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Defective thyroglobulin synthesis in an experimental rat thyroid tumor: iodination and thyroid hormone synthesis in isolated tumor thyroglobulin.

Purified rat tumor thyroglobulin from the experimental rat thyroid tumor, line 1-1C2, was studied for its thyroid hormone content after in vivo and in vitro iodination and compared with normal and desialylated normal rat thyroglobulin. Tumor thyroglobulin had a very low sialic acid and iodine content; after in vivo iodination it contained only small amounts of triiodothyronine (T3) and no detectable thyroxine (T4). After in vitro iodination with 125I it showed a distribution of T3 and T4 very similar to that of normal and desialylated normal thyroglobulin iodinated in vitro. In vitro iodination dissociated tumor and desialylated normal thyroglobulin to a greater extent than normal thyroglobulin. Tumor tissue, on the other hand, showed considerable iodinating activity in the 105,000 X g pellet when studied with exogenous acceptors. These results are compatible with a role for sialic acid in the maturation and migration of thyroglobulin to the iodination site, rpovided that the intracellular distribution of the iodinating enzymes are normal.

Animals

[Radioimmunological determination of calcitonin (TCT) in the course of thyroid tumor pathology (84 cases)].

The dosage of calcitonin was done in 13 thyroid carcinoma and 71 begnin thyroid tumors. In one case, the preoperative diagnosis of medullary thyroid carcinoma (M.T.C.) was alloved; in one another case of M.T.C. the repeatted dosage allows the evolution survey and the exploration of the family; in a third case, the dosage allows to doubt the diagnosis of M.T.C. in post-mortem. In 71 cases of begnin thyroid tumors, the calcitonin immunoassay is in the normal range. The interest and limits of the preoperative dosage was drawn of this experience.

Adenocarcinoma

Comparative ultrastructure of thyroid, tongue and eyelid lesions in the neuroma phenotype of medullary carcinoma of the thyroid: association of amyloid with fibroblasts in thyroid tumor and in mucosal neuromas.

Electron-microscopic and histochemical studies of thyroid tumor, tongue neuromas and eyelid neuromas from the lesions of a patient with medullary thyroid carcinoma were compared. In the thyroid tumor, a significant number of the C cells showed heterogeneity of granule types; no C cells, however, were identified in the tongue and eyelid neuromas. Amyloid was clearly shown by Congo red staining in the thyroid neoplasm and in the tongue neuromas. In all tissues, amyloid fibrils were found to be ultrastructurally closely associated with fibroblasts. These fingings suggest that the fibroblast rather than the C cell may have played the important role in the deposition of amyloid in this patient's thyroid carcinoma.

Amyloid

Relationship of gangliosides to the structure and function of thyrotropin receptors: their absence on plasma membranes of a thyroid tumor defective in thyrotropin receptor activity.

Plasma membranes derived from rat thyroid tumor (1-8R) which is unresponsive to thyrotropin but is responsive to dibutyryl adenosine 3':5'-cyclic monophosphate bind less than 20% of the [125I] thyrotropin which can be bound to plasma membranes from normal rat thyroids under conditions which optimize tumor membrane binding relative to normal thyroid membranes. In addition, the binding is different from thyrotropin binding to normal thyroid membranes both in its altered sensitivity to changes in hydrogen ion concentration and in a decreased sensitivity to competition by unlabeled thyrotropin. This reduced capacity to bind [125I] thyrotropin cannot be attributed to degradation of the hormone by membrane-associated proteases. Although the supernatant phase of the thyroid tumor homogenates contains a soluble component which inhibits [125I] thyrotropin binding to thyrotropin receptors on plasma membranes, its level is the same as in homogenates of normal thyroid tissue. Trypsin digestion does not expose thyrotropin receptors in a manner analogous to that seen in normal thyroid tissue. The major ganglioside in the tumor membranes is N-acetylneuraminylgalactosylglucosylceramide and the membranes lack the N-acetylgalactosaminyltransferase required for the synthesis of more complex gangliosides. In contrast, the normal rat thyroid membranes contain more complex gangliosides such as galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide and N-acetylneuraminylgalactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosyl ceramide as well as the glycosyltransferase activities required for their syntheses. Galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide can also be detected in normal membranes, but not in tumor membranes, by selective labeling with galactose oxidase (D-galactose: oxygen 6-oxidoreductase, EC 1.1.3.9) and [3H] sodium borohydride. These results support the hypothesis that gangliosides are important structural or functional components of thyrotropin receptors on thyroid plasma membranes.

Animals

Tetanus toxin interactions with the thyroid: decreased toxin binding to membranes from a thyroid tumor with a thyrotropin receptor defect and in vivo stimulation of thyroid function.

