Thyrotropin May Not Be the Dominant Growth Factor in Benign and Malignant Thyroid Tumors1

Michael Derwahl, Martina Broecker and Zaki Kraiem

Department of Medicine, Division of Endocrinology, St. Willehad Hospital (M.D.), 26382 Wilhelmshaven, Germany; University Clinic of Internal Medicine, Ruhr-University of Bochum (M.D., M.B.), 44789 Bochum, Germany; and Endocrine Research Unit, Carmel Medical Center, and Technion Faculty of Medicine (Z.K.), 34362 Haifa, Israel

Address all correspondence and requests for reprints to: Prof. Michael Derwahl, Klinik für Innere Medizin I, St. Willehad Hospital, Ansgaristrasse 12, 26382 Wilhelmshaven, Germany. E-mail: derwahl.k.m.{at}dgn.de


    Introduction
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
TSH, in synergistic action with insulin and/or insulin-like growth factor I, is still regarded by many researchers to play the major, if not the exclusive, role in the regulation of thyroid cell growth. However, this view needs reevaluation because of recent findings on the diversity of TSH-dependent signaling, including coupling of the receptor to different G protein-dependent pathways, cross-talk between different cAMP-dependent and -independent pathways, and integration of different pathways at the nuclear level. The concept seems to emerge that TSH may be one of many links within a complex network of interacting signals that modulates and controls stimulation of thyroid cell growth and function. This newly emerging concept has altered our understanding of the pathogenesis of thyroid growth in disease. We shall attempt to review some of these novel findings as they relate to benign and malignant human thyroid cell growth.


    TSH and growth of diffuse nontoxic goiter
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
In patients with TSH-secreting pituitary adenoma or generalized thyroid hormone resistance, increased TSH secretion results in an enlargement of the thyroid gland (1, 2). An increase in goiter size due to enhanced TSH secretion may also develop in patients with Graves’ disease who are overtreated with antithyroid drugs (3). Chronically elevated, feedback-mediated TSH secretion is also considered to cause endemic iodine deficiency goiters, although increased serum TSH levels have not yet been directly demonstrated in this condition.

An indirect hint that points to the relevance of TSH for the regulation of iodine deficiency goiter comes from therapeutic studies. Not only does levothyroxine treatment of patients with iodine deficiency goiter decrease TSH levels by directly inhibiting TSH secretion, but administration of iodide shows the same, albeit less pronounced, effect (4). This points to a relative increase in TSH under iodine deficiency conditions.

At first glance, these clinical examples seem to argue in favor of the concept that TSH is the major, if not the sole, growth factor of the thyroid gland. However, this straightforward interpretation neglects recent findings that point to an intricate complexity of TSH-dependent and -independent mechanisms within a network of interacting positive and negative signals (reviewed in Ref. 5). There is no doubt that TSH is not only involved in the control of differentiated functions, including expression of thyroid-specific genes and several housekeeping genes, but that it also regulates the expression of growth factors and their receptors (reviewed in Refs. 5, 6). This has been demonstrated, for example, for the expression of epidermal growth factor (EGF) receptors, which is increased by TSH stimulation (7), and for insulin-like growth factor I (IGF-I)-dependent signaling (8). Indeed, TSH promotes the insulin IGF-I signaling system by three separate mechanisms: TSH enhances the expression of IGF-I messenger ribonucleic acid (mRNA) (9) and insulin receptor mRNA (10), and decreases protein levels of different IGF-I-binding proteins (11), thereby probably raising the availability of free IGF-I (12). Moreover, exposure to TSH- or cAMP-elevating agents increased the responsiveness of thyroid cells to stimulation with insulin, IGF-I and IGF-II (10), and EGF (7).

Accumulated evidence indicates that IGF-I-dependent, TSH-independent signaling may be of major importance for growth regulation of the human thyroid gland. This assumption is supported by findings in conditions not accompanied by increased TSH secretion, such as in acromegaly, in which high intrathyroidal IGF-I levels may contribute to goiter development (13), and in part in patients with toxic thyroid adenomas (see below), whose growth is most likely modulated by IGF-I (14). Thus, on the one hand, TSH induces the expression of growth factors and their receptors and may contribute to an increased responsiveness to growth factor-stimulated tyrosine kinase signaling with consequent proliferation via pathways other than the cAMP cascade. On the other hand, as discussed below, growth factor expression may increase proliferation regardless of the prevailing TSH levels.


    TSH and growth of thyroid nodules and adenomas
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
The most striking evidence that thyroid growth may proceed without support from elevated TSH levels, or in the presence of very low TSH, comes from patients with nodular goiters whose TSH levels are suppressed as a consequence of functional autonomy with increased local production of thyroid hormones and subsequent inhibition of TSH secretion (15). There is even an inverse relationship between serum TSH levels and multinodular goiter size (16, 17, 18, 19). Thus, toxic nodular goiters may function and grow in the absence of significant TSH levels. Nevertheless, the cAMP signaling cascade may still be highly active at least in some nodules. This assumption is supported by recent findings of activating mutations of the cascade in a subset of toxic thyroid adenomas and hyperfunctioning goiter nodules (20). In these tumors, mutations in the TSH receptor or the Gs{alpha} gene have been detected that lead to constitutive activation of the TSH receptor-dependent adenylate cyclase cascade, thus replacing the stimulatory effect of TSH. There is compelling evidence that these mutations represent an initial step in the pathogenesis of some, but not all, toxic adenomas by altering the signaling network of the affected thyrocytes (21, 22).

