The impact of age and gender on papillary thyroid cancer survival.

CONTEXT: Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. OBJECTIVE: The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. DESIGN: Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS). PARTICIPANTS AND SETTING: Patients were followed in a prospective registry. MAIN OUTCOME MEASURE: The relationships between gender, age, and PTC outcomes were analyzed. RESULTS: The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85). CONCLUSIONS: Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.

Butyrate alters the expression and activity of cell cycle components in anaplastic thyroid carcinoma cells.

Anaplastic thyroid carcinoma (ATC) is the most malignant and aggressive form of thyroid cancer. Most patients die within months of diagnosis, primarily due to the absence of effective chemotherapeutic strategies. Identifying alternative therapies is necessary to increase long-term survival. Butyrate elicits a number of responses from cancer cells both in vitro and in vivo including growth repression, cell cycle arrest, differentiation, and apoptosis. Even though many types of cancer cells have been studied, little is known of the response of ATC cells to this drug. In this study, we report that butyrate induces differential cell cycle arrest (arrest in G1 and G2/M phases) in an ATC cell line that correlates with changes in the expression, phosphorylation, and activity of key components of the cell cycle machinery. Exposure to butyrate increases the expression of the cyclin-dependent kinase inhibitors, p21/Cip1 and p27/Kip1, decreases the expression of cyclin A and cyclin B, inhibits the phosphorylation of the retinoblastoma protein (pRb), and decreases the activity of cdk1 and cdk2-associated kinases. These results suggest that butyrate may be useful in the clinical treatment of ATC.

Role of spermine in amyloid beta-peptide-associated free radical-induced neurotoxicity.

The polyamines, relatively low-molecular-weight aliphatic compounds, are the main inducers of eukaryotic cell growth and proliferation. Although polyamine requirements for cell growth are well defined, their role is still enigmatic. We have previously reported that amyloid beta-peptide (A beta), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is toxic to neurons through a free radical-dependent oxidative stress mechanism and that A beta(1--42), the principal form of A beta in AD brain, causes an increase in polyamine metabolism manifested by up-regulated polyamine uptake and increased ornithine decarboxylase (ODC) activity. Both effects were prevented by the free radical scavenger vitamin E. Spermine has been reported to function directly as a free radical scavenger. In the current study, we aimed to address whether up-regulation of polyamine metabolism is a defense against, or a result of, A beta-induced oxidative stress by investigating the capability of spermine to quench A beta-associated free radicals in solution and to assert a protective function of spermine in neuronal culture against A beta. Pretreatment of cultured neurons with spermine prior to A beta exposure failed to prevent A beta-induced cell death. Indeed, A beta plus spermine added to cultured neurons was even more neurotoxic than either agent alone. Additionally, inhibition of the polyamine synthesis by difluoromethylornithine (DFMO) did not protect cells from A beta-induced free radical toxicity, and stimulation of the synthesis of putrescine and spermine by the aminopropyltransferase inhibitor S-adenosyl-1,8-diamino-thiooctane (AdoDATO), rather, further enhanced A beta-induced toxicity. Although spermine is capable of scavenging free radicals generated by A beta in solution as measured by electron paramagnetic resonance (EPR) spectroscopy, the up-regulated transport of exogenously added spermine together with A beta may lead to overaccumulation of a cellular spermine pool, with resulting enhanced neurotoxicity.

Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group.

