Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma.
(9/4130)
Tumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre (P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor. (+info)
Expression of somatostatin receptors in oncocytic (Hurthle cell) neoplasia of the thyroid.
(10/4130)
Ten consecutive patients with Hurthle cell lesions of the thyroid (nodule/adenoma/carcinoma) were studied by (111)In-DTPA-D-Phe1-octreotide scintigraphy. Octreotide scintigraphy localized the primary Hurthle cell tumour in eight patients as distinct areas of increased uptake of radionuclide. Two patients with Hurthle cell carcinoma, previously thyroidectomized, had their metastases visualized by octreotide scintigraphy. Northern analyses showed expression of multiple somatostain receptor subtypes. Visualization of the Hurthle cell tumour may be due to a higher expression of somatostatin receptors in the lesions than in surrounding normal thyroid tissue. The tissue/blood (111)In concentration ratios for tumour samples from five patients showed clearly higher values than observed for normal connective tissue, muscle or lymph nodes. A relatively high uptake of (111)In was also observed in goiter tissue, which may lead to misinterpretations. The main indication for octreotide scintigraphy in patients with Hurthle cell carcinoma is suspicion of metastatic disease. (+info)
Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma.
(11/4130)
Angiogenesis is implicated in several pathological conditions, such as inflammation and tumor growth. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a potent stimulator of endothelial cell proliferation in vitro and in vivo. The present work aimed to compare VEGF expression in human normal thyroid glands, thyroiditis tissue and thyroid carcinomas using immunohistochemistry and in situ hybridization (ISH). Both chronic lymphocytic thyroiditis and differentiated thyroid carcinomas were found to strongly express VEGF mRNA and encode larger amounts of VEGF than normal thyroid tissue as attested by a VEGF immunostaining score. In addition, tumor samples from patients with metastases showed a higher immunostaining score than their non-metastatic counterparts (P<0.05). Carcinomas with the greatest contents of VEGF mRNA and VEGF protein had the most intense mitogenic activity. Special focus on endothelial cells showed intense mitogenic activity in neoplastic tissues in contrast to the total quiescence of endothelial cells in non-tumoral tissues. An intense VEGF production by differentiated thyroid carcinoma, attested either by a higher immunostaining score or a strong VEGF mRNA expression using ISH, could be a promising marker of tumor aggressiveness and may also be useful as a predictor of metastatic potential. (+info)
Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression.
(12/4130)
Although initiating mutations in the ret protooncogene have been found in familial and sporadic medullary thyroid carcinoma (MTC), the molecular events underlying subsequent tumor progression stages are unknown. We now report that changes in trk family neurotrophin receptor expression appear to be involved in both preneoplastic thyroid C cell hyperplasia and later tumor progression. Only a subset of normal C cells expresses trk family receptors, but, in C cell hyperplasia, the affected cells consistently express trkB, with variable expression of trkA and trkC. In later stages of gross MTC tumors, trkB expression was substantially reduced, while trkC expression was increased and often intense. In a cell culture model of MTC, exogenous trkB expression resulted in severely impaired tumorigenicity and was associated with 11-fold lower levels of the angiogenesis factor vascular endothelial growth factor. These results suggest that trk family receptor genes participate in MTC development and progression, and, in particular, that trkB may limit MTC tumor growth by inhibition of angiogenesis. (+info)
Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma.
(13/4130)
Beta-catenin is an ubiquitously expressed cytoplasmic protein that has a crucial role in both E-cadherin-mediated cell-cell adhesion and as a downstream signaling molecule in the wingless pathway. Stabilization of beta-catenin followed by nuclear translocation and subsequent T-cell factor/lymphoid-enhancing factor-mediated transcriptional activation has been proposed as an important step in oncogenesis. Stabilization may occur through activating mutations in exon-3 at the phosphorylation sites for ubiquitination and degradation of beta-catenin. Immunohistochemical subcellular localization of beta-catenin and mutational analysis of exon-3 of the beta-catenin gene by single-strand conformational polymorphism followed by DNA sequencing was performed on 37 samples from 31 patients with anaplastic thyroid carcinoma. Immunofluorescent staining showed nuclear localization in 15 (42%) of the 36 samples examined. Nucleotide sequencing of mobility shifts detected by single-strand conformational polymorphism revealed somatic alterations in 19 (61%) of the 31 patients analyzed. We conclude that mutations in beta-catenin are common in anaplastic thyroid cancer and that they may activate transcription, as illustrated by frequent nuclear localization of the protein. These findings support the idea that beta-catenin acts as an oncogene and contributes to the highly aggressive behavior of this tumor. (+info)
Gastroenteropancreatic neuroendocrine tumor metastases to the thyroid gland: differential diagnosis with medullary thyroid carcinoma.
(14/4130)
Neuroendocrine tumors (NET) of the thyroid gland are rare. Apart from medullary thyroid carcinoma (MTC), metastases of gastroenteropancreatic (GEP) NET may also occur. Features of six patients (five men, one female: age range, 39-67 years) with thyroid metastases from a GEP-NET are described. Thyroid metastases were bilateral in all patients and were associated with enlarged neck lymph nodes in five. In four cases, the thyroid tumor was either the first sign of the disease (n = 2) or was an isolated site of recurrence (n = 2). The tumors were well (n = 3) or poorly differentiated (n = 3). Five tumors for which the primary site could be determined corresponded to foregut-derived tumors (3 lungs, 1 thymus and 1 pancreatic NET). One tumor demonstrated calcitonin (CT) production as shown by immunohistochemistry and elevated plasma CT levels. However, the disease history and the clinical features strongly favored a metastasizing GEP-NET. No tumoral RET proto-oncogene mutation was found in this patient. The differential diagnosis between metastatic GEP-NET and MTC is crucial because prognosis, work-up, and treatment differ greatly. (+info)
Roles of circulating carcinoembryonic antigen and calcitonin in diagnosis of medullary thyroid carcinoma: a comparative study.
(15/4130)
Carcinoembryonic antigen (CEA) and calcitonin (CT) were simultaneously determined in sera and tumor tissues from 15 patients with medullary carcinoma of the thyroid (MCT). Serum CEA was increased in all but one patient, and CT did in all of them. Both levels were significantly related to the weight of excised tumor, but not to the presence of metastasis. Furthermore, a significant correlation was noted between the basal levels of CT and CEA. Both levels fell to normal after a radical operation had been performed. Tissue concentrations of CEA and CT in the MCT were more than 100 times those in hyperthyroidism, and the ratios of tissue over serum levels averaged 770 in CEA and 1000 in CT. In the calcium infusion test, CEA levels were not significantly changed in contrast with a distinct increase in CT levels. The results indicate that CEA and CT represent separate activities of the tumor cells, and that circulating CEA together with CT is a useful indicator in the diagnosis and follow-up of the disease. (+info)
Multiple endocrine neoplasia type 2A with the identical somatic mutation in medullary thyroid carcinoma and pheochromocytoma without germline mutation at the corresponding site in the RET proto-oncogene.
(16/4130)
A germline mutation either in exon 10 or 11 of the RET proto-oncogene is found in the majority of patients with multiple endocrine neoplasia type 2A (MEN 2A). A 41-year-old female patient was referred for further evaluation of incidentally discovered right adrenal tumor. She had bilateral adrenal pheochromocytomas and medullary thyroid carcinomas detected by endocrinological and radiological examination, and diagnosed as MEN 2A. Molecular genetic testing of the RET exons 10 and 11 exhibited the identical somatic missense mutation at codon 634 in both tumors but did not confirm germline mutations in the corresponding sites. Possible mechanisms for tumorigenesis in this patient are discussed. (+info)