These mutations alone, however, are insufficient to generate the tumors (21). Support for this claim comes from the clinical course of a number of thyroid diseases, including iodine deficiency goiter, Graves’ disease caused by chronic TSH receptor antibody-mediated stimulation (6, 23), autosomal dominant hyperthyroidism due to TSH receptor gene mutations with subsequent stimulation of the entire thyroid gland (24), and the above-mentioned examples of TSH-secreting pituitary adenomas and thyroid hormone resistance (1, 2). In all of these thyroid diseases, diffuse goiter develops at first, and nodular transformation may occur only secondarily and as a late event, often taking years or even decades (5, 6, 25). Yet, focal nodular growth cannot be explained solely by TSH receptor gene or Gs{alpha} gene mutation, which should in principle affect all thyrocytes to the same extent, nor can chronic TSH stimulation per se cause heterogeneous, i.e. multinodular, growth.

In addition, in vitro evidence argues against the assumption that activation of the adenylate cyclase cascade is sufficient to cause nodular transformation. In human thyrocytes held in primary culture, expression of the Gs{alpha} gene mutant under control of a retroviral vector did not increase the growth of transfected cells, demonstrating that the sole stimulatory effect of this mutant is too weak to induce cell proliferation (26). In contrast, transfected FRTL-5 cells expressing a cAMP-stimulating gene underwent neoplastic transformation when implanted into nude mice (27). The same investigators, however, when using transgenic mice expressing the same cAMP-stimulating gene in the thyroid, found hyperthyroidism and thyroid hyperplasia, but no evidence of neoplasia (28). This discrepancy may have been due to the use of an immortalized cell line, FRTL-5, which may have been altered by mutational events (28). Another study using transgenic mice expressing a cAMP-stimulating gene found hyperthyroid nodular transformation only as a late event in older animals (29).

The question therefore arises as to which secondary pathogenic mechanisms are operative that promote cellular growth with consequent nodule formation. As mentioned above, excessive constitutive synthesis of IGF-I may be involved in abnormal growth, at least in toxic adenomas (14). Furthermore, as noted above, TSH stimulates the insulin/IGF-I signaling system. As activating mutations of the TSH receptor or Gs{alpha} gene mimic and potentiate the effect of TSH, an enhanced activation of the mitogenic insulin/IGF-I pathway is likely to occur in toxic adenomas and nodules that harbor such mutations. Thus, autonomous overactivity of TSH-dependent cascades may represent only the first step in a sequence of other molecular events. At least in some nodular goiters and adenomas, additional mechanisms include an increased expression of EGF receptors (30, 31) and basic fibroblast growth factor (32), a decreased synthesis of growth inhibitory transforming growth factor-ß (TGF-ß) (33) and enhanced synthesis of Ras (34) and Gs{alpha} protein (22, 35). Moreover, it has been shown that constitutive resistance to the growth inhibitory effect of TGF-ß may not only occur in a subset of normal thyrocytes but may also be acquired by chronically exposed cells (36). Of particular relevance, TGF-ß resistance is very frequent in thyrocytes derived from human nodular goiters (36).

The rarity of toxic adenomas and nodular goiters in regions with sufficient iodine intake points to an important pathogenetic role of iodine deficiency in this disease. This is most likely a consequence of subtle, chronic stimulation of TSH-dependent signaling at the level of the TSH receptor or enhanced cAMP formation, which is decreased by the administration of iodine (4, 21). In addition, it has been demonstrated that different iodine compounds inhibit the signaling of growth-promoting pathways, e.g. the EGF receptor cascade (37). However, the physiological concentrations of the iodine compounds at the unknown site of intracellular action remain elusive. Additional evidence is required to determine whether the lack of such an inhibitory effect of iodine compounds may result in a relatively higher activity of growth-promoting pathways and thus contribute to the higher prevalence of goiter nodules and adenomas in regions with iodine deficiency.


    Cross-talk between TSH-dependent and -independent pathways in the growth and function of benign nodules
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
Besides the cAMP-protein kinase A (PKA) pathway, both the phospholipase C (PLC)-protein kinase C (PKC) and the protein tyrosine kinase cascades are implicated in the signal transduction pathways that control human thyroid cell growth and function (38). The complexity of the interactions of these pathways is particularly well illustrated by experiments conducted with human thyroid follicles prepared from colloid nodular tissue (39, 40).

The above studies lead to the following conclusions. EGF, acting via tyrosine kinase, and activation of PKC inhibit cell function (iodide uptake, organification, and thyroid hormone secretion) induced by the TSH-PKA pathway. (39). The TSH-PKA cascade is mitogenic, but much less so than the PKC and EGF-tyrosine kinase pathways, as judged by measuring cell growth as well as human thyroid cell proliferation-associated c-jun and c-fos gene expression (39, 40). Because PKA inhibits the PKC and EGF-tyrosine kinase pathways in this (39, 40) and other systems (reviewed in Refs. 41, 42), it is therefore not surprising that the net effect of combined TSH-PKA and PKC or EGF-tyrosine kinase action regarding cell proliferation and c-jun, c-fos gene expression was, albeit still mitogenic, decreased rather than additive compared to the PKC or EGF-tyrosine kinase cascades alone (39, 40). The above results are summarized in Table 1Go. The mechanism(s) underlying the antagonistic interactions between TSH-PKA and PKC or EGF-tyrosine kinase signaling pathways remains to be determined. Also unknown is whether TSH at high concentration stimulates the PKC pathway in these cells derived from colloid nodules as has been demonstrated in normal human thyrocytes (43).


