Growth Factor Thyroid Hyperplasia and Neoplasia

Staffan Smeds, MD, PhD ■ Nils-Erik Heldin, PhD

Thyroid tissue homeostasis is controlled at several levels: directly or indirectly by thyroid-stimulating hormone (TSH), by locally acting growth stimulatory substances (i.e., epidermal growth factor [EGF], transforming growth factor-a [TGF-a], insulin-like growth factors [IGFs], fibroblast growth factors [FGFs], hepatocyte growth factor [HGF], platelet-derived growth factor [PDGF], and the growth inhibitory TGF-J3), and also by apoptotic mechanisms regulating cell death. Variation of thyroid volume reflects either the demand of the organism through TSH or a disturbance of the intricate network interaction between the locally acting growth regulatory substances and the expression of their receptors. Many of the latter are related to identified protooncogene products.

In nodular goiter, hyperplasia seems related to increased growth propensity, inherited from mother to daughter cells in a subpopulation of cells at multiple sites in the gland. Nodules can, however, be monoclonal, as is characteristic for early neoplastic lesions.

Genetic events (i.e., oncogene activation) seem to be operational along both hyperplastic and neoplastic growth deregulation lines. From this early "gray zone" event, further degeneration seems linked to specific mutations that give the neoplasias their characteristic phenotypic expression. Deregulation of the cell cycle by ablation of p53 and Rb gene expression seems to add a farther malignant potential to the neoplastic degeneration.

Growth regulation of the thyroid gland comprises an intricate network of interaction between regulatory signals and the genetic template for cell reactions. The regulatory mechanisms include autocrine and paracrine signal loops as well as varying oncogene and growth suppressor gene expressions, which interfere with and can disrupt cell cycle transition. Qualitative and quantitative changes of the signal pattern alter the phenotypic expression of thyroid function or growth, and a number of mutations give constitutive genetic lesions that stepwise alter the phenotypic expression of tissue integrity, growth, and function.

Integration of the thyroid gland in the homeostasis of the organism is monitored by hormonal, neural, and immunologic systems. In this first level of thyroid control, the TSH is the most important factor for function and growth. On a second level, tissue homeostasis seems controlled by a number of locally acting signal substances, some of which are referred to as growth regulatory factors. On a third level, cell to cell adhesion and parenchyma integrity are controlled by a number of factors, the loss of which results in deregulation of thyroid growth control.1 At the genetic level, new insights into programmed cell death (apoptosis) add a fourth level of control to the complex hierarchy of thyroid growth control.2

Apart from fetal and adolescent increase in thyroid volume, the thyroid gland normally does not grow. Each follicle cell is assumed to pass five mitotic cycles during adulthood, indicating small kinetic cell compartments undergoing proliferation and apoptosis.3 The rest of the follicle cell population expresses their differentiated functions (i.e., secretion of thyroid hormones that inhibit secretion of pituitary thyrotrophs of TSH by the well-known negative feedback mechanism). The follicle cells, however, retain their capacity to grow (hypertrophy) and multiply (hyperplasia) in response to stimuli. Thus, decreased thyroid hormone secretion, as induced by iodine deficiency or administration of goitrogen or antithyroid drugs, gives increased TSH secretion, with concomitant stimulated thyroid function and growth. The latter shows that a follicle cell is reversibly terminally differentiated.

Thyroid follicle cell proliferation is under the control of several factors, including hormones, classic growth factors, and different low-molecular-weight agents. Because both stimulatory and inhibitory factors are described, the net growth effect is a sum of all these stimuli. Most of the knowledge of thyroid growth regulation is from in vitro experiments in different culture systems. In Table 28-1, we have listed the major thyroid growth-promoting and growth-inhibiting factors. As seen in Table 28-1, the factors involved in thyroid growth regulation can be divided into three major groups according to the intracellular signal pathway used.

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