Anaplastic thyroid carcinoma is a rare, lethal disease with no effective systemic therapies. Preclinical studies demonstrated antineoplastic activity of paclitaxel. This prompted a prospective phase 2 clinical trial to determine activity of paclitaxel against anaplastic thyroid carcinoma in patients with persistent or metastatic disease despite surgery or local radiation therapy. Twenty patients, entered through 6 of 12 study sites, were treated with 96-hour continuous infusion paclitaxel every 3 weeks for 1 to 6 cycles; the first 7 patients received 120 mg/m2 per 96 hours and the rest received 140 mg/m2 per 96 hours. Total responses to therapy were assessed using modified criteria with response durability acceptable at 2 or more weeks, due to the exceedingly rapid growth rate of this tumor. Plasma samples were obtained for pharmacokinetic analyses. Off-protocol, data showed that 9 patients were later treated with 225 mg/m2 paclitaxel as weekly 1-hour infusions. Nineteen evaluable patients demonstrated a 53% total response rate (95% confidence interval, 29%-76%) with one complete response and nine partial responses (including one off protocol). Results of historical review off-protocol showed 2 of 7 patients, with prior partial responses to the 96-hour infusion, had subsequent partial responses to weekly treatment and 1 of 2 prior nonresponders gained a partial response to weekly therapy. No toxicities greater than grade 2 were seen with 96-hour infusions, while peripheral neuropathy (up to grade 3) was most common with postprotocol weekly infusions. Paclitaxel appears to be the only agent with significant clinical systemic activity against anaplastic thyroid carcinoma; however, it is not capable of altering the lethality of this malignancy, suggesting the need for additional therapeutic innovations. Decreased time intervals between paclitaxel infusions may be more efficacious.

American Thyroid Association guidelines for detection of thyroid dysfunction.

OBJECTIVE: To define the optimal approach to identify patients with thyroid dysfunction. PARTICIPANTS: The 8-member Standards of Care Committee of the American Thyroid Association prepared a draft, which was reviewed by the association's 780 members, 50 of whom responded with suggested revisions. EVIDENCE: Relevant published studies were identified through MEDLINE and the association membership's personal resources. CONSENSUS PROCESS: Consensus was reached at group meetings. The first draft was prepared by a single author (P.W.L.) after group discussion. Suggested revisions were incorporated after consideration by the committee. CONCLUSIONS: The American Thyroid Association recommends that adults be screened for thyroid dysfunction by measurement of the serum thyrotropin concentration, beginning at age 35 years and every 5 years thereafter. The indication for screening is particularly compelling in women, but it can also be justified in men as a relatively cost-effective measure in the context of the periodic health examination. Individuals with symptoms and signs potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent serum thyrotropin testing.

Management of undifferentiated thyroid cancer.

Management of thyroid carcinoma relies upon the tumour cells maintaining the differentiated functions that are typical of normal thyroid follicular cells, such as: dependence upon thyrotropin for growth, production of thyroglobulin and effective transport of iodine. Likewise, differentiated thyroid carcinomas often exhibit an auspicious clinical behaviour with a slow rate of growth and low potential for invasion and distant metastasis. These features permit therapy of disseminated tumour, effective follow-up surveillance and the assumption of a good prognosis. As each of these features are lost, the opportunities for both disease status assessment and therapeutic intervention diminish accordingly. A major obstacle is our failure to define effective systemic treatments to replace radioiodine therapy, whose loss is consonant with the loss of iodine transport and retention. The extreme of undifferentiated clinical behaviour is epitomized by anaplastic thyroid carcinoma, a rare, terminally dedifferentiated malignancy that is rapidly and invariably fatal. It is important to be attuned to clinical clues suggesting the presence of dedifferentiated tumour and related prognostic signs. This allows the application of currently limited therapeutic options and defines the need for research to develop new systemic treatments.

Polyamine synthesis and transport inhibition in a human anaplastic thyroid carcinoma cell line in vitro and as xenograft tumors.

Polyamines are essential cellular components for neoplastic transformation and cell proliferation. Antineoplastic efforts that inhibit polyamine synthesis are insufficient to induce cytotoxicity, due to compensatory induction of polyamine transport. Treatment of an anaplastic human thyroid carcinoma cell line (DRO90-1) with a novel polymeric spermine conjugate (polyspermine; PSpm) caused in vitro cytotoxicity and inhibited the growth of xenograft tumors at low concentrations. Similar in vitro antineoplastic effects were noted with two other human anaplastic thyroid carcinoma cell lines. This coincided with inhibition of polyamine uptake and synthetic enzyme activities, with reduced ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAM-DC) but increased spermidine/spermine N1-acetyltransferase (SSAT) activities, as measured in DRO90-1 cells. In subsequent studies using these cells, PSpm was effective in reducing the intracellular levels of all polyamines in vitro, resulting in cytotoxicity that was not reversed by administration of extracellular polyamines. Low-dose PSpm inhibited tumor growth in vivo, but high doses of PSpm potentiated xenograft tumor growth. PSpm degradation products produced with in vivo treatment may be produced that function as substrates for polyamine biosynthesis. These studies suggest that polyamine metabolism inhibition is a viable target for antineoplastic therapy of anaplastic thyroid carcinoma, although the in vivo response to PSpm suggests that this agent will have limited clinical utility.