View this table:
[in this window]
[in a new window]
 
Table 1. Interactions of TSH-dependent and -independent pathways in the control of growth and function of human thyrocytes derived from benign colloid nodules (39 40 )

 
There is a large body of literature dealing with the cross-talk between Ras and PKA. In some cells, cAMP stimulates the mitogen-activated protein kinase (MAPK) cascade, whereas in others, cAMP inhibits Ras signaling through Raf and MAPK (reviewed in Ref. 44). In human thyrocytes, Ras exhibits a growth stimulatory and partially oncogenic effect (45, 46). In addition, it has been demonstrated that both Ras and PKA activity are required for the mitogenic effect of TSH (47), although TSH down-regulates signaling through Raf and the MAPK cascade (48, 49). These results indicate that cAMP displays differential effects on distinct Ras effector pathways in thyroid cells (48). Using specific Ras mutants, Miller and co-workers recently demonstrated that rat thyrocytes expressing Ras mutants that are competent to bind to Raf grew more slowly in the presence than in the absence of TSH, whereas Ras mutants that bind RalGDS, the Ras-related protein Ral, increased their growth rate in the presence of TSH (48). These results again support the concept that TSH-dependent cAMP synthesis is only one player in a complex growth-regulating signal network.


    TSH-suppressive therapy for treatment of thyroid nodules
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
The justification for levothyroxine (L-T4) administration with the aim of suppressing TSH long enough so as to decrease the size or arrest the growth of thyroid nodules has been a highly controversial issue (reviewed in Refs. 50, 51). Most of the current evidence seems to suggest that thyroid hormone therapy is not effective in shrinking the majority of thyroid nodules (51). Furthermore, the high incidence of a spontaneous decrease in nodule size without any therapy together with the adverse skeletal and cardiac effects associated with long term L-T4 administration has led most clinical investigators to recommend the routine use of L-T4 only in selected patients with thyroid nodules (reviewed in Refs. 50, 51). Indeed, in a recent comprehensive review of the literature, Gharib and Mazzaferri concluded that the potential risks of long term L-T4 therapy outweigh the potential benefits in most patients, especially in postmenopausal women (52).

The clinical experience mentioned above fits in well with the concept that TSH-dependent signaling is but one link in a complex network of interacting signals that regulate thyroid growth. Indeed, there are additional findings that argue against a dominant role of TSH-dependent signaling in cold benign nodules and nodular goiters. First, it has been demonstrated that cold thyroid nodules, in contrast to some, but not all, toxic thyroid adenomas, do not harbor any activating mutations in the TSH receptor (53). Second, widely varying basal and TSH-stimulated cAMP levels have been determined in different regions within single nodular goiters (54). Finally, in nonfunctioning adenomas, both normal expression and overexpression of Gs{alpha} protein have been reported (35). The clinical evidence mentioned previously of an inverse relationship between TSH level and multinodular goiter size is also relevant in this regard. All of these observations lead to the conclusion that at least a fraction of all thyroid nodules and tumors grow independently of TSH-induced signal transduction.


    TSH and growth of thyroid carcinomas
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
In some studies, TSH displayed an inhibitory influence on the growth of thyroid carcinoma cells (55, 56). In contrast, TSH has also been reported (57) as mitogenic (via PKC stimulation) or devoid of any effect (58, 59, 60, 61) on the proliferation of thyroid carcinoma cells. Regarding signal transduction mechanisms, the PKC (57) and EGF-tyrosine kinase pathways (58, 61, 62) enhanced thyroid carcinoma cell proliferation, although an antimitogenic effect of EGF has also been reported (55). Many (56, 58, 59, 62, 63, 64), but not all (57), reports have noted growth inhibition of thyroid carcinoma cells by the cAMP pathway, and a recent study (60) indicated a ß-adrenergic receptor- rather than TSH receptor-mediated pathway of cAMP production and consequent inhibition of thyroid carcinoma cell proliferation. Some studies have demonstrated the pivotal role of the PLC-PKC pathway in the pathogenesis of some thyroid neoplasms (65), and that costimulation of both the PLC and adenylate cyclase-cAMP pathways promotes malignant transformation of thyroid follicular cells in transgenic mice (66).

Although our knowledge of TSH-dependent signaling in differentiated thyroid carcinoma tissue is still fragmentary, it seems that almost all papillary and follicular carcinomas express TSH receptor mRNA, albeit at varying levels (67, 68). However, even if functional TSH receptors are expressed, TSH-dependent signaling may be profoundly disrupted in thyroid cancer. This has been demonstrated for both the TSH receptor-Gs{alpha} protein-adenylate cyclase cascade as well as for the TSH receptor-Gq protein-PLC pathway. In the Gs{alpha}-adenylate cyclase cascade, a functional disruption between the TSH receptor and Gs{alpha} (59) or between Gs{alpha} and adenylate cyclase activity may occur (22, 35), whereas aberrant TSH-stimulated Gq-PLC activity has been described in thyroid cancers in vivo and in vitro (65, 69). There is evidence that the interruption of the TSH receptor-Gq-PLC signaling is due to high protein kinase C activity, possibly provoked by simultaneous overactivation of growth factor receptors, such as EGF receptors (69).


