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The Natural Thyroid Diet

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Hyperplasia

invasion

invasion

Anaplasia

Metastasis

27/27(100%)

23/27(85%)

20/27(74%)

10/27(37%)

7/27(26%)

via homologous recombination and the Cre/loxP system. The mutation is called PV mouse) after a patient with the mutation who suffers from the disease known as resistance to thyroid hormone (RTH) (44, 45). RTH is a syndrome characterized by the elevated levels of circulating thyroid hormone that are associated with non-suppressible TSH. Some of the clinical features include attention-deficit hyperactivity disorder, mental retardation, short stature, decreased -weight, tachycardia, and hearing abnormalities (44, 45). PV has a unique mutation in exon 10, a C-insertion at codon 448, which produces a frame shift of the carboxyl-terminal 14 amino acids of In vitro studies revealed that PV has completely lost T3-binding activity, lacks transcriptional capacity, and exhibits potent dominant negative activity (46). Extensive characterization of the phenotype indicates that the mouse faithfully reproduces the human RTH (43). This TR|3PV mouse provides a valuable model for clarifying the role of germline mutations of the TR|3 gene in carcinogenesis.

In addition to the phenotypes of RTH, homozygous mice exhibited the phenotype of age-dependent increased mortality. By the age of about 10 months, 50% had died, and by the age of 14-15 months, all mice were dead. In contrast, the heterozygous (TR(3' mice did not exhibit such abnormalities. Morphological examinations of the moribund TR|3PV^PV mice indicate that as these mice aged, they spontaneously developed thyroid carcinoma (47). Histological evaluation of thyroids of 27 moribund mice showed capsular invasion (85%), vascular invasion

(74%), anaplasia (37%), and metastasis to the lung and heart (26%) but not to lymph nodes (Table 1).

Representative examples of the pathological features of capsular invasion (Panel A), vascular invasion (Panel B), anaplasia (Panel C), and metastasis to the lung (Panel D) are shown in Figure 1. The histological features and the metastatic patterns indicate that the thyroid carcinoma developed in mice is follicular. Thus TR|3PV/PV

mice provide the first animal model for studying the molecular genetics underlying follicular thyroid carcinogenesis.

Using microarrays consisting of 20,000 mouse cDNAs, Ying et al. recently profiled the global alterations in gene expression in the thyroids ofTR|3pv/pv mice at 6 months of age, at which time metastasis had begun (48). They found that 185 genes were up-regulated (2- to 17-fold) and 92 were down-regulated (2- to 20-fold). The majority (~60%) of these altered genes are unnamed. Functional clustering of named genes with reported functions (100 genes) indicated that ~39% were tumor-, metastasis/invasion-, and cell cycle-related. Importantly, several tumor-related genes, such as cyclin D1, pituitary tumor transforming gene-1, cathespin D, and transforming growth factor that have been reported to be over-expressed in human thyroid

Figure 1. Pathological features in thyroid glands and metastasis in the lung ofTR(3Fv^Fvmice. Histologic sections from tissues of TR|3pv'pvmice showed evidence of capsular invasion in thyroid (A) (arrows), vascular invsion in thyroid (B)(arrows), anaplasia in thyroid (C) and metastatic thyroid carcinoma lesions in lung (arrow).

Figure 1. Pathological features in thyroid glands and metastasis in the lung ofTR(3Fv^Fvmice. Histologic sections from tissues of TR|3pv'pvmice showed evidence of capsular invasion in thyroid (A) (arrows), vascular invsion in thyroid (B)(arrows), anaplasia in thyroid (C) and metastatic thyroid carcinoma lesions in lung (arrow).

cancers were found to be activated in the arrays (49-53). Analyses of the gene profiles suggested that the signaling pathways mediated by TSH, peptide growth factors, transforming growth tumor necrosis and nuclear factor were activated, whereas pathways mediated by peroxisome proliferator-activated receptor y (PPARy) were repressed (48). These findings suggest that the expression of the TR|3 mutant directly and indirectly alters multiple signaling pathways that could contribute to the development of thyroid cancer and that thyroid carcinogenesis is mediated by multiple genetic events.

The frequent occurrence of the somatic mutations in several human cancers (30, 32, 36, 54, 55) and the development of follicular thyroid carcinoma in TR|3PV,/PV mice (47) raise the question of whether PV could function to initiate carcinogenesis. On the basis of observations that but not TR(3PV/+ mice develop follicular thyroid carcinoma, it is unlikely that PV could act alone to initiate thyroid carcinogenesis. One of the significant differences in phenotypes between TR|3PV/PV andTR|3pv/+ mice is that the circulating serum TSH concentration in TR(3PV^PV mice is ~275-fold higher than that in (43). TSH is the main regulator of thyrocyte differentiation and proliferation, and the possibility that it is an initiator of thyroid carcinogenesis has been intensively studied (56, 57). Recent clinical and biochemical studies, however, do not support the role of TSH as an initiator of follicular carcinoma (58, 57). Additional genetic changes need to occur for the transformation of the hyperproliferative thyroid cells to cancer cells. On the basis of these considerations, it is reasonable to propose that mutation of the two alleles of the TR|3 gene could be one of the genetic changes leading to the transformation of the hyperproliferative thyroid cells to cancer cells. This hypothesis needs to be tested in future studies.

