Vitamin D in thyroid tumorigenesis and development.

Besides its classical role in bone and calcium homeostasis, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has many non-classical effects; antiproliferative, anti-apoptotic and prodifferentiating effects of 1,25(OH)2D3 have been described in several tumour types in preclinical models. This review focuses on the insights gained in the elucidation of the role of 1,25(OH)2D3 in the normal thyroid and in the pathogenesis, progression and treatment of thyroid cancer, the most common endocrine malignancy. An increasing amount of observations points towards a role for impaired 1,25(OH)2D3-VDR signalling in the occurrence and progression of thyroid cancer, and a potential for structural analogues in the multimodal treatment of dedifferentiated iodine-resistant thyroid cancer. A role for vitamin D in thyroid-related autoimmunity is less convincing and needs further study. Altered 1,25(OH)2D3-VDR signalling does not influence normal thyroid development nor thyrocyte function, but does affect C-cell function, at least in rodents. If these findings also apply to humans deserves further study.

Altered expression of key players in vitamin D metabolism and signaling in malignant and benign thyroid tumors.

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, mediates antitumor effects in various cancers. The expression of key players in vitamin D signaling in thyroid tumors was investigated. Vitamin D receptor (VDR) and CYP27B1 and CYP24A1 (respectively activating and catabolizing vitamin D) expression was studied (RT-PCR, immunohistochemistry) in normal thyroid, follicular adenoma (FA), differentiated thyroid cancer (DTC) consisting of the papillary (PTC) and follicular (FTC) subtype, and anaplastic thyroid cancer (ATC). VDR, CYP27B1, and CYP24A1 expression was increased in FA and DTC compared with normal thyroid. However, in PTC with lymph node metastasis, VDR and CYP24A1 were decreased compared with non-metastasized PTC. In ATC, VDR expression was often lost, whereas CYP27B1/CYP24A1 expression was comparable to DTC. Moreover, ATC with high Ki67 expression (>30%) or distant metastases at diagnosis was characterized by more negative VDR/CYP24A1/CYP27B1 staining. In conclusion, increased expression of key players involved in local 1,25(OH)(2)D(3) signaling was demonstrated in benign and differentiated malignant thyroid tumors, but a decrease was observed for local nodal and especially distant metastasis, suggesting a local antitumor response of 1,25(OH)(2)D(3) in early cancer stages. These findings advocate further studies with 1,25(OH)(2)D(3) and analogs in persistent and recurrent iodine-refractory DTC.

The vitamin d receptor in thyroid development and function.

BACKGROUND AND OBJECTIVE: Vitamin D is known to modulate thyroid neoplastic and autoimmune disease. We investigated the role of the vitamin D receptor (VDR) in normal thyroid development and function (thyrocytes and C cells). METHODS: The thyroid phenotype of VDR knockout mice was studied in comparison to wild-type controls. The mice were fed a normal diet or a calcium-rich diet to circumvent effects induced by hypocalcemia. RESULTS: Thyroid morphology was unaltered in VDR knockout mice. Also, expression of different parameters of thyrocyte function was comparable (immunohistochemistry). C cell physiology was, however, affected in the absence of the VDR, resulting in increased thyroidal calcitonin expression (immunohistochemistry), paralleled by increased serum calcitonin levels, but only in normocalcemic mice. To study a possible effect of vitamin D status on basal calcitonin levels in humans, serum calcitonin concentrations were compared between vitamin D-deficient and -sufficient patients (serum 25-OH vitamin D3 ≤10 and ≥40 ng/ml, respectively), but no difference was observed. CONCLUSIONS: In mice, the VDR is redundant for normal thyrocyte function, but not for C cell function, where it mediates the negative control of calcitonin by 1,25-dihydroxyvitamin D3. In patients, vitamin D status does not affect basal serum calcitonin levels. A study in healthy individuals is needed to confirm these findings.

1,25-dihydroxyvitamin D3 and a superagonistic analog in combination with paclitaxel or suberoylanilide hydroxamic acid have potent antiproliferative effects on anaplastic thyroid cancer.

Anaplastic thyroid cancer represents one of the most aggressive cancers. The active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), has been shown to have antiproliferative and/or redifferentiating properties in several malignancies, including thyroid cancer. The objective of this study was to investigate the effects of 1,25(OH)(2)D(3) and the superagonistic analog CD578 in anaplastic thyroid cancer, alone or in combination with paclitaxel, a taxane, and suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase inhibitor with promising effects in undifferentiated thyroid cancer. Four human thyroid cancer cell lines (FTC-133, C643, 8505C and HTh74) were treated with 1,25(OH)(2)D(3) or CD578, alone or in combination with paclitaxel or SAHA. Effects on cell growth and differentiation were evaluated. Clear effects on growth arrest were observed in a clonogenic assay, and absolute cell counts demonstrated a 24-36% reduction in all cell lines after 72h treatment with 1,25(OH)(2)D(3) (10(-6)M) and a 60% inhibition after 120h in the most sensitive cell line HTh74. A similar growth inhibition was shown after treatment with a 1000-fold lower concentration of analog CD578. This growth arrest was explained by antiproliferative effects, further supported by an increased % of cells in the G(0)-G(1) phase of the cell cycle and by a decreased transcription factor E2F1 mRNA expression. Combination treatments of 1,25(OH)(2)D(3) or CD578 with paclitaxel or SAHA resulted in an additive and in some conditions a synergistic effect on the inhibition of proliferation. Redifferentiation analysis revealed only a modest increase in sodium iodide symporter and thyroglobulin mRNA expression after treatment with 1,25(OH)(2)D(3), without additive effect after combination treatment. No effects were observed on TSH-receptor or thyroid peroxidase mRNA expression. Our in vitro findings demonstrate that the superagonistic vitamin D analog CD578 holds promise as adjuvant antiproliferative therapy of anaplastic thyroid cancer, especially in combination with other drugs such as paclitaxel or SAHA.

FMRFamide related peptide ligands activate the Caenorhabditis elegans orphan GPCR Y59H11AL.1.

G-protein coupled receptors (GPCRs) are ancient molecules that can sense environmental and physiological signals. Currently, the majority of the predicted Caenorhabditis elegans GPCRs are orphan. Here, we describe the characterization of such an orphan C. elegans GPCR, which is categorized in the tachykinin-like group of receptors. Since the C. elegans genome predicts only one tachykinin-like peptide (SFDRMGGTEFGLM), which could not activate the receptor, we hypothesized that one or some of the numerous FMRFamide related peptides (FaRPs) could be the cognate ligands for this receptor. This hypothesis was based on the suggestion that RFamides may be ancestral neuropeptides, from which a lot of the amidated neuropeptides, including tachykinins, derived. Indeed, we found that the orphan receptor encoded by the Y59H11AL.1 gene is activated by several C. elegans neuropeptides, including SPMERSAMVRFamide. These peptides activate the receptor in a concentration-dependent way.