TRAIL death pathway expression and induction in thyroid follicular cells.

To determine whether programmed cell death in thyroid follicular cells can be related to activation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, we examined the expression and function of this pathway in primary thyroid follicular cells and a papillary thyroid carcinoma cell line in vitro. Despite the expression of TRAIL receptors death receptor 4 and death receptor 5, purified TRAIL could not induce programmed cell death (PCD) in any of the thyroid follicular cells examined. However, pre-incubation with cycloheximide before TRAIL facilitated the induction of rapid and massive PCD. This suggested that despite the presence of a labile inhibitor of the TRAIL pathway, TRAIL could mediate PCD under appropriate conditions. To determine whether there were sources of TRAIL in the thyroid that could interact with thyroid follicular cell TRAIL receptors, RNase protection assays were used to determine TRAIL mRNA expression. TRAIL message was expressed in intrathyroidal lymphocytes isolated from a patient with thyroiditis, and unexpectedly, thyroid follicular cells themselves could be induced to express abundant TRAIL message in the presence of the inflammatory cytokines interferon gamma, tumor necrosis factor alpha, and interleukin 1beta. Furthermore, the papillary thyroid carcinoma cell line could be induced to kill the TRAIL-sensitive lymphoma cell line BJAB through a TRAIL-dependent mechanism.

Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I-symporter gene methylation status.

Disseminated dedifferentiated thyroid epithelial carcinoma, which cannot sufficiently concentrate therapeutic radioiodide, is a terminal disease without any effective systemic treatment or chemotherapy. This is a likely consequence of loss of human sodium-iodide symporter (hNIS) function. We hypothesized that hNIS transcriptional failure in thyroid carcinoma could be consequent to methylation of DNA in critical regulatory regions and could be reversed with chemical demethylation treatment. Analysis of hNIS messenger ribonucleic acid (mRNA) expression in 23 tumor samples revealed that although loss of this expression corresponded to loss of clinical radioiodide uptake, some thyroid carcinomas with hNIS mRNA expression did not concentrate iodide, suggesting additional posttranscriptional mechanisms for loss of hNIS function. In addition, analysis of DNA methylation in CpG-rich regions of the hNIS promoter extending to the first intron failed to define specific methylation patterns associated with transcriptional failure in human thyroid tumor samples. In seven human thyroid carcinoma cell lines lacking hNIS mRNA, treatment with 5-azacytidine or sodium butyrate was able to restore hNIS mRNA expression in four cell lines and iodide transport in two cell lines. Investigation of methylation patterns in these cell lines revealed that successful restoration of hNIS transcription was associated with demethylation of hNIS DNA in the untranslated region within the first exon. This was also associated with restoration of expression of thyroid transcription factor-1. These results suggest a role for DNA methylation in loss of hNIS expression in thyroid carcinomas as well as a potential application for chemical demethylation therapy in restoring responsiveness to therapeutic radioiodide.

Alzheimer's amyloid beta-peptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity: protective effect of vitamin E.

Recent evidence indicates that alterations in brain polyamine metabolism may be critical for nerve cell survival after a free radical initiated neurodegenerative process. It has been shown previously that A beta(1-42) and A beta(25-35) are toxic to neurons through a free radical dependent oxidative mechanism. Treatment of rat embryonic hippocampal neuronal cultures with A beta-peptides increased ornithine decarboxylase (ODC) activity and spermidine uptake, suggesting that oxidative stress upregulates the polyamine mechanism for the repair of free radical damage. Pretreatment of the cells with vitamin E prior to A beta exposure decreased ODC activity and spermidine uptake to control level. This study is the first to demonstrate that A beta treated cells show an increased polyamine metabolism in response to free radical mediated oxidative stress and that the free radical scavenger vitamin E prevents these attenuations. These results are discussed with reference to Alzheimer's disease.

Lithium as a potential adjuvant to 131I therapy of metastatic, well differentiated thyroid carcinoma.

As lithium inhibits the release of iodine from the thyroid but does not change iodine uptake, it may potentiate 131I therapy of thyroid cancer. The effects of lithium on the accumulation and retention of 131I in metastatic lesions and thyroid remnants were evaluated in 15 patients with differentiated thyroid carcinoma. Two 131I turnover studies were performed while the patients were hypothyroid. One was performed while the patient received lithium; the second served as a control study. From a series of gamma-camera images, it was found that lithium increased 131I retention in 24 of 31 metastatic lesions and in 6 of 7 thyroid remnants. A comparison of 131I retention during lithium with that during the control period showed that the mean increase in the biological or retention half-life was 50% in tumors and 90% in remnants. This increase occurred in at least 1 lesion in each patient and was proportionally greater in lesions with poor 131I retention. When the control biological half life was less than 3 days, lithium prolonged the effective half-life, which combines both biological turnover and isotope decay, in responding metastases by more than 50%. More 131I also accumulated during lithium therapy, probably as a consequence of its effect on iodine release. The increase in the accumulated 131I and the lengthening of the effective half-life combined to increase the estimated 131I radiation dose in metastatic tumor by 2.29 +/- 0.58 (mean +/- SEM) times. These studies suggest that lithium may be a useful adjuvant for 131I therapy of thyroid cancer, augmenting both the accumulation and retention of 131I in lesions.

Anaplastic thyroid carcinoma: a therapeutic challenge.

Anaplastic thyroid carcinoma is an extremely aggressive solid tumor that resists most therapeutic efforts and is almost always fatal. It typically arises as a terminal dedifferentiation of unrecognized long-standing differentiated thyroid carcinoma. Current chemotherapeutic agents are not capable of consistent beneficial therapeutic responses, although rare patients may gain additional months of survival. Aggressive local tumor control with surgery and external beam radiotherapy may provide palliation and delay eventual death from distant metastatic disease. This disease challenges clinicians and researchers to develop new systemic therapies as well as to aggressively treat differentiated thyroid cancers before they become anaplastic tumors.

Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry.

The ideal therapy for differentiated thyroid cancer is uncertain. Although thyroid hormone treatment is pivotal, the degree of thyrotropin (TSH) suppression that is required to prevent recurrences has not been studied in detail. We have examined the relation of TSH suppression to baseline disease characteristics and to the likelihood of disease progression in a cohort of thyroid cancer patients who have been followed in a multicenter thyroid cancer registry that was established in 1986. The present study describes 617 patients with papillary and 66 patients with follicular thyroid cancer followed annually for a median of 4.5 years (range 1-8.6 years). Cancer staging was assessed using a staging scheme developed and validated by the registry. Cancer status was defined as no residual disease; progressive disease at any follow-up time; or death from thyroid cancer. A mean TSH score was calculated for each patient by averaging all available TSH determinations, where 1 = undetectable TSH; 2 = subnormal TSH; 3 = normal TSH; and 4 = elevated TSH. Patients were also grouped by their TSH scores: group 1: mean TSH score 1.0-1.99; group 2: mean TSH score 2.0-2.99; group 3: mean TSH score 3.0-4.0. The degree of TSH suppression did not differ between papillary and follicular thyroid cancer patients. However, TSH suppression was greater in papillary cancer patients who were initially classified as being at higher risk for recurrence. This was not the case for follicular cancer patients, where TSH suppression was similar for all patients. For all stages of papillary cancer, a Cox proportional hazards model showed that disease stage, patient age, and radioiodine therapy all predicted disease progression, but TSH score category did not. However, TSH score category was an independent predictor of disease progression in high risk patients (p = 0.03), but was no longer significant when radioiodine therapy was included in the model (p = 0.09). There were too few patients with follicular cancer for multivariate analysis. These data suggest that physicians use greater degrees of TSH suppression in higher risk papillary cancer patients. Our data do not support the concept that greater degrees of TSH suppression are required to prevent disease progression in low-risk patients, but this possibility remains in high-risk patients. Additional studies with more patients and longer follow-up may provide the answer to this important question.

