T h y ro t ro p i n i n t h e D e v e l o p m e n t an d M a n a g e m e n t o f D i ff e re n t i a t e d T h y ro i d C a n c e r Donald S.A. McLeod,
MBBS, FRACP, MPH
a,b,c,
*
KEYWORDS Thyrotropin Thyroid cancer Recombinant human TSH Thyroid hormone TSH KEY POINTS Thyrotropin (TSH) is the major growth factor and regulator of the thyroid. Further research is required to definitely show that higher serum TSH causes human thyroid cancer, whether prediagnostic serum TSH predicts ultimate prognosis, and how best to use serum TSH in determining which patients with thyroid nodules should undergo biopsy. TSH is important in the management of thyroid cancer, with TSH stimulation of thyroid cells (either by thyroid hormone withdrawal or recombinant human [rh]-TSH) facilitating radioiodine uptake and detection of occult persistent thyroid tissue via release of serum thyroglobulin. The development of rh-TSH was an important advance in thyroid cancer management, permitting TSH stimulation to occur without hypothyroidism, albeit at greater financial cost. Further work is required to prove that rh-TSH is equivalent to thyroid hormone withdrawal in patients with metastatic disease. A risk-benefit approach to TSH targets in thyroid cancer management may maximize clinical benefit of this therapy while minimizing complications.
Funding Source: Cancer Council Queensland. Conflict of Interest: Nil. a Department of Internal Medicine & Aged Care, Royal Brisbane & Women’s Hospital, Level 3, Dr James Mayne Building, Herston, Queensland 4029, Australia; b Department of Endocrinology, Royal Brisbane & Women’s Hospital, Level 1, Dr James Mayne Building, Herston, Queensland 4029, Australia; c Department of Population Health, QIMR Berghofer Medical Research Institute, Herston Road, Herston, Queensland 4029, Australia * Department of Internal Medicine & Aged Care, Level 1, Dr James Mayne Building, Royal Brisbane & Women’s Hospital, Herston, Queensland 4029, Australia. E-mail address: [email protected] Endocrinol Metab Clin N Am 43 (2014) 367–383 http://dx.doi.org/10.1016/j.ecl.2014.02.012 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
368
McLeod
INTRODUCTION
Over the past decade, knowledge of the potential role of TSH in the development of differentiated thyroid cancer has expanded. In addition, the therapeutic role of TSH has continued to evolve. This review synthesizes current knowledge of TSH in both the development and management of differentiated thyroid cancer. TSH BIOLOGY History
The crucial role of the anterior pituitary in thyroid growth and function was recognized in the early twentieth century, initially with studies in amphibians,1–3 followed by demonstration in mammals.4,5 TSH was identified as a distinct hormone secreted from the anterior pituitary shortly after,6 although it took until 1971 before its structure was elucidated.7 Physiology of TSH
TSH is the major regulator and growth factor of the thyroid. The approximately 28-kDa glycoprotein heterodimer is secreted under negative feedback from thyroid hormone, which occurs at both the levels of the pituitary and the hypothalamus (inhibiting secretion of TSH-releasing hormone, which as the name suggests, prompts release of TSH from the anterior pituitary).8 TSH controls the processes that lead to increased thyroid hormone production and secretion from follicular thyroid cells. These include increasing the number, size, and secretory activity of thyrocytes; increasing the activity of the sodium-iodide symporter (NIS); increasing the organification of iodide; increasing the cleavage and release of preformed thