Signal Transduction in Thyroid Neoplasms

Serdar T. Tezelman, MD ■ Allan E. Siperstein, MD

In vivo and in vitro cellular proliferation, differentiation, and protein phosphorylation of thyroid cells are regulated and influenced by many stimulatory and inhibitory hormones, neurotransmitters, and growth factors through several signal transduction systems, including the adenylate cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) system, the phospholipase C (PLC)-protein kinase C (PKC) system, and the growth factor-tyrosine kinase signal transduction system. In the past decade, advances in molecular biology and biochemistry have improved our knowledge and understanding of signal transduction systems. Multiple endocrine, paracrine, and autocrine factors, including thyroid-stimulating hormone (TSH), epidermal growth factor (EGF), vasoactive intestinal polypeptide (VIP), somatostatin, insulin, insulin-like growth factor I (IGF-I), and estrogen, bind to a variety of cell surface-specific and intracellular receptors on the thyrocyte and cause a specific second messenger response or directly activate PKC, such as 12-0-tetradecanoyl phorbol-13 acetate (TPA) (Table 29-1). Multiple mutations or abnormalities in the regulation of thyroid cell growth are responsible for uncontrolled growth and the formation of benign and malignant thyroid neoplasms.

Thyrotropin (TSH) is secreted by the anterior pituitary hormone and is a major regulator of thyroid growth and differentiated functions, including thyroid hormone synthesis, formation, and degradation as well as secretion, iodide uptake, iodide organification, thyroid peroxidase, thyroglobu-lin, and protein synthesis.1'2 The expression of the thyroglob-ulin gene is mediated by a cAMP-dependent mechanism and is under the positive control of TSH.3 TSH has a tissue-specific trophic effect on both normal and neoplastic tissue. Although the effect of TSH on thyroid function is well understood, its role in regulating thyroid growth is controversial. The suppression of TSH by thyroid hormone administration is used clinically to decrease the size of benign tumors and to prevent the development of new or recurrent tumors in patients after thyroidectomy for thyroid cancer of follicular origin.45 A better understanding of signal transduction systems in benign and malignant thyroid tumors should provide us with new diagnostic and therapeutic opportunities.

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