Normal rat thyroid membranes adsorb neurotoxicity when incubated with purified tetanus toxin. Membranes from a rat thyroid tumor with a thyrotropin receptor defect adsorb very little neurotoxicity when similarly evaluated. This inability of the tumor membranes to adsorb neurotoxicity is correlated with a defect in their ability to bind both 125I-labeled tetanus toxin and [125I]iodothyrotropin. The effect of tetanus toxin on the release of radioiodine from the thyroids of appropriately prepared mice has been measured by adapting methods used for the bioassay of thyrotropin. One minimum lethal dose of tetanus toxin given sc caused a significant release of radioiodine into the blood of mice 48 h after injection. In mice subjected to the stress of prior bleedings or anesthesia, the release of radioiodine from the thyroid by tetanus toxin was accelerated, i.e., the increase in blood radioiodine could be measured 24 h after injection. These results again suggest that tetanus toxin may interact with thyrotropin receptors on thyroid plasma membranes. The "sympathetic overactivity syndrome" seen in some patients with tetanus and the syndrome characterized as "thyroid storm" in patients with Graves' disease are discussed as they may relate to these observations.

Animals

Transmission and scanning electron microscopy of experimentally induced thyroid tumors in rats.

Irradiation of the neck region of 10 days old Wistar rats with 300 rads X-rays and their subsequent treatment with MTU leads to the development of thyroid tumors. The ultrastructure of the thyroid tumors induced was studied by transmission (TEM) and scanning electron microscopy (SEM). In follicular carcinomas, cylindrical or high columnar cells with abundant microvilli, well-developed ergastoplasmic reticulum and a hypertrophied Golgi complex predominate. The cytoplasm of the tumor cells of papillary carcinomas was composed of large pleomorphic cisternae, irregular in shape mitochondria, dense bodies, phagolysosomes and lamellar or multivesicular structures. Scanning electron microscopy revealed in the control animals a regular pattern of thyroid follicles tied to each other by tissue bridges and covered by set of blood and lymph vessels. The relief of the follicular carcinomas was irregular indicating follicles different in size and shape. The internal surface of the neoplastic follicles was also irregular as result of deep invaginations and intrafollicular cell growth. The apical region of the normal and neoplastic thyroid follicular cells was covered with abundant microvilli protruding into the colloid.

Adenocarcinoma

Thyroid cancer: a study of 573 thyroid tumors and 161 autopsy cases observed over a thirty-year period.

Five hundred and seventy-three thyroid tumors from surgical material and 161 autopsy cases were studied as to incidence, types, and precursor changes using the new WHO-classification. In the surgical material 225 tumors were follicular, 145 papillary, 147 anaplastic, 23 squamous cell, and 10 medullary. Twenty-three sarcomas were found. tthe percentage of follicular carcinoma had decreased, whereas that of papillary carcinoma increased and that of anaplastic carcinoma remained constant. In over 50% of anaplastic carcinomas neoplastic follicular structures have been identified. As a rule the more sections are prepared, the more papillary carcinomas and the less sarcomas are diagnosed. Thyroid tumors leading to death were found in 0.33% of 53,134 consecutive autopsies. Anaplastic (52.3%) and follicular (33.5%) carcinoma were most frequently encountered. Metastases of follicular and anaplastic carcinoma were most often found in the lung, pleura, and bones, whereas lymph nodes of the neck, lung, and bones were predominantly involved in cases of the papillary type. Therapy of thyroid carcinoma is total thyroidectomy. The transition of follicular carcinoma to the anaplastic type has to be avoided whenever possible.

Adenocarcinoma

The structure of tight junctions in human thyroid tumors. A systematic freeze-fracture study.

Tight junctions of normal human epithelium comprise 6--8 intramembranous ridges. Tight junctions of adenomas and one case of follicular carcinoma were morphologically identical with normal controls. Another follicular carcinoma (clinically less malignant than the case mentioned above), however, showed loss of junctional polarity with spreading of ridges on lateral cell membranes. One case of papillary carcinoma (clinically low malignancy) displayed only focal attenuations of the tight junction belt. Another more malignant tumor of the same histologic type showed breaks of ridges and focal interruptions of the tight junction meshwork. Cell membranes of two anaplastic carcinomas of high malignancy were completely devoid of tight junction ridges. We conclude that tight junction alterations are not necessarily implicated in malignant transformation and that they correspond with tumor differentiation rather than directly with a single parameter of thyroid tumor malignancy.

Adenocarcinoma

Studies on a cell line from a functional rat thyroid tumor in continuous culture.

A clonal cell line derived from a functional and transplantable rat thyroid tumor was established in continuous monolayer culture by the use of enzymatic dissociation followed by an alternate culture-animal passage procedure. After being implanted backin the animal and again plated in culture, epithelial-like cells aggregated and rearranged themselves over the bottoms of dishes in structures resembling cross sections of a normal thyroid gland. The same morphology and growth pattern were maintained after innumerable subcultures and freeze/thawing periods. Cells grew with a population-doubling time of about 24 h in serum-supplemented synthetic medium. Cell monolayers stained with periodic acid-Schiff (PAS) showed a uniformly epithelial-like morphology; their cytoplasm contained abundant PAS-positive material that was resistant to enzymatic digestion with amylase. Thin-layer chromatography of acid-butanol cell extracts in primary and clonal cultures, followed by a specific and sensitive staining method for iodine compounds, demonstrated the presence of monoiodotyrosine (MIT), diiodotyrosine, and triiodothyronine-thyroxine. In contrast, in similar extracts obtained from a cultured liver cell line, the only iodinated amino acid was MIT. Thus, with regard to the above criteria, this cell line preserved specialized thyroid cell morphology and function.

