Stabilization of b-catenin by inhibition of its phosphorylation is characteristic of an activation of the canonical Wnt/b-catenin signaling pathway and is associated with various human carcinomas. It contrasts to an as yet incompletely characterized action of an alternative noncanonical Wnt signaling pathway on neoplastic transformation. The aim of the present study was to test the effects of a member of the noncanonical Wnt signaling pathway, Wnt-5a, in primary thyroid carcinomas and in thyroid carcinoma cell lines. Compared to normal tissue Wnt-5a mRNA expression was clearly increased in thyroid carcinomas. Immunohistochemically, a bellshaped response was observed with low to undetectable levels in normal tissue and in anaplastic tumors whereas differentiated thyroid carcinomas showed strong positive immunostaining for Wnt-5a. Transfection of Wnt-5a in a thyroid tumor cell line FTC-133 was able to reduce proliferation, migration, invasiveness and clonogenicity in these cells. These effects of Wnt-5a are associated with membranous b-catenin translocation and c-myc oncogene suppression and are mediated through an increase in intracellular Ca 2 þ release, which via CaMKII pathways promotes b-catenin phosphorylation. Specific inhibition of b-catenin phosphorylation by W-7, a calmodulin inhibitor, or by KN-93, a CaMKII inhibitor, supports these findings whereas PKC inhibitors were without effect. This interaction occurs downstream of GSK-3b as no Wnt-5a effect was seen on the Ser 9 phosphorylation of GSK-3b. Our data are compatible with the hypothesis that Wnt-5a serves as an antagonist to the canonical Wnt-signaling pathway with tumor suppressor activity in differentiated thyroid carcinomas.

Background: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMPresponseelementbinding protein (CREB) pathway, recent data indicate that Wnt/b-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3b inhibition, which in turn stabilizes cytosolic free b-catenin. Here we investigated the potential modulation of Wnt/b-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. Methods: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. Results: LiCl dose-dependently inhibited GSK-3b, stabilized free b-catenin and inhibited b-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cadherin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by b-catenin, since nuclear b-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/b-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/b-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. Conclusion: Our data indicate that Wnt/b-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.

Objective: Most patients who have been treated for craniopharyngioma (CP) are GH deficient (GHD). GH replacement therapy (GHRT) may stimulate tumour regrowth; and one of the concerns with long-term GHRT is the risk of tumour progression. Therefore, the objective was to study tumour progression in CP patients on long-term GHRT. Design: Case-control study. Patients and methods:The criteria for inclusion of cases were: i) GHD caused by CP; ii) GHRT O3 years; and iii) regular imaging. This resulted in 56 patients (mean age at diagnosis 25G16 years) with a mean duration of GHRT of 13.6G5.0 years. As controls, 70 CP patients who had not received GHRT were sampled with regard to follow-up, gender, age at diagnosis and initial radiation therapy (RT). Results: The 10-year tumour progression-free survival rate (PFSR) for the entire population was 72%. There was an association (hazard ratio, P value) between PFSR and initial RT (0.13, !0.001) and residual tumour (3.2, !0.001). The 10-year PFSR was 88% for the GHRT group and 57% for the control group. Substitution with GHRT resulted in the following associations to PFSR: GHRT (0.57, 0.17), initial RT (0.16, !0.001), residual tumour (2.6, !0.01) and gender (0.57, 0.10). Adjusted for these factors, the 10-year PFSR was 85% for the GHRT group and 65% for the control group. Conclusions: In patients with CP, the most important prognostic factors for the PFSR were initial RT and residual tumour after initial treatment. Long-term GHRT did not affect the PFSR in patients with CP.

The journal apologizes for an error in Fig. 2 of this article published in the European Journal of Endocrinology 166 1061-1068. The GH-treated group and non-GH-treated group were incorrectly identified. The correct figure is published in full below. European Journal of Endocrinology 167 135Figure 2 Cox regression of progression-free survival rates adjusted for initial RT, residual tumour after primary treatment and gender in patients treated with and without GHRT. No association between GHRT and tumour progression was found (HR 0.57; P valueZ0.17). The 95% CI for each group are indicated by the red and blue colours (GHRT, GH replacement therapy; RT, radiation therapy).

Our data provide a molecular mechanism for the antitumor activity of imatinib that may help to develop it as a therapeutic option in a subset of ATC patients.