    Thyroid hormone treatment of thyroid carcinomas
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
Patients with thyroid carcinomas are treated with L-T4 for two recognized reasons: to avoid hypothyroidism after surgical and radioiodine treatment and to suppress alleged TSH-promoted tumor growth. There may be an additional justification, however, for L-T4 treatment in these patients. This is because TSH is the most important regulator of gene expression in normal thyrocytes and presumably also in thyroid carcinoma cells that are known to maintain, albeit at a variable degree, expression of thyroid-specific genes (67) and expression of other cAMP-dependent genes, e.g. the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene (70). Therefore, even if L-T4 therapy does not affect the growth of these carcinomas, it seems advisable to maintain a TSH-suppressive therapy, because suppression of at least some TSH-dependent gene expression in the tumor cells may also be of benefit for the prognosis of these tumors.

Thyroid hormone treatment has been shown, although not unanimously, to result in fewer recurrences and a lower mortality rate (reviewed in Ref. 71). Controversy continues, however, regarding the optimal dose of thyroid hormone required to achieve TSH suppression, mainly because prolonged T4 overreplacement may lead to an increased risk of osteoporosis and adverse effects on cardiac function even in the absence of overt hyperthyroid symptoms (reviewed in Refs. 50, 71, 72, 73). Many investigators have suggested that for low risk thyroid cancer patients, TSH levels should be held at or just below normal limits (50, 71, 72, 74), whereas others have recommended a high level of TSH suppression (75).


    Intratumoral heterogeneity of growth mechanisms: a phenomenon independent of TSH
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
Almost all studies on thyroid cell lines, monolayer or follicle cultures, and tissue homogenates assume that all cells of a growing tissue proliferate homogeneously according to a similar metabolic pattern. This assumption is most likely to be incorrect. Two points mentioned above can serve to illustrate this claim. First, both basal and TSH-dependent adenylate cyclase activities may vary markedly between different samples taken from the same goiter (54). Second, resistance to TGF-ß is also variable between cells of a given nodule (36). Moreover, experimental evidence obtained with thyrocyte cultures (76), as well as immunohistochemical studies on goiter nodules (77), demonstrate that thyroid growth proceeds within small clusters of coordinated cells that replicate by irregularly spaced growth spurts alternating with quiescent intervals. This growth pattern cannot solely depend on TSH, but, rather, substantiates the existence of intercellular regulatory mechanisms.


    Integration of TSH-dependent signaling at the nuclear level and thyroid growth
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
The final step in the cAMP signaling cascade is very frequently the activation of the cAMP-responsive transcription factor CREB (cAMP-responsive element-binding protein) and CREM (cAMP-responsive element modulator) that control transcription of cAMP-responsive genes (78, 79). Activation of CREB and CREM occurs after phosphorylation of serine residues located in the transcriptional activation domain (80, 81). However, activation of CREB and CREM is not restricted to phosphorylation by the cAMP-dependent PKA, but may also be mediated by other protein kinases, e.g. PKC, casein kinase II, or growth factor-dependent CREB kinase (81, 82). An integration of various signaling pathways by cAMP-responsive transcription factors may also be effective in thyroid cells. Indeed, an enhanced phosphorylation of CREB in response to both TSH as well as 12-O-tetraphorbol 12-myristate 13-acetate-stimulated PKC has been demonstrated in thyroid cells (83). Further studies on the integration of various signals by cAMP-responsive transcription factors may answer the question as to whether in thyroid tumor cells the integration of different pathways at the nuclear level may be altered.

To understand the role of TSH-dependent signaling at the nuclear level in the pathogenesis of thyroid nodules and tumors, two other questions have to be addressed. First, it is still unknown how activation of the cAMP-dependent pathway enhances insulin receptor and EGF receptor expression and decreases levels of IGF-binding proteins, as no cAMP-responsive sequence motifs have been shown in the promoters of genes that encode these genes (84, 85). One exception is the IGF-I gene whose expression is stimulated by TSH and in which the cAMP-responsive sequence in the promoter region of the gene has been described; this is most likely responsible for its cAMP-dependent transcriptional regulation (86). Second, the direct effect of cAMP on the cell cycle-related protein, cyclin, remains to be elucidated. Indeed, cAMP response elements have been described in the promoters of cyclin D1 and cyclin A genes (87, 88). In addition, in FRTL-5 cells activation of the cAMP cascade has been demonstrated to affect the cell cycle in that it decreases p27kip-1, an inhibitor of cyclin-dependent kinase-2 that is activated for entry into the S phase of the cell cycle (89). However, in primary cultures of thyroid epithelial cells the contrary was found, i.e. a paradoxical accumulation of p27kip-1 inhibitor during the cAMP-dependent mitogenic stimulation (90). Finally, there is evidence that other cAMP-dependent, as yet unknown, signaling pathways that do not result in CREB phosphorylation may contribute to the control of thyroid gene expression and modulate thyroid growth (91).


    Conclusions
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 
This survey has attempted to summarize, with no claim to comprehensiveness, some of the major strides made toward understanding the mechanisms that link TSH-dependent and -independent human thyroid cell growth in neoplastic thyroid disease. A major conclusion is the demonstration that TSH is but one of many factors in pathological thyroid growth and, even more relevant, that thyroid tumors may well evolve in the absence of TSH stimulation. Major gaps still remain, in particular with regard to thyroid carcinomas. Progress in this field will probably depend on fresh methodological approaches to overcome the limitations of sole reliance on cell lines and tissue homogenates. These issues are of practical clinical importance to enable reaching valid recommendations with regard to TSH-suppressive therapy using thyroid hormone. As noted earlier, a subset of thyroid tumors grow independently of TSH, and others are even inhibited by TSH. This finding in addition to the adverse effects of long term T4 administration emphasize the necessity of setting proper guidelines to answer questions such as who should be selected for TSH-suppressive therapy with T4, for how long, and what should be the magnitude of TSH suppression.


