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PubMed2003

The role of human achaete-scute homolog-1 in medullary thyroid cancer cells.

BACKGROUND: Human achaete-scute homolog-1 (hASH1) is a transcription factor that is expressed highly in neuroendocrine tumors such as medullary thyroid cancer (MTC). Thyroid C-cells do not develop in hASH1 knockout mice, which suggests that hASH1 is essential for normal C-cell development. METHODS: To determine the effect of raf-1 induction on hASH1 and hormone production, we used an estrogen inducible raf-1 construct in MTC cell line (TT) cells (TT-raf cells). TT or TT-raf cells were treated with control or 1 microM estradiol. After 48 hours, the cells were analyzed for levels of hASH1 and chromogranin A by Western blotting and for calcitonin production by enzyme-linked immunosorbent assay. RESULTS: Activation of raf-1 in the TT-raf cells resulted in high levels of phosphorylated MEK and ERK1/2, a morphologic transdifferentiation, and a decrease in chromogranin A and calcitonin levels that are associated with a reduction in hASH1 production. Furthermore, using MEK inhibitors, we demonstrated that these raf-1-mediated changes are dependent on MEK but not ERK1/2 activation. CONCLUSION: hASH1 down-regulation by raf-1 in MTC cells is associated with a significant decrease in hormone production. Thus, hASH1 appears to be important in the endocrine phenotype of MTC tumors and may serve as a molecular target for the treatment of patients with MTC.

Basic Helix-Loop-Helix Proteins↗
PubMed1996

Differentiation of medullary thyroid cancer by C-Raf-1 silences expression of the neural transcription factor human achaete-scute homolog-1.

BACKGROUND: Human achaete-scute homolog-1 (hASH1), a fetal neural transcription factor, is highly expressed in neuroendocrine tumors such as medullary thyroid cancer (MTC). Although hASH1 probably plays a part in the growth and development of these tumors, its precise role and mechanism are unknown. METHODS: To further elucidate the function and regulation of hASH1 in neuroendocrine tumor differentiation, we used a model of MTC tumor differentiation mediated by the ras/raf-1 signaling pathway. The MTC TT cells alone or transduced with a beta-estradiol activatable raf-1 construct (TT: delta Raf-1:ER) were treated with beta-estradiol or carrier. Northern analysis and nuclear run-off assays were performed to determine the hASH1 messenger RNA (mRNA) levels and transcription rate, respectively. RESULTS: The TT: delta Raf-1:ER cells treated with beta-estradiol underwent marked biochemical and morphologic changes, including cell rounding, increase in calcitonin transcription, loss of RET proto-oncogene expression, and cessation of cell growth. During this differentiation process expression of hASH1 mRNA was silenced. Nuclear run-off experiments revealed that this decrease in steady-state hASH1 mRNA by raf-1 activation resulted predominantly from transcriptional inhibition. CONCLUSIONS: Silencing of hASH1 in parallel with loss of RET is associated with development of a mature C-cell differentiation pattern. Mechanisms leading to transcriptional silencing of hASH1 may be crucial in regulating the proliferative capacity or differentiation status of MTC. Downstream targets of hASH1 could play a role in C-cell proliferation and progression to MTC.

Basic Helix-Loop-Helix Proteins↗
PubMed2000

Expression of thyroid transcription factor-1 (TTF-1) in human C cells and medullary thyroid carcinomas.

Thyroid transcription factor-1 (TTF-1) has been known to regulate the transcriptional activity of thyroid-specific genes in thyroid follicular cells. We recently identified TTF-1 mRNA expression in rat thyroid C cells. The current study was undertaken to elucidate how TTF-1 is expressed in human C cells and medullary thyroid carcinomas (MTCs), and how this expression influences the functions and clinical behavior of these cells. By immunohistochemistry, the nuclei of normal and hyperplastic C cells distinctively reacted with antibody against TTF-1, whereas the immunostaining intensity in C cells was rather weak and heterogeneous in comparison with that in follicular cells. Identical TTF-1 immunoreactivity was observed in all 15 MTC specimens examined. The reaction intensity did not depend on tumor patterns or cell features. In nonisotopic in situ hybridization, an antisense riboprobe clearly hybridized the cytoplasms of C cells and MTC cells, which concurrently showed immunohistochemical positivity for calcitonin. Northern blot analysis indicated a marked hybridization with TTF-1 mRNA of approximately 2.3 kb in an MTC specimen. Furthermore, the presence of TTF-1 mRNA was confirmed by reverse transcription polymerase chain reaction (RT-PCR) in the human MTC cell line, TT. Our results suggest that human thyroid C cells and MTC cells express TTF-1 in connection with their functional ability. Therefore, TTF-1 expression can be a functional marker not only for follicular cells and follicular cell tumors but also for C cells and medullary C cell carcinomas.

