Non-autocrine, constitutive activation of Met in human anaplastic thyroid carcinoma cells in culture.
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Activation of Met by its ligand HGF has been shown to elicit both mitogenic and motogenic responses in thyrocytes in vitro. In the present study we have investigated the expression of Met in human anaplastic thyroid carcinoma cells in culture. There was a variation in expression level and size of Met in the different cell lines; high Met expression was found in four cell lines, compared to non-neoplastic human thyrocytes. Treatment with glucoproteinase F showed that the size differences observed were due to variances in the degree of glycosylation. Interestingly, in cell lines with high expression of Met, the receptor proteins were found to be constitutively tyrosine phosphorylated. None of these cell lines expressed HGF mRNA, and addition of suramin did not affect the level of tyrosine phosphorylation of Met in unstimulated cells, suggesting the absence of autocrine stimulatory pathways. Furthermore, we did not observe MET gene amplification, activating mutations or phosphatase defects. The tyrosine phosphorylated receptors appeared functionally active since the receptors associated with the adaptor molecule Shc. In summary, we have found ligand-independent constitutively activated Met in four out of six anaplastic thyroid carcinoma cell lines. (+info)
Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection.
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OBJECTIVE: To establish the frequency, pattern and location of cervical lymph node metastases from palpable medullary thyroid carcinoma (MTC). Recommendations are made regarding the extent of surgery for this tumor. SUMMARY BACKGROUND DATA: Medullary thyroid carcinoma is a tumor of neuroendocrine origin that does not concentrate iodine. Surgical extirpation of the thyroid tumor and cervical node metastases is the only potentially curative therapeutic option. Patterns of node metastases in the neck and guidelines for the extent of dissection for palpable MTC are not well established. METHODS: Seventy-three patients underwent thyroidectomy for palpable MTC with immediate or delayed central and bilateral functional neck dissections. The number and location of lymph node metastases in the central (levels VI and VII) and bilateral (levels II to V) nodal groups were noted and were correlated with the size and location of the primary thyroid tumor. Intraoperative assessment of nodal status by palpation and inspection by the surgeon was correlated with results of histologic examination. RESULTS: Patients with unilateral intrathyroid tumors had lymph node metastases in 81% of central node dissections, 81% of ipsilateral functional (levels II to V) dissections, and 44% of contralateral functional (levels II to V) dissections. In patients with bilateral intrathyroid tumors, nodal metastases were present in 78% of central node dissections, 71% of functional (levels II to V) node dissections ipsilateral to the largest intrathyroid tumor, and 49% of functional (levels II to V) node dissections contralateral to the largest thyroid tumor. The sensitivity of the surgeon's intraoperative assessment for nodal metastases was 64%, and the specificity was 71%. CONCLUSION: In this series, >75% of patients with palpable MTC had associated nodal metastases, which often were not apparent to the surgeon. Routine central and bilateral functional neck dissections should be considered in all patients with palpable MTC. (+info)
Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: implications for treatment.
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Three infants, who presented with intestinal obstruction due to diffuse transmural intestinal ganglioneuromatosis, are described. Mutation analysis of exon 16 of the RET proto-oncogene revealed germline M918T and thus, a molecular diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). Two infants developed medullary carcinoma of the thyroid. The third had a prophylactic thyroidectomy despite no obvious thyroid masses and normal calcitonin concentrations, but microscopic multifocal medullary carcinoma was found on histological examination. Early recognition of intestinal ganglioneuromatosis with germline RET M918T mutation in pseudo-Hirschsprung's disease is an indication for prophylactic thyroidectomy. (+info)
Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice.
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The RET/PTC1 oncogene, a rearranged form of the RET proto-oncogene, has been reported to be associated with human papillary thyroid carcinomas. We have shown that targeted expression of RET/PTC1 in the thyroid gland leads to the development of thyroid carcinomas in transgenic mice with histologic and cytologic similarities to human papillary thyroid carcinoma. To further investigate how RET/PTC1 expression contributes to the pathogenesis of papillary thyroid tumor, the time of tumor onset and the early phenotypic consequences of RET/PTC1 expression in thyrocytes were determined. All high copy transgenic mice developed bilateral thyroid tumors as early as 4 days of age. At embryological days 16-18, increased proliferation rate, distorted thyroid follicle formation and reduced radioiodide concentrating activity were identified in transgenic embryos. The reduced radioiodide concentrating activity was attributed to decreased expression of the sodium-iodide symporter. Our study showed that RET/PTC1 not only increased proliferation of thyrocytes, it also altered morphogenesis and differentiation. These findings provide a model for the role of RET/PTC1 in the formation of abnormal follicles with reduced iodide uptake ability observed in human papillary thyroid carcinoma. (+info)
Human telomerase reverse transcriptase (hTERT) gene expression in thyroid neoplasms.