Animals

Epithelial thyroid tumors in cows.

From 1964 to 1973, 370 tumors were collected from cows of unknown age. Ten (2.7%) of these were primary thyroid tumors. Three were malignant. The benign tumors were solitary encapsulated adenomas in the parenchyma with more or less defined trabeculae, tubular, and microfollicular pattern. One of the malignant tumors was a cystic papillary adenocarcinoma, and two were small cell carcinomas consisting of small, sometimes binuclear, pleomorphic cells.

Adenoma

Diminished binding of thyroid-stimulating hormone in a transplantable rat thyroid tumor as a possible cause of hormone unresponsiveness.

The adenylate cyclase activity and the binding of 125I-labeled thyroid-stimulating hormone (TSH) of normal and tumor rat thyroid plasma membranes were compared. No significant difference in the basal and fluoride-sensitive adenylate cyclase activity between normal and tumor plasma membranes was observed. Thyroid plasma membranes responded to TSH, whereas the enzyme from the tumor plasma membranes was TSH insensitive. Thyroid plasma membranes boud 125I-TSH. Tumor plasma membranes bound 125I-TSH poorly. At the highest concentration of unlabeled TSH used, 80% of the 125I-TSH that was bound to thyroid plasma membranes was displaced, whereas only 10% of the 125I-TSH bound to tumor plasma membranes was displaced. Therefore, it seems likely that the failure of this tumor to respond to TSH is due to an alteration in the functional unit of membrane adenylate cyclase at the level of the receptor subunit.

Adenylyl Cyclases

An unusual thyroid tumor in a child.

Malignant neoplasms of the thyroid gland are quite rare in children. Winship, in his classic article, could find only 562 cases in the literature. The histopathological patterns resemble those of the adult tumors. Despite early cervical metastasis, the prognosis in general is favorable, with many long-term survivals. Prior exposure to radiation of the head and neck is a definite pre-disposing factor. Teratomas of the neck are a medical curiosity--less than 100 cases are described in the literature. The vast majority of these are found during the neonatal period, and are benign histologically. These are usually large, cystic, bulky masses which produce mechanical obstruction of the upper airway and digestive tract. Only one of these tumors, described by Pupovac in 1896, has been considered malignant. A six-year-old child was examined with a right thyroid mass of three months' duration. The thyroid scan showed a "cold nodule." At surgery, a well-encapsulated mass was found. The pathology showed a predominance of malignant spindle cells, with areas of papillary carcinoma; however, there were well-defined mucous glands present in the tumor. Clinically the child has remained well and asymptomatic. The slides have been extensively reviewed. To my knowledge no such tumor has been previously described. The tumor is considered to be a malignant thyroid tumor growing out of teratomatous tissue.

Age Factors

Differences in phosphofructokinase regulation in normal and tumor rat thyroid cells.

The kinetic and molecular properties of a phosphofructokinase derived from a transplantable rat thyroid tumor lacking regulatory control on the glycolytic pathway were studied. The properties of the near-purified enzyme (specific activity 140 units/mg) were compared with those of phosphofructokinase from normal rat thyroid (specific activity 134 units/mg). The electrophoretic mobilities and gel elution behavior of these two enzymes were almost similar. The thyroid tumor phosphofructokinase showed, however, a greater degree of size and/or shape heterogeneity in the presence of ATP than the normal thyroid enzyme, as determined by gel filtration and sucrose density gradient centrifugation. Kinetic studies below pH 7.4 showed a sigmoid response curve for both enzymes when the velocity was determined at 1 mM ATP with varying levels of fructose-6-P. The interaction coefficient, however, was 4.2 and 2.6 for normal and tumor thyroid phosphofructokinase, respectively. Ammonium sulfate decreased the cooperative interactions with the substrate fructose-6-P in both enzymes. The thyroid tumor enzyme, however, was less sensitive to the inhibition by ATP and by citrate. The reversal of citrate inhibition by cyclic 3':5'-adenosine monophosphate was also less effective with the thyroid tumor phosphofructokinase, while the protective effect of fructose-6-P was stronger. The difference in citrate inhibition between tumor and normal thyroid enzyme was not strongly affected by varying the MgCl2 concentration up to 10 mM. It is concluded that the complex allosteric regulation typical of the normal thyroid phosphofructokinase is still present in the enzyme isolated from the thyroid tumor tissue. The latter, however, is more loosely controlled by its physiological effectors, such as ATP, citrate, and cyclic AMP.

Adenosine Triphosphate