    Acknowledgments
 
We thank Prof. Hugo Studer (Berne, Switzerland) for valuable and helpful discussions.


    Footnotes
 
1 This work was supported by the Charles Krown Research Fund (Israel), and the Dr. Mildred Scheel Foundation for Cancer Research (Bonn, Germany). Back

Received July 27, 1998.

Revised November 12, 1998.

Accepted November 20, 1998.


    References
 Top
 Introduction
 TSH and growth of...
 TSH and growth of...
 Cross-talk between TSH-dependent...
 TSH-suppressive therapy for...
 TSH and growth of...
 Thyroid hormone treatment of...
 Intratumoral heterogeneity of...
 Integration of TSH-dependent...
 Conclusions
 References
 

  1. Abs R, Stevenaert A, Beckers A. 1994 Autonomously functioning thyroid nodules in a patient with thyrotropin-secreting pituitary adenoma: possible cause-effect relationship. Eur J Endocrinol. 131:355–358.[Medline]
  2. Refetoff S, Weiss RE, Usala SJ. 1993 The syndromes of resistance to thyroid hormone. Endocr Rev. 14:348–399.[Medline]
  3. Cooper D. 1984 Antithyroid drugs. N Engl J Med. 311:1353–1362.[Abstract]
  4. Hintze G, Emrich D, Köbberling J. 1989 Treatment of endemic goitre due to iodine deficiency with iodine, levothyroxine or both: results of a multicentre trial. Eur J Clin Invest. 19:527–534.[Medline]
  5. Derwahl M, Studer H. 1998 Pathogenesis and treatment of multinodular goiter. In: Fagin JA, ed. Thyroid cancer. Boston/Dordrecht/London: Kluwer; 155–186.
  6. Studer H, Derwahl M. 1995 Mechanisms of nonneoplastic endocrine hyperplasia–a changing concept: a review focused on the thyroid gland. Endocr Rev. 16:411–426.[Abstract]
  7. Westermark K, Karlsson FA, Westermark B. 1985 Thyrotropin modulates EGF receptor function in porcine thyroid follicle cells. Mol Cell Endocrinol. 40:17–23.[CrossRef][Medline]
  8. Eggo MC, Bachrach LK, Burrow GN. 1990 Interaction of TSH, insulin and insulin-like growth factors in regulating thyroid growth and function. Growth Factors. 2:99–109.[Medline]
  9. Hofbauer LC, Rafferzeder M, Janssen OE, Gärtner R. 1995 Insulin-like growth factor I messenger ribonucleic acid expression in porcine thyroid follicles is regulated by thyrotropin and iodine. Eur J Endocrinol. 132:605–610.[Medline]
  10. Burikhanov R, Coulonval K, Pirson I, Lamy F, Dumont JE, Roger PP. 1996 Thyrotropin via cyclic AMP induces insulin receptor expression and insulin co-stimulation of growth and amplifies insulin and insulin-like growth factor signaling pathways in dog thyroid epithelial cells. J Biol Chem. 271:29400–29406.[Abstract/Free Full Text]
  11. Eggo MC, King WJ, Black EG, Sheppard MC. 1996 Functional human thyroid cells and their insulin-like growth factor-binding proteins: regulation by thyrotropin cyclic 3',5' adenosine monophosphate, and growth factors. J Clin Endocrinol Metab. 81:3056–3062.[Abstract]
  12. Clark R. 1997 The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocr Rev. 18:157–179.[Abstract/Free Full Text]
  13. Cheung NW, Boyages SC. 1997 The thyroid gland in acromegaly: an ultrasonographic study. Clin Endocrinol (Oxf). 46:545–549.[Medline]
  14. Williams DW, Williams ED, Wynford-Thomas D. 1989 Evidence for autocrine production of IGF-1 in human thyroid adenomas. Mol Cell Endocrinol. 61:139–143.[CrossRef][Medline]
  15. Studer H, Gerber H. 1991 Toxic multinodular goiter. In: Braverman LE, Utiger RE, eds. The thyroid, 6th ed. Philadelphia: Lippincott; 692–697, 1107–1117.
  16. Bregengard C, Kirkegaard C, Faber J, Poulsen S, Hasselstrom K, Sierbaek-Nielsen K, Friis Z. 1987 Relationships between serum thyrotropin, serum free thyroxine (T4) and 3,5,3'-triiodothyronine (T3), and the daily T4 and T3 production rates in euthyroid patients with multinodular goiter. J Clin Endocrinol Metab. 65:258–261.[Abstract]
  17. Fenzi GF, Ceccarelle C, Macchia E, et al. 1985 Reciprocal changes of serum thyroglobulin and TSH in residents of a moderate endemic goitre area. Clin Endocrinol (Oxf). 23:115–122.[Medline]
  18. Gemsenjäger E, Staub JJ, Girard J, Heitz PH. 1967 Preclinical hyperthyroidism in multinodular goiter. J Clin Endocrinol Metab. 43:810–816.[Abstract]
  19. Rieu M, Bekka S, Sambor B, Berrod JL, Fombeur JP. 1993 Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonic parameters in patients with non-toxic nodular goitre. Clin Endocrinol (Oxf). 39:67–71.[Medline]
  20. Paschke R, Ludgate M. 1997 The thyrotropin receptor in thyroid diseases. N Engl J Med. 337:1675–1681.[Free Full Text]
  21. Derwahl M. 1996 Editorial: TSH receptor and Gs{alpha} gene mutations in the pathogenesis of toxic thyroid adenomas: a note of caution. J Clin Endocrinol Metab. 81:1–3.[Medline]