Adolescent↗
PubMed1997

Expression of the calcitonin gene family in medullary thyroid carcinoma.

The regulatory peptide calcitonin was discovered in 1962. During the last decade it has been demonstrated to be part of a gene family. Calcitonin is synthesized in the parafollicular cells (C cells) of the thyroid gland. These cells give rise to an endocrine tumor, medullary thyroid carcinoma (MTC), which is found in a sporadic and an inherited form. Calcitonin is used as a tumor marker for MTC. The calcitonin gene was demonstrated in 1981 to give rise to an alternative peptide product, alpha-CGRP, and a second gene encoding a very similar peptide, beta-CGRP, has also been identified. A third CGRP-like peptide, amylin, was identified in 1986. This article summarizes the present knowledge about gene structure, regulation of gene expression, and expression of the calcitonin gene family in MTC and in MTC-derived cell lines. The methods employed for detection of gene expression and for measurement and characterized of peptide products are described, and finally the relevance of biochemical tumor markers is discussed in relation to the new diagnostic methods for inherited MTC based on molecular biological techniques.

Amino Acid Sequence↗
PubMed1998

Germline and somatic mutations of the RET proto-oncogene in apparently sporadic medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) occur sporadically or as part of inherited multiple endocrine neoplasia (MEN) type 2 syndromes. To recognize misdiagnosed familial cases and to establish the frequency of somatic mutations, a series of 50 patients, clinically diagnosed with sporadic MTC, were analyzed for mutations in the RET proto-oncogene. The clinical management of the patient and of the family is different in the two cases. Germline mutations were detected in three independent cases, demonstrating that they were associated to familial MTC. The mutations affected exon 11 in two cases and exon 14 in one case. Somatic mutations were detected in eight patients (30%) and they were indicative of sporadic MTC. In seven cases the mutation affected codon 918 of exon 16 and in one case codon 634 in exon 11. No RET mutations were detected in the remaining patients. A different genetic and clinical management is proposed for individuals with a diagnosis of familial or sporadic MTC.

Carcinoma, Medullary↗
PubMed1995

RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma.

The identification of RET proto-oncogene mutations in patients with MEN2 2 years ago was a watershed event in the management of this genetic cancer syndrome. The identification of a finite number of mutations that together causes more than 95% of hereditary and 15-25% of sporadic MTC has made it possible to develop simple and definitive tests to screen individuals at risk for this tumour syndrome. The impact of this technology is enormous. It is now possible to reassure 50% of family members at risk that they, and their children, do not have to worry about developing MTC. In the other 50% who are gene carriers, it is now possible to approach clinical management with greater certainty and plot strategies that are likely to result in a greater percentage of curative therapy. It seems likely that this technology will also have an impact on the management of sporadic MTC, although it is still too early to define a specific role for mutational analysis in these patients, except to exclude hereditary disease. The identification of specific mutations causative for MTC makes it possible to conceive future strategies for the treatment or prevention of MTC and to further extend the impact of these exciting findings.

Carcinoma, Medullary↗
PubMed2002

Presurgical assessment of the tumor burden of familial medullary thyroid carcinoma by calcitonin testing.

BACKGROUND: Early diagnosis of familial medullary thyroid carcinoma (MTC) is currently done by genetic analysis. These techniques have replaced calcitonin stimulation testing, which was previously used for this purpose. Some studies suggest a relationship between MTC spread and calcitonin levels. The aim of this study was to assess whether the tumor burden of MTC associated with multiple endocrine neoplasia type 2A (MEN 2A) syndrome can be estimated from the plasma calcitonin values before surgery. STUDY DESIGN: We retrospectively studied the relationship of basal and peak calcitonin values before thyroidectomy with histopathologic findings in 53 patients with MEN 2A syndrome from 14 families. The MTC was classified according to TNM staging. Analysis of variance was used for statistical analysis complemented with equality contrasts for pairs of means by the least significant difference method with a Student's t-test and with the Bonferroni's adjustment. RESULTS: A positive association was found between tumor stage and basal and peak calcitonin levels. There were significant differences between the following: mean basal concentrations of patients with C cell hyperplasia (CCH) (34.3 pg/mL) and TNM stage II (1,097.4 pg/mL), p < 0.01; CCH and TNM stage III (2,940.8 pg/mL), p < 0.001; TNM stage I (165.3 pg/mL) and stage II (1,097.4 pg/mL), p < 0.01, and between TNM stages I and III, p < 0.001. Poststimulation mean concentrations were different between CCH (48.7 pg/mL) and TNM I (514.2 pg/mL), p < 0.001. CONCLUSIONS: Preoperative calcitonin testing may be useful for assessing tumor spread and should be considered when deciding the extent of surgery for MEN 2A MTC.

Adolescent↗
PubMedDate not supplied

Topical mitomycin C effect on swine vocal folds healing.

UNLABELLED: Several adjuvant therapies to surgery have been used to modulate the healing process of vocal folds, including topic mitomycin (MTC). AIM: to evaluate the effect of topical MTC in the healing process of vocal folds 30 days after the exeresis of a mucosal fragment with CO2 laser in a swine model (control group without mitomycin and study group with topical MTC), with collagen deposition measurement. STUDY TYPE: prospective experimental in swine. METHODS: two groups of 6 swine each were subjected to exeresis of a mucosal fragment of the vocal fold with CO2 laser. Immediately after the procedure MTC was applied topically for three minutes on the study group. Thirty days later the animals were slaughtered and samples of the vocal folds were collected for histological analysis, with the purpose of quantifying collagen deposition by Picrosirius Red stain. RESULTS: the average area of total collagen in the vocal folds in the control group was 2.648,03 microm2, whereas in the study group it was 2.200,30 microm2 (p=0.0043). CONCLUSION: topical application of MTC after the exeresis of a mucous fragment of vocal fold with CO2 laser in swine significantly decreased total collagen deposition.

Administration, Topical↗
PubMed1998

Current diagnosis and management of medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) originates in the thyroid C cells, accounting for 5% to 10% of all thyroid malignancies. Approximately 75% of cases are sporadic. Significant advances have been made in the molecular biology of MTC, but some aspects of diagnosis and management still remain controversial. DESIGN: We reviewed relevant articles published in major English-language medical journals. We used the MEDLINE database, selected bibliographies, and articles available in our personal files. RESULTS: Mutations of the RET proto-oncogene have been identified in the germline DNA of patients with familial MTC syndromes. Genetic testing can identify patients affected by multiple endocrine neoplasia types IIA and IIB and familial MTC, allowing early diagnosis and possible cure. Surgical treatment is total thyroidectomy. Plasma calcitonin measurements are excellent markers for postoperative follow-up. Adjunctive therapy includes radiotherapy and chemotherapy. The overall prognosis is worse than papillary thyroid carcinoma. CONCLUSIONS: Recent advances in genetic testing allow early diagnosis and treatment of familial MTC syndromes. Despite some advances in treatment, optimal management remains controversial.

Carcinoma, Medullary↗
PubMed1998

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the calcitonin secreting thyroid C-cells. Somatic and germline mutations in the RET proto-oncogene are associated with sporadic and inherited cases of MTC, respectively. The human MTC cell line, TT, can be differentiated by activated raf-1. This differentiation is characterized, in part, by down-regulation of the RET proto-oncogene. We now show that raf-1 induction is followed by activation of the downstream kinases MEK1/2 and ERK1/2 and that differentiation is dependent on activation of MEK1/2. The concurrent down-regulation of RET appears to involve altered nuclear compartmentalization and transport of RET mRNA. Although RET is down-regulated during raf-1 mediated differentiation, overexpression of activated RET alleles which resist down-regulation does not alter the raf-1 mediated differentiation response. These data suggest that RET down-regulation is associated with, but not required, for raf-1 mediated MTC cell differentiation and that the raf-1 signal transduction pathway plays a dominant role in promoting MTC cell differentiation.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2001

Allelic imbalance of the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma.

