT-cells As shown in Fig. 1, a significant stimulation of GAWK-LI secretion was seen in the presence of TPA and its stimulation was in a doseresponsive manner. A23187 M) resulted in a three-fold increase in the secretion of GAWK-LI (Fig. 2) and addition of P A together with A23187 revealed an additive effect on the secretion of GAWK-LI (Fig. 2). A dose-responsive stimulation of GAWK-LI secretion was observed in the presence of forskolin (Fig. 3). Forskolin was the most potent secretagogue for the GAWK-LI secretion. Similarly, stimulation of CT secretion was observed after addition of TPA, A23187, A23187+TPA and forskolin as was GAWK-LI secretion, however the magnitude of the increase in the secretion of CT was higher than that of GAWK-LI (data not shown). Gel permeation chromatographyAs shown in Fig. 4, the majority of G...

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Chromogranin A and B and Secretogranin II in Medullary Carcinomas of the Thyroid

Cited by 59 publications

References 0 publications

”Atypical" medullary thyroid carcinoma with little or no calcitonin expression

”Atypical" medullary thyroid carcinoma with little or no calcitonin expression

Pretargeted immunoscintigraphy in patients with medullary thyroid carcinoma

Secretion of GAWK, a Presumed Product of Chromogranin B Processing, by a Human Medullary Thyroid Carcinoma Cell Line: Effect of Phorbol Ester, Forskolin and Calcium‐lonophore

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