  22. Derwahl M, Hamacher C, Russo D, et al. 1996 Constitutive activation of the Gs{alpha}-protein-adenylate cyclase pathway may not be sufficient to generate toxic thyroid. J Clin Endocrinol Metab. 81:1898–1904.[Abstract]
  23. Studer H, Huber G, Derwahl M, Fey P. 1989 Die Umwandlung von Basedowstrumen in Knotenkröpfe: ein Grund des Hyperthyreoserezidivs. Schweiz Med Wochenschr. 119:203–208.[Medline]
  24. Kopp P, van Sande J, Parma J, et al. 1995 Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin receptor gene. N Engl J Med. 332:150–154.[Free Full Text]
  25. Lemoine NR, Thurstin V. 1989 Experimental thyroid tumours. In: Wynford-Thomas D, Williams ED, eds. Thyroid tumours. London: Churchill Livingstone; 4–37.
  26. Ivan M. Ludgate M, Gire V, Bond JA, Wynford-Thomas D. 1997 An amphotropic retroviral vector expressing a mutant gsp oncogene: effects on human thyroid cells in vitro. J Clin Endocrinol Metab. 82:2702–2708.[Abstract/Free Full Text]
  27. Zeiger MA, Saji M, Caturegli P, Westra WH, Kohn LD, Levine MA. 1996 Transformation of rat thyroid cells stably transfected with cholera toxin A1 fragment. Endocrinology. 137:5392–5399.[Abstract]
  28. Zeiger MA, Saji M, Gusev Y, et al. 1997 Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice. Endocrinology. 138:3133–3140.[Abstract/Free Full Text]
  29. Michiels FM, Caillou B, Talbot M, et al. 1994 Oncogenic potential of guanine nucleotide stimulatory factor {alpha} subunit in thyroid glands of transgenic mice. Proc Natl Acad Sci USA. 91:10488–10492.[Abstract/Free Full Text]
  30. Di Carlo A, Mariano A, Pisano G, Parmeggiani U, Beguinot L, Macchia V. 1990 Epidermal growth factor and thyrotropin response in human thyroid tissues. J Endocrinol Invest. 13:293–299.[Medline]
  31. Mäkinen T, Pekonen F, Franssila K, Lamberg BA. 1988 Receptors for epidermal growth factor and thyrotropin in thyroid carcinomas. Acta Endocrinol (Copenh). 117:45–50.[Medline]
  32. Gärtner R, Veitenhansl M, Atkas J, Schophol D. 1996 Role of basic fibroblast growth factor in the pathogenesis of nodular goiter. Exp Clin Endocrinol Diabetes. 104:36–38.[Medline]
  33. Morosini PP, Taccaliti A, Montironi R, et al. 1996 TGF-ß1 immunohistochemistry in goiter: comparison of patients with recurrence or no recurrence. Thyroid. 6:417–422.[Medline]
  34. Aeschimann S, Kopp PA, Kimura ET, Zbaeren J, Tobler A, Fey MF, Studer H. 1993 Morphological and functional polymorphism within clonal thyroid nodules. J Clin Endocrinol Metab. 77:846–851.[Abstract]
  35. Hamacher C, Studer H, Zbaeren J, Schatz H, Derwahl M. 1995 Expression of functional stimulatory guanine nucleotide binding protein in nonfunctioning thyroid adenomas is not correlated to adenylate cyclase activity and growth of these tumors. J Clin Endocrinol Metab. 80:1724–1732.[Abstract]
  36. Asmis LM, Kaempf J, Von Gruenigen C, Kimura ET, Wagner HE, Studer H. 1996 Acquired and naturally occurring resistance of thyroid follicular cells to the growth inhibitory action of transforming growth factor-ß1 (TGF-ß1). J Endocrinol. 149:485–496.[Abstract]
  37. Gärtner R, Dugrillon A, Bechtner G. 1996 Evidence that iodolactones are the mediators of growth inhibition by iodine on the thyroid. Acta Med Austr. 23:47–51.
  38. Dumont JE, Lamy F, Roger P, Maenhaut C. 1992 Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiol Rev. 72:667–679.[Free Full Text]
  39. Kraiem Z, Sadeh O, Yosef M, Aharon A. 1995 Mutual antagonistic interaction between the thyrotropin (adenosine 3',5'-monophosphate) and protein kinase C/epidermal growth factor-tyrosine kinase pathways in cell proliferation and differentiation of cultured human thyroid follicles. Endocrinology. 136:585–590.[Abstract]
  40. Heinrich R, Kraiem Z. 1997 The protein kinase A pathway inhibits c-jun and c-fos protooncogene expression induced by the protein kinase C and tyrosine kinase pathways in cultured human thyroid follicles. J Clin Endocrinol Metab. 82:1839–1844.[Abstract/Free Full Text]
  41. Marx J. 1993 Two major signals pathways linked. Nature. 262:988–989.
  42. Graves LM, Lawrence Jr JC. 1996 Insulin, growth factors, and cAMP. Antagonism in the signal transduction pathways. Trends Endocrinol Metab. 7:43–50.[CrossRef]
  43. Laurent E, Mockel J, Van Sande J, Graff I, Dumont JE. 1987 Dual activation by thyrotropin of phospholipase C and cyclic AMP cascades in human thyroid. Mol Cell Endocrinol. 52:273–278.[CrossRef][Medline]
  44. Burgering BMT, Bos JL. 1995 Regulation of Ras-mediated signalling: more than one way to skin a cat. Trends Biochem Sci. 20:18–22.[CrossRef][Medline]
  45. Meinkoth JL, Dela-Cruz J, Burrow GN. 1991 TSH, IGF-1 and activated ras protein induce DNA synthesis in cultured thyroid cells. Thyroidology. 3:103–107.[Medline]