Germline mutations of the RET proto-oncogene are responsible for the familial tumor syndrome called multiple endocrine neoplasia type 2 (MEN 2) that includes medullary thyroid carcinoma (MTC). Although inherited mutations of RET lead to tumor formation in patients with MEN 2, it is not understood why only selected cells develop into tumors. We have recently shown that duplication of the mutated RET allele or loss of the wild-type allele might represent mechanisms of tumorigenesis in patients with MEN 2A-related pheochromocytoma. We now analysed 19 DNA samples of MTC (15 of which were non-microdissected, four of which were microdissected) from patients with MEN 2A. Using polymorphic marker and phosphorimage densitometry analyses, we found allelic imbalance of the mutated and wild-type RET allele in six of 19 DNA MTC samples. Of note, two of the four microdissected tumor DNA samples showed allelic imbalance of RET, whereas only four of the 15 non-microdissected MTC samples did. These results underscore the significance of microdissection in the analysis of tumor DNA. In our study, some of the non-microdissected tumor DNA samples may have failed to display allelic imbalance of RET, because of contamination of tumor DNA with nonneoplastic DNA or noninformative microsatellite marker analysis. Taken together, our results suggest allelic imbalance between mutated and wild-type RET as a possible mechanism for tumor formation in some patients with MEN 2A-related MTC.

Alleles↗
PubMed1998

Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine.

BACKGROUND: Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management. OBJECTIVE: To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis. DESIGN AND PATIENTS: Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database. MEASUREMENTS: Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis. RESULTS: Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage. CONCLUSION: Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

Adult↗
PubMed2000

Galectin-3 and carcinoembryonic antigen expression in medullary thyroid carcinoma: possible relation to tumour progression.

AIMS: Galectin-3 is a beta-galactoside binding protein involved in multiple biological processes through interactions with complementary glycoconjugates. We analysed the expression and coexpression of galectin-3 and carcinoembryonic antigen (CEA), one of the putative galectin-3 ligands, in medullary thyroid carcinoma (MTC). METHODS AND RESULTS: An immunohistochemical study using monoclonal antibodies was performed on paraffin sections of 20 cases of sporadic MTC comprising 10 cases without and 10 cases with lymph node metastases at the time of surgery. CEA expression was found in all tumours, distributed predominantly in the cytoplasm and occasionally at the cell surface. In the majority of cases (18/20) moderate to strong intensity of staining was found in most of the cells. Positive cytoplasmic staining for galectin-3 was found in 16/20 cases, but varied in intensity and distribution from weak/focal (7/16) to moderate (7/16) or strong (2/16). More intense staining for galectin-3 was mainly associated with MTC cases involving lymph node metastases. Eight out of these 10 cases showed moderate to strong galectin-3 expression concomitant with CEA expression throughout the tumour tissue. CONCLUSIONS: These findings suggest that galectin-3 might play a role in the pathobiology of MTC. Simultaneous expression of galectin-3 and CEA in the same tumour cells at an advanced stage of MTC indicates the possibility of their autocrine cooperation during tumour progression.

Adult↗
PubMed2000

Diagnosis and treatment of medullary thyroid cancer.

Medullary carcinoma of the thyroid (MTC) is a rare tumour derived from thyroid C cells with serum calcitonin as a specific and sensitive marker. MTC is inherited in 25% of cases, with an autosomal dominant transmission, age-related penetrance and variable expressivity. MTC is an obligatory component of multiple endocrine neoplasia type 2 (MEN2), which comprises three well defined syndromes: MEN2A, which may be associated with pheochromocytoma and/or hyperparathyroidism; the much rarer MEN2B, which occurs early and is accompanied by developmental abnormalities; while in contrast, familial MTC (FMTC) is not associated with any endocrinopathy. The RET proto-oncogene is the causative gene of the MEN2 syndromes and mutations in this gene are found in >90% of inherited cases, allowing easier and more reliable family screening than pentagastrin stimulation tests. Nevertheless, the correlation between the genotype and the different clinical phenotypes is not perfect. The prognosis of MTC depends on its staging at presentation, and the early appearance of cervical lymph node metastases emphasizes the need for extensive surgery, although many patients still do not normalize calcitonin levels post-operatively, and they remain a challenge for the further management.

Calcitonin↗
PubMed1998

Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes.