Prospective multicenter study of thyroiscarcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group.

BACKGROUND: A novel prognostic staging classification encompassing all forms of thyroid carcinoma was created for the National Thyroid Cancer Treatment Cooperative Study (NTCTCS) Registry, with the goal of prospective validation and comparison with other available staging classifications. METHODS: Patient information was recorded prospectively from 14 institutions. Clinicopathologic staging was based on patient age at diagnosis, tumor histology, tumor size, intrathyroidal multifocality, extraglandular invasion, metastases, and tumor differentiation. RESULTS: Between 1987 and 1995, 1607 patients were registered. Approximately 43% of patients were classified as NTCTCS Stage I, 24% Stage II, 24% Stage III, and 9% Stage IV. Patients with follicular carcinoma were more likely to have "high risk" Stage III or IV disease than those with papillary carcinoma. Of 1562 patients for whom censored follow-up was available (median follow-up, 40 months), 78 died of thyroid carcinoma or complications of its treatment. Five-year product-limit patient disease specific survival was 99.8% for Stage I, 100% for Stage II, 91.9% for Stage III, and 48.9% for Stage IV (P < 0.0001). The frequency of remaining disease free also declined significantly with increasing stage (94.3% for Stage I, 93.1%for Stage II, 77.8% for Stage III, and 24.6% for Stage IV). The same patients also were staged applying six previously published classifications as appropriate for their tumor type. The predictive value of the NTCTCS Registry staging classification consistently was among the highest for disease specific mortality and for remaining disease free, regardless of the tumor type. CONCLUSIONS: The NTCTCS Registry staging classification provides a prospectively validated scheme for predicting short term prognosis for patients with thyroid carcinoma.

Anaplastic thyroid carcinoma: behavior, biology, and therapeutic approaches.

Anaplastic thyroid carcinoma (ATC), although exceedingly rare, is the most aggressive solid tumor known. Early studies on the effects of different therapies may be biased by the inclusion of responsive "small cell" ATC patients, which are now known to be mostly lymphoma patients. Local control of disease with surgery and/or external beam radiotherapy (XRT) is of fundamental importance to enhance survival. Ultimately, nearly all ATC patients die from their disease, which is widely metastatic. Development of effective systemic chemotherapy agents would provide the best chance for long-term survival of patients. Early preliminary data suggest that paclitaxel may be helpful, although no agent has yet been identified to result in dramatic improvements in survival. Select patients may benefit from aggressive multimodal therapy, although it is important to provide appropriate palliative care when desired.

A unique interaction between polyamine and multidrug resistance (P-glycoprotein) transporters in cultured Chinese hamster ovary cells transfected with mouse mdr-1 gene.

We have shown that a functional link exists between the polyamine transporter and the multi-drug resistance (MDR) efflux transporter (P-glycoprotein, P-gp) in MDR-positive cancer cells. To further explore the nature of this interaction, we have examined the effect of reduced polyamine transport activity on cellular expression and activity of P-gp acquired by either selection or transfection. Chinese hamster ovary (CHO) cells and their polyamine transport-deficient mutants (CHOMGBG) were transfected with mouse mdr-1b gene. The activity of P-gp in these cells was quantified by measuring cellular accumulation of radiolabeled taxol and etoposide in the presence and absence of the P-gp modulator SDZ PSC-833 (valspodar; a semisynthetic undecapeptide derived from cyclosporin D). The mdr-1b-transfected CHO cells accumulated 2- to 3-fold less taxol and etoposide than the controls, an accumulation defect reversed by the potent MDR modulator PSC-833. Despite expression of P-gp on the surface of mdr-1b-transfected CHOMGBG cells, this classic MDR phenotype was not observed. Similarly, CHO cells, but not CHOMGBG cells, showed MDR activity after selection with doxorubicin as determined by reduced accumulation of radiolabeled taxol. Treatment with 50 microM of reduced polymer of spermine and glutaraldehyde, a selective blocker of the polyamine transport system, reduced MDR activity in mdr-1-transfected CHO cells and restored cellular accumulation of etoposide and taxol to control levels, effects not observed in mdr-1-transfected CHOMGBG cells. Notably, mdr-1-transfected CHO cells were 4- to 16-fold more resistant to the cytotoxic effects of the P-gp substrates doxorubicin, taxol, and etoposide than were the mdr-1-transfected CHOMGBG cells. CHO cells transfected with the mdr-1 gene exhibited a 23% reduction in cellular uptake of [14C]spermidine compared with untransfected controls; spermidine accumulation in CHOMGBG cells was no different than that in untransfected controls. These data suggest that the existence of a functioning polyamine transport system may be a requirement for MDR transporter activity, while the expression of functioning P-gp appears to reduce polyamine transporter activity.

Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells.

We investigated the p53 status and the ability of exogenous wildtype (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulation of p53 or induction of p21WAF1/CIP1 or Mdm-2 and did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had mutant p53. SW-1736 cells were functionally mutant because of marked down-regulation of wt p53 messenger ribonucleic acid, representing a novel mechanism of p53 dysfunction. Infection with a p53-expressing adenovirus (Ad-p53) induced high levels of p21 and Mdm-2 proteins. In BHT-101 cells, induction of p21 and Mdm-2 was evident 10 h after infection. In KAT-4 cells, induction of p21 and Mdm-2 was observed 1 day after infection, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effect of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 cells were most sensitive to killing by Ad-p53, with an IC50 of less than 2 multiplicity of infection; SW-1736 cells were intermediate in sensitivity; KAT-4 cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrease in IC50 values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating anaplastic thyroid cancer.

Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle's cell, and poorly differentiated human thyroid carcinoma.

Expression of the invasion/metastasis suppressor, E-cadherin, is diminished or lost in thyroid carcinomas. Yet, mutational inactivation of E-cadherin is rare. Herein, we show that this loss is associated with hypermethylation of the E-cadherin 5' CpG island in a panel of human thyroid cancer cell lines. This aberrant methylation is evident in 83% of papillary thyroid carcinoma, 11% of follicular thyroid carcinoma, 40% of Hurthle's cell carcinoma, and 21% of poorly differentiated thyroid carcinomas. Contrary to previous reports, the majority of these poorly differentiated thyroid carcinomas express E-cadherin, but often within the cytoplasm rather than at the cell surface. Together, our data indicate that the invasion/metastasis suppressor function of E-cadherin is frequently compromised in human papillary, Hurthle's cell, and poorly differentiated thyroid carcinoma by epigenetic and biochemical events.

Cloning of the human sodium-iodide symporter promoter and characterization in a differentiated human thyroid cell line, KAT-50.

Elucidation of the regulation of human sodium-iodide symporter (hNIS) gene expression is critical to understanding its effects on iodide concentration abilities of thyroid and thyroid carcinomas. To explore this issue, a 1.2-kb portion of the 5'-flanking region of the hNIS gene was isolated and characterized. Transient transfections with chimeric luciferase-reporter constructs into a differentiated human thyroid cell line, KAT-50, as well as non-thyroidal cells, defined an active promoter with tissue-specificity. Reverse-transcriptase polymerase chain reaction analysis for hNIS mRNA expression in normal human tissues was positive in thyroid, salivary gland, omentum, and gallbladder. KAT-50 cells expressed hNIS mRNA and were capable of thyrotropin-responsive iodide uptake in vitro. Despite the failure to exhibit iodide concentration in clinical anaplastic carcinoma tumors, 4 of 5 cell lines from this cancer phenotype expressed hNIS mRNA. Definition of the active promoter provides further insights and tools to uncover new approaches to use of radioiodine for therapy of thyroid carcinomas.