  46. Burns JS, Blaydes JP, Wright Pa, Lemoine L, Bond JA, Williams ED, Wynford-Thomas D. 1992 Stepwise transformation of primary thyroid epithelial cells by a mutant Ha-ras oncogene: an in vitro model of tumor progression. Mol Carcinog. 6:129–139.[Medline]
  47. Kupperman E, Wen W, Meinkoth JL. 1993 Inhibition of thyrotropin-stimulated DNA synthesis by microinjection of inhibitors of cellular ras and cyclic AMP-dependent protein kinase. Mol Cell Biol. 13:4477–4484.[Abstract]
  48. Miller MJ, Rioux L, Prendergast GV, Cannon S, White MA, Meinkoth JL. 1998 Differential effects of protein kinase A on ras effector pathways. Mol Cell Biol. 18:3718–3726.[Abstract/Free Full Text]
  49. Al-Alawi N, Rose DW, Buckmaster C, Ahn N, Rapp U, Meinkoth J, Feramisco JR. 1995 Thyrotropin-induced mitogenesis is Ras dependent but appears to bypass the Raf-dependent cytoplasmic kinase cascade. Mol Cell Biol. 15:1162–1168.[Abstract]
  50. Singer PA, Cooper DS, Daniels GH, et al. 1996 Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med. 156:2165–2172.[Abstract]
  51. Gharib H. 1997 Changing concepts in the diagnosis and management of thyroid nodules. Endocrinol Metab Clin North Am. 26:777–800.[Medline]
  52. Gharib H, Mazzaferri EL. 1998 Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med. 128:386–394.[Abstract/Free Full Text]
  53. Matsuo K, Friedman E, Gejman PV, Fagin JA. 1993 The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the {alpha}-subunit of Gs in human thyroid neoplasms. J Clin Endocrinol Metab. 76:1446–1451.[Abstract]
  54. Rentsch H, Studer H, Frauchiger B, Siebenhüner L. 1981 Topographical heterogeneity of basal and thyrotropin-stimulated adenosine 3'5'-monophosphate in human nodular goiter. J Clin Endocrinol Metab. 53:514–521.[Medline]
  55. Ain KB, Taylor KD. 1994 Somatostatin analogs affect proliferation of human thyroid carcinoma cell lines in vitro. J Clin Endocrinol Metab. 78:1097–1102.[Abstract]
  56. Gustavsson B, Hermansson A, Andersson AC, Grimelius L, Bergh J, Westermark B, Heldin NE. 1996 Decreased growth rate and tumour formation of human anaplastic thyroid carcinoma cells transfected with a human thyrotropic receptor cDNA in NMRI nude mice treated with propylthiouracil. Mol Cell Endocrinol. 121:143–151.[CrossRef][Medline]
  57. Hoelting T, Tezelman S, Siperstein AE, Duh QY, Clark OH. 1993 Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC-rather than PKA-activation. Biochem Biophys Res Commun. 195:1230–1236.[CrossRef][Medline]
  58. Heldin NE, Crejic D, Smeds S, Westermark B. 1991 Expression of functionally active receptors for thyrotropin and platelet-derived growth factor in human thyroid carcinoma cells. Endocrinology. 129:2187–2193.[Abstract]
  59. Kimura H, Yamashita S, Namba H, et al. 1992 Impairment of the TSH signal transduction system in human thyroid carcinoma cells. Exp Cell Res. 203:402–406.[Medline]
  60. Ohta K, Pang XP, Berg L, Hershman JM. 1997 Growth inhibition of new human thyroid carcinoma cell lines by activation of adenylate cyclase through the ß-adrenergic receptor. J Clin Endocrinol Metab. 82:2633–2638.[Abstract/Free Full Text]
  61. Hoelting T, Siperstein AE, Clark OH, Duh QY. 1994 Epidermal growth factor enhances proliferation, migration and invasion of follicular and papillary thyroid cancer in vitro and in vivo. J Clin Endocrinol Metab. 79:401–408.[Abstract]
  62. Hishinuma A, Yamanaka T, Kasai K, So S, Bamba N, Shimoda SI. 1994 Growth regulation of the human papillary thyroid cancer cell line by protein kinase and cAMP-dependent protein kinase. Endocr J. 41:399–407.[Medline]
  63. Broecker M, Derwahl M. 1992 Thyrotropin receptor and growth of thyroid carcinomas. Exp Clin Endocrinol. 100:57–61.[Medline]
  64. Derwahl M, Kuemmel M, Goretzki P, Schatz H, Broecker M. 1993 Expression of the human TSH receptor in a human thyroid carcinoma cell line that lacks an endogenous TSH receptor: growth inhibition by cAMP. Biochem Biophys Res Commun. 191:1131–1138.[CrossRef][Medline]
  65. Shaver JK, Tezelman S, Siperstein AE, Duh QY, Clark OH. 1993 Thyroid-stimulating hormone activates phospholipase C in normal and neoplastic thyroid tissue. Surgery. 114:1064–1069.[Medline]
  66. Ledent C, Denef JF, Cottecchia S, Lefkowitz R, Dumont J, Vassart G, Parmentier M. 1997 Costimulation of adenylyl cyclase and phospholipase C by a mutant {alpha}1B-adrenergic receptor transgene promotes malignant transformation of thyroid follicular cells. Endocrinology. 138:369–378.[Abstract/Free Full Text]
  67. Brabant G, Maenhaut C, Köhrle J, et al. 1991 Human thyrotropin receptor gene: expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation. Mol Cell Endocrinol. 82:R7–R12.