ABNORMALITIES OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR y IN THYROID CANCER

is a nuclear receptor that is involved in a wide range of cellular processes including adipogenesis, inflammation, atherosclerosis, cell cycle control, apoptosis, and carcinogenesis (59, 60). PPARy mRNA is abundantly expressed in adipose tissue, large intestine, and hematopoietic cells, and it is moderately expressed in kidney, liver, and small intestine (61). It was recently found also to express in the thyroid (48). inhibits cell growth, and one of the mechanisms in inhibition of cell proliferation is by reducing E2F/DP DNA-binding and transcriptional activity (62). Consistently, activation of signaling by its ligands has been shown to block cell proliferation of various malignant cells and, in some cases, to induce differentiation and apoptosis (63-68). Ohta et al. reported that PPARy mRNA is expressed in human papillary thyroid carcinoma cell lines (69). Significant, but variable expression of was detected in four of the six cell lines studied. Consistent with findings in other cancer cell lines (63-68), cell proliferation was inhibited and apoptosis was induced by treatment with troglitazone. Ohta et al. also found that troglitazone significantly reduced tumor growth and prevented distant metastasis of BHP18-21 tumors in nude mice in vivo (69). In a more recent study, Martelli et al. also evaluated whether PPARy is involved in the growth regulation of normal and tumor thyroid cells (70). No mutations were detected in exons 3 and 5 in human thyroid carcinoma cell lines and tissues. The growth of PPARy-expressing thyroid carcinoma cells was inhibited by treatment with agonists, but no growth inhibitory effect was observed in NPA cells by PPARy agonists that did not express PPARy. Growth inhibition induced by agonists or by overexpression of the gene in thyroid carcinoma cells was associated with increased p27 protein levels and apoptotic cell death (70).

TR(3i>v/i>v mice provide an unprecedented opportunity to study the role of in thyroid carcinogenesis in vivo. Using quantitative real-time PCR and Northern blotting, Yin et al. found that the expression of PPARy mRNA was repressed 50%-60% in the thyroids ofTR|3pv/pv mice at the ages of 4, 6, and 12 months (71). Immunohistologic analysis demonstrated that the expression of PPARy protein in the primary lesions ofTR(3FV/PV mice was less than that in the thyroids of wild-type mice and was not detectable in the metastasis in the lung (unpublished results), an indication that the expression of protein remained low during thyroid carcinogenesis.

Moreover, PV was found to abolish ligand (troglitazone)-dependent transcriptional activity of in primary cultured thyroid cells from wild-type mice (71). The

PV-induced transcriptional repression could be due to PV's competition with PPARy for binding to the peroxisome proliferator-activated receptor response element (PPRE) present in the downstream target genes. Indeed, gel shift assay showed that the in vitro translated PV protein could bind to PPRE. This notion is supported by the

Figure 2. Camparison of the expression of PPARy and lipoprotein (LpL) mRNA in the thyroids of TR|3PV,/PV and wild-type mice at different ages by quantitative real-time PCR. Relative expression levels of PPARy(A) and LpL(B) mRNA in the thyroid glands were determined using age matched wild-type and mutant mice at the ages of4 and 12 months as marked. The data are expressed as mean ± SD(/i = 4).

Figure 2. Camparison of the expression of PPARy and lipoprotein (LpL) mRNA in the thyroids of TR|3PV,/PV and wild-type mice at different ages by quantitative real-time PCR. Relative expression levels of PPARy(A) and LpL(B) mRNA in the thyroid glands were determined using age matched wild-type and mutant mice at the ages of4 and 12 months as marked. The data are expressed as mean ± SD(/i = 4).

finding that the lipoprotein lipase (LpL) gene, a known PPARy downstream target gene (72), was repressed ~5-fold, as shown by cDNA microarrays (48). Subsequent analyses by quantitative real-time PCR further demonstrated that the expression of the LpL gene was down-regulated (Panel B; Figure 2) concurrently with PPARy mRNA (Panel A; Figure 2) in the thyroid glands of TR(3PV/PV mice at the ages of 6 and 12 months, thus confirming the repression of signal pathways during thyroid carcinogenesis (71). These results indicate that reduced expression of PPARy mRNA and repression of its transcriptional activity are associated with thyroid carcinogenesis and raise the possibility that can be tested as a potential molecular target for prevention and treatment of follicular thyroid carcinoma.

That the attenuation of the PPARy signaling pathways is associated with the development and progression of follicular thyroid carcinoma is also supported by the findings that the rearrangement occurs frequently in human follicular thyroid carcinomas, less frequently in adenomas, but not at all in papillary thyroid carcinomas (73-76). Even though the molecular actions of the PAX8-PPAR~y rearrangement, particularly in its relation to the thyroid follicular carcinoma, has yet to be clarified, it is known that the fusion of PAX8, a thyroid transcription factor, to the amino terminus of results in the loss of the transcriptional activity of (73). Moreover, protein acts to inhibit thiazolidinedione-induced transacti-vation by in a dominant negative manner (73). Taken together, these studies suggest that suppression of signaling is closely linked to the development and progression of follicular thyroid carcinoma.

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