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Ten percent of fine-needle aspirations (FNAs) of the thyroid are deemed "indeterminate" or "suspicious" for malignancy by the cytopathologist, but most of these lesions are benign. Therefore, additional markers of malignancy may prove to be a useful adjunct. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been found to be reactivated in immortalized cell lines. Reverse transcription-PCR of the hTERT gene revealed expression in 15 (79%) of 19 malignant thyroid neoplasms, including 6 of 6 follicular carcinomas and 9 of 13 papillary carcinomas. In contrast, hTERT gene expression was detected in only 5 (28%) of 18 benign thyroid nodules, including 2 of 7 follicular adenomas and 3 of 11 hyperplastic nodules. All five benign thyroids exhibiting hTERT gene expression had lymphocytic thyroiditis. No normal thyroids exhibited hTERT gene expression. Telomerase enzyme activity was examined in all 37 nodules and was found to correlate with hTERT gene expression in 35 (95%) nodules. The two cases in which telomerase activity and hTERT expression results were discrepant were in two papillary carcinomas that were telomerase activity negative and hTERT positive. Finally, we have demonstrated that hTERT gene expression can be measured in in vivo FNA samples. These results suggest that hTERT expression may be more accurate than telomerase activity in distinguishing benign from malignant and may be measured in FNA samples from suspicious thyroid lesions. (+info)
A dimeric mutant of human pancreatic ribonuclease with selective cytotoxicity toward malignant cells.
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Monomeric human pancreatic RNase, devoid of any biological activity other than its RNA degrading ability, was engineered into a dimeric protein with a cytotoxic action on mouse and human tumor cells, but lacking any appreciable toxicity on mouse and human normal cells. This dimeric variant of human pancreas RNase selectively sensitizes to apoptotic death cells derived from a human thyroid tumor. Because of its selectivity for tumor cells, and because of its human origin, this protein represents a potentially very attractive, novel tool for anticancer therapy. (+info)
Enhanced efficacy of transcriptionally targeted suicide gene/prodrug therapy for thyroid carcinoma with the Cre-loxP system.
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Our recent study demonstrates the feasibility of the thyroglobulin (TG) promoter in transcriptionally targeted gene therapy for thyroid carcinomas expressing TG, albeit less effectively than the constitutive viral promoter. The present study was, therefore, designed to enhance the activity of the TG promoter with the Cre-loxP system. Our data demonstrate that the in vitro cytotoxic effect of herpes simplex virus thymidine kinase/ganciclovir obtained with the TG promoter and the Cre-loxP system is approximately 5-10-fold higher than that with the TG promoter alone. Enhanced tumor growth inhibition was also observed in in vivo tumor models. These data indicate the usefulness of the Cre-loxP system to enhance the activity of a tissue (or tumor)-specific promoter in transcriptionally targeted cancer gene therapy. (+info)
Sclerosing Mucoepidermoid carcinoma with eosinophilia of the thyroid glands: a case report with clinical manifestation of recurrent neck mass.
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Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently recognized malignant neoplasm of the thyroid gland. About 14 cases of SMECE have been reported and this is the first reported case in Korea. A 57-year-old woman presented with right neck mass for 20 years. Total thyroidectomy was performed under the impression of thyroid carcinoma. The resected thyroid gland showed a poorly circumscribed hard mass. Histologically, the tumor consisted of solid nests of large atypical cells with dense fibrous stroma. The tumor cells showed squamoid appearance with abundant eosinophilic cytoplasm. There were also rare mucin-containing cells within the nests. Within the hyalinized stroma, numerous eosinophils were found. The surrounding thyroid parenchyma displayed Hashimoto's thyroiditis. There was metastasis in a regional lymph node. Two years after initial surgery, she underwent a modified radical neck dissection due to recurrent neck mass. After the radiation therapy for eight weeks, laryngectomy and esophagectomy were performed due to a recurrent carcinoma in the esophageal wall. We report an additional case of SMECE, with metastasis to regional lymph nodes and esophagus. The tumor appears to be more aggressive than previously reported and a correct diagnosis can be rendered by just examining the metastatic lesions. (+info)