Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer.

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Molecular pathogenesis and mechanisms of thyroid cancer

Thyroid cancer is one of the few malignancies that are increasing in incidence. Recent advances have improved our understanding of its pathogenesis; these include the identification of genetic alterations that activate a common effector pathway involving the RET-Ras-BRAF signalling cascade, and other unique chromosomal rearrangements. Some of these have been associated with radiation exposure as a pathogenetic mechanism. Defects in transcriptional and post-transcriptional regulation of adhesion molecules and cell-cycle control elements seem to affect tumour progression. This information can provide powerful ancillary diagnostic tools and can also be used to identify new therapeutic targets.

Pathogenetic mechanisms in thyroid follicular-cell neoplasia

The Na(+)/I(-) symporter (NIS) is an integral plasma membrane glycoprotein that mediates active I(-) transport into the thyroid follicular cells, the first step in thyroid hormone biosynthesis. NIS-mediated thyroidal I(-) transport from the bloodstream to the colloid is a vectorial process made possible by the selective targeting of NIS to the basolateral membrane. NIS also mediates active I(-) transport in other tissues, including salivary glands, gastric mucosa, and lactating mammary gland, in which it translocates I(-) into the milk for thyroid hormone biosynthesis by the nursing newborn. NIS provides the basis for the effective diagnostic and therapeutic management of thyroid cancer and its metastases with radioiodide. NIS research has proceeded at an astounding pace after the 1996 isolation of the rat NIS cDNA, comprising the elucidation of NIS secondary structure and topology, biogenesis and posttranslational modifications, transcriptional and posttranscriptional regulation, electrophysiological analysis, isolation of the human NIS cDNA, and determination of the human NIS genomic organization. Clinically related topics include the analysis of congenital I(-) transport defect-causing NIS mutations and the role of NIS in thyroid cancer. NIS has been transduced into various kinds of cancer cells to render them susceptible to destruction with radioiodide. Most dramatically, the discovery of endogenous NIS expression in more than 80% of human breast cancer samples has raised the possibility that radioiodide may be a valuable novel tool in breast cancer diagnosis and treatment.

The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance.

Thyroid gland organogenesis results in an organ the shape, size, and position of which are largely conserved among adult individuals of the same species, thus suggesting that genetic factors must be involved in controlling these parameters. In humans, the organogenesis of the thyroid gland is often disturbed, leading to a variety of conditions, such as agenesis, ectopy, and hypoplasia, which are collectively called thyroid dysgenesis (TD). The molecular mechanisms leading to TD are largely unknown. Studies in murine models and in a few patients with dysgenesis revealed that mutations in regulatory genes expressed in the developing thyroid are responsible for this condition, thus showing that TD can be a genetic and inheritable disease. These studies open the way to a novel working hypothesis on the molecular and genetic basis of this frequent human condition and render the thyroid an important model in the understanding of molecular mechanisms regulating the size, shape, and position of organs.

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Thyroid development and its disorders: genetics and molecular mechanisms.

TSH via cAMP, and various growth factors, in cooperation with insulin or IGF-I stimulate cell cycle progression and proliferation in various thyrocyte culture systems, including rat thyroid cell lines (FRTL-5, WRT, PC Cl3) and primary cultures of rat, dog, sheep and human thyroid. The available data on cell signaling cascades, cell cycle kinetics, and cell cycle-regulatory proteins are thoroughly and critically reviewed in these experimental systems. In most FRTL-5 cells, TSH (cAMP) merely acts as a priming/competence factor amplifying PI3K and MAPK pathway activation and DNA synthesis elicited by insulin/IGF-I. In WRT cells, TSH and insulin/IGF-I can independently activate Ras and PI3K pathways and DNA synthesis. In dog thyroid primary cultures, TSH (cAMP) does not activate Ras and PI3K, and cAMP must be continuously elevated by TSH to directly control the progression through G(1) phase. This effect is exerted, at least in part, via the cAMP-dependent activation of the required cyclin D3, itself synthesized in response to insulin/IGF-I. This and other discrepancies show that the mechanistic logics of cell cycle stimulation by cAMP profoundly diverge in these different in vitro models of the same cell. Therefore, although these different thyrocyte systems constitute interesting models of the wide diversity of possible mechanisms of cAMP-dependent proliferation in various cell types, extrapolation of in vitro mechanistic data to TSH-dependent goitrogenesis in man can only be accepted in the cases where independent validation is provided.

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Regulation of Thyroid Cell Proliferation by TSH and Other Factors: A Critical Evaluation of in Vitro Models

In the rat thyroid cell lines PC Cl3, FRTL- 5 and WRT, proliferation is mainly regulated by insulin or IGF, and TSH. However, the mechanism regulating cell mass doubling prior to division is still unknown. Our laboratory has shown that in dog thyroid cells insulin promotes growth in size while TSH in the presence of insulin triggers DNA replication. In the absence of insulin, TSH has no effect on cell growth. In this report we investigated insulin action on both cell mass and DNA synthesis and its modulation by TSH and insulin in PC Cl3 and FRTL-5 cells. In PC Cl3 cells, insulin activated not only DNA synthesis but also protein synthesis and accumulation. Although TSH potentiated the stimulation of DNA synthesis induced by insulin, enhancement of protein synthesis by both agents was additive. All TSH effects were reproduced by forskolin. Similar effects were also obtained in FRTL-5 cells. This suggests that insulin and TSH, via cAMP, modulate both growth in size and DNA replication in these cell lines. Lovastatin, which blocks 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreased the induction of DNA synthesis, but not of protein synthesis induced by insulin or TSH in PC Cl3 cells. In FRTL-5 cells, lovastatin reduced protein and DNA synthesis stimulated by insulin but not TSH-induced protein synthesis. Taking these data together, we propose that insulin and/or TSH both modulate cell mass doubling and DNA synthesis in these cell lines, presumably via different pathways, and that there are at least two pathways which regulate growth in size in FRTL-5 thyroid cells: one triggered by insulin, which is lovastatin sensitive, and the other activated by TSH, which is not sensitive to lovastatin.

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Takao Kimura

Papers

Regulation of Thyroid Cell Proliferation by TSH and Other Factors: A Critical Evaluation of in Vitro Models

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells.

Loss of several cell functions including okadaic acid-induced apoptosis after multiple passages in FRTL-5 cells.