Since the discovery that germ-line mutations in the RET protooncogene are responsible for the multiple endocrine neoplasia (MEN) syndromes types 2A and 2B, prophylactic thyroidectomy has been recommended for MEN patients to prevent medullary thyroid carcinoma (MTC). In this report, we present the medium-term follow up results on the earliest group of 18 patients having prophylactic thyroidectomy for MEN 2A. There were no operative complications. Microscopic or grossly evident MTC was present in 14 (78%) of the resected patients. None of the patients had metastasis of their MTC to regional lymph nodes. At three years' follow up, there is no evidence of residual or recurrent MTC, based on biochemical testing. We conclude that prophylactic thyroidectomy, based on direct DNA testing for RET gene mutations, is an effective and safe way to manage MTC in patients with MEN 2A.

Adolescent↗
PubMed2005

[Decision making in postoperative incidentally found small C-cell-carcinoma].

Surgical therapy of incidentally postoperative diagnosed small sporadic medullary thyroid cancer (MTC) is discussed controversially. In principle completion thyroidectomy with neck dissection and regulary tumor follow-up are under discussion. A total of 277 patients with MTC were treated between 1986 and 2004. In 22 cases diagnosis of a small (pT1 or pT2) sporadic MTC was incidental and only postoperatively confirmed. Normally total thyroidectomy with neck dissection is standard surgical therapy of a known MTC. Because of postoperative incidental diagnosis in all 22 cases surgical therapy was less then total thyroidectomy. Mutation analysis of RET Proto-Oncogen and familial history were negative in all cases. All patients were systematically followed-up in defined intervals by calcitonin, pentagastrin stimulation test, carcinoembryonic antigen and ultrasound. Median follow-up is 6.2 years (range: 2-13 years) and although a hemithyroidectomy or less was performed all 22 patients are cured by the MTC. We conclude that completion thyroidectomy and neck dissection are not mandatory in such patients, if the tumor is completely resected and genetic background is excluded. Indispensably a systematic long term follow-up of at least 10 years, better a life-long, is mandatory.

Adult↗
PubMed1993

[The prognostic importance of calcitonin screening in familial medullary thyroid carcinoma].

In 34 of 139 patients (63 men, 76 women, mean age 41.2 +/- 15.6 years) with medullary thyroid carcinoma (MTC) the disease was of the familial variety. 13 of the 34 cases were discovered in the preclinical stage by screening (calcitonin stimulation with pentagastrin). This group was on average younger (16.8 +/- 10.7 years) than the 21 clinically manifest patients with MTC (28.0 +/- 11.9 years) or the 105 patients with sporadic MTC (45.7 +/- 13.6 years). The patients diagnosed through the screening programme had a more favourable tumour stage (12 in stage I or II) and were thus more likely to be cured. Their survival rate was higher (100% at both 5 and 10 years) than the survival rate of the patients with clinically manifest tumour (94 and 87%, respectively). But the group with manifest familial MTC did not differ from those with sporadic occurrence as regards the tumour stage (predominantly advanced stages), limited chance of cure and survival rate (5 years: 94%, 10 years: 81%). These data show that screening of family members decisively improves the prognosis of MTC of the familial variety.

Adult↗
PubMed2000

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation.

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by mutations in the RET proto-oncogene. METHODS: We used a multiplex polymerase chain reaction-based assay to screen exons 10, 11, 13, and 14 of RET for mutations in 2 families with FMTC. We correlated mutation status with calcitonin and pathologic studies to determine genotype-phenotype correlations. RESULTS: We identified a mutation in codon 804 in exon 14 (GTG-->ATG; V804M) in both families. An 86-year-old person who was a gene carrier and other individuals over age 70 who were suspected by pedigree analysis to be gene carriers had no overt clinical evidence of MTC. Four of 21 patients who underwent a thyroidectomy also had papillary thyroid cancer. One individual in each family had metastatic MTC at age 30 and 32 years, and all 26 people having thyroidectomies had either MTC or C-cell hyperplasia, leading us to continue to recommend prophylactic thyroidectomy for all identified patients who were gene carriers. CONCLUSIONS: Because of active MTC in younger members of these families, including metastases, we have continued to advocate thyroid surgery in mutation-positive individuals. While DNA diagnosis of gene carriers and subsequent genetic counseling was relatively straightforward, the acceptance of surgical recommendations was more difficult for some individuals. These families demonstrate that the search for RET mutations should include exons 13, 14, 15, and 16 in patients whose studies in exons 10 and 11 are negative.

Adult↗