Growth factors and goitrogenesis

Abstract

By combining data from studies of multinodular non-toxic goitre (MNTG) with data from rat models of goitre induction and in vitro models, a map of the growth factors involved in goitrogenesis has been constructed. We have addressed the roles of the insulin-like growth factors, transforming growth factors, fibroblast growth factors, endothelins, etc. We hypothesise that an imbalance in the interactions between the various growth factor axes exists in MNTG which favours cell replication. Thyrotrophin, although not significantly elevated in MNTG, exerts critical effects through interactions with autocrine and paracrine factors and their receptors. Expansion of the thyroidal vascular bed through angiogenesis is closely co-ordinated with follicular cell expansion and folliculoneogenesis, and while the integrated paracrine actions of fibroblast growth factors, vascular endothelial growth factor and endothelin probably play central roles, additional, as yet elusive, factors are probably involved. The combination of in vitro and in vivo approaches, designed to address specific questions, will undoubtedly continue to prove invaluable in dissecting further the complex interactions that exist between these growth factors, their binding proteins and receptors in goitrogenesis.

The Functional Interaction between the Paired Domain Transcription Factor Pax8 and Smad3 Is Involved in Transforming Growth Factor-β Repression of the Sodium/Iodide Symporter Gene

“…The inhibition we observed, as well as that reported by others (18,45), was relative to the TSH-stimulated levels of NIS. At present, it is thought that the potent suppression of thyroid growth and differentiation elicited by TGF-␤ modulates the effects of TSH and other growth factors to maintain thyroid gland homeostasis (46). In addition to NIS, TGF-␤ acts as a potent suppressor of other thyroidrestricted genes such as thyroglobulin, TPO, and TSHR (31,35,44,45), again suggesting that TGF-␤ modulates the TSH-stimulated effect on these genes (45).…”

Relationships between cell division, expression of growth factors and microcirculation in the thyroids of Tg-A2aR transgenic mice and patients with Graves' disease

“…As a consequence, epithelial and endothelial compartments enlarged homogeneously and synchronously, as commonly described in the early steps of endocrine hyperplasia (Derwahl & Studer 2002). Iodine deficiency induced an increase in the number of dividing cells for the first 12 days and then a gradual return to control values at 3 months, indicating that autocrine and paracrine regulatory mechanisms were activated within the gland to limit goitre size (Bidey et al 1999). In the mouse Tg-A2aR transgenic model, the level of stimulation was markedly stronger.…”

“…In our study, endothelial cells were positive for FGF-2, ET-1, NOSIII, VEGF and TGF . All these factors have already been shown to regulate the growth of thyrocytes (Eggo & Sheppard 1994, Bidey et al 1999. Alternatively, thyrocytes themselves could be the main cellular targets and could release, in response to increased TSH concentrations, vasoactive and angiogenic factors that in turn will stimulate endothelial cells (Emoto et al 1991, Colin et al 1992, Bechtner et al 1993, Pekari et al 1995, Sato et al 1995, Patel et al 1996, Viglietto et al 1997, Toda et al 1999.…”

Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue

“…We have no reason to suppose that vascular growth in the thyroid due to TSH stimulation differs in any fundamental aspect from angiogenesis in other tissues. During goitrogenesis vascular growth is coordinated, the thyroid endothelial cells responding to VEGF, as do endothelial cells of many other tissues, with VEGF being produced locally by follicular cells in response to TSH stimulation (Sato et al, 1995;Viglietto et al, 1997;Wang et al, 1998;Bidey et al, 1999). There is no evidence that the endothelial cells respond directly to TSH.…”

“…This induces a coordinated programme of neovascularization in which endothelial cell proliferation is regulated by pro-angiogenic growth factors, for example vascular endothelial growth factor (VEGF), derived from follicular cells (Bidey et al, 1999). Following goitrogen treatment, thyroid growth is induced in rodents within 2 days and continues at a high rate for about 2 weeks.…”