  68. Shi Y, Zou M, Farid NR. 1993 Expression of thyrotropin receptor gene in thyroid carcinoma is associated with good prognosis. Clin Endocrinol (Oxf). 39:269–274.[Medline]
  69. Broecker M, Mayr G, Derwahl M. 1997 Suppression of thyrotropin receptor-G protein-phospholipase C coupling by activation of protein kinase C in thyroid carcinoma cells. Endocrinology. 138:3787–3796.[Abstract/Free Full Text]
  70. Bifulco M, Perillo B, Saji M, Laezza C, Tedesco I, Kohn LD, Aloj SM. 1995 Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in FRTL-5 cells. J Biol Chem. 270:15231–15236.[Abstract/Free Full Text]
  71. Dulgeroff AJ, Hershman JM. 1994 Medical therapy for differentiated thyroid carcinoma. Endocr Rev. 15:500–515.[Abstract]
  72. Burmeister LA. 1994 Thyroid hormone in the treatment of thyroid cancer. Thyroid Today. 17:1–9.
  73. Solomon BL, Wartowsky L, Burman KD. 1996 Current trends in the management of well differentiated papillary thyroid carcinoma. J Clin Endocrinol Metab. 81:333–339.[Abstract]
  74. Burmeister LA, Goumaz MA, Mariash CN, Oppenheimer JH. 1992 Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab. 75:344–350.[Abstract]
  75. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol C. 1996 Degree of thyrotropin suppression as prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab. 81:4318–4322.[Abstract]
  76. Derwahl M, Studer H, Huber G, Gerber H, Peter HJ. 1990 Intercellular propagation of individually programmed growth bursts in FRTL-5 cells. Implications for interpreting growth factor actions. Endocrinology. 127:2104–2110.[Abstract]
  77. Studer H, Peter HJ, Gerber H. 1989 Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr Rev. 10:125–135.[Medline]
  78. Meyer TE, Habener JF. 1993 Cyclic AMP response element binding protein CREB and related transcription-activating DNA-binding proteins. Endocr Rev. 14:269–290.[Medline]
  79. Lalli E, Sassone-Corsi P. 1994 Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem. 269:17359–17362.[Free Full Text]
  80. Gonzales GA, Montminy MR. 1989 Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at Ser 133. Cell. 59:675–680.[Medline]
  81. De Groot RP, den Hertog J, Vandenheede JR, Goris J, Sassone-Corsi P. 1993 Multiple and cooperative phosphorylation events regulate the CREM activator function. EMBO J. 12:3903–3911.[Abstract]
  82. Xing J, Ginty DD, Greenberg ME. 1996 Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 273:959–963.[Abstract]
  83. Broecker M, Webers T, Sobke A, Hammer J, Derwahl M. 1998 The PKA pathway and tyrosine kinase-dependent pathways modulate activation of the transcription factor CREB and expression of the inducible cAMP early repressor ICER in thyroid cells. J Endocrinol Invest. 21(Suppl):85.
  84. Werner H, Rauscher III FJ, Sukhatme VP, Drummond IA, Roberts Jr CT, LeRoith D. 1994 Transcriptional repression of the insulin-like growth factor I receptor (IGF-I-R) gene by the tumor suppressor WT1 involves binding to sequences both upstream and downstream of the IGF-I-R gene transcription start site. J Biol Chem. 269:12577–12582.[Abstract/Free Full Text]
  85. Johnson AC, Ishii S, Jinno Y, Pastan I, Merlino GT. 1988 Epidermal growth factor receptor gene promoter. Deletion analysis and identification of nuclear protein binding sites. J Biol Chem. 263:5693–5699.[Abstract/Free Full Text]
  86. Thomas MJ, Kikuchi K, Bichell DP, Rotwein P. 1994 Rapid activation of rat insulin-like growth factor-I gene transcription by growth hormone reveals no alterations in deoxyribonucleic acid-protein interactions within the major promoter. Endocrinology. 135:1584–1592.[Abstract]
  87. Desdouets C, Matesic G, Molina CA, Foulkes NS, Sassone-Corsi P, Brechot C, Sobzak-Thepot J. 1995 Cell cycle regulation of cyclin A gene expression by cyclic AMP-responsive transcription factors CREB and CREM. Mol Cell Biol. 15:3301–3309.[Abstract]
  88. Herber B, Truss M, Beato M, Müller R. 1994 Inducible regulatory elements in the human cyclin D1 promoter. Oncogene. 9:1295–1304.[Medline]
  89. Hirai A, Nakamura S, Noguchi Y, et al. 1997 Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells. J Biol Chem. 272:13–16.[Abstract/Free Full Text]
  90. Depoortere F, Dumont JE, Roger PP. 1996 Paradoxical accumulation of the cyclin-dependent kinase inhibitor p27kip1 during the cAMP-dependent mitogenic stimulation of thyroid epithelial cells. J Cell Sci. 109:1759–1764.[Abstract/Free Full Text]
  91. Dremier S, Pohl V, Poteet-Smith C, et al. 1997 Activation of cyclic AMP-dependent kinase is required but may not be sufficient to mimic cyclic AMP-dependent DNA synthesis and thyroglobulin expression in dog thyroid cells. Mol Cell Biol. 17:6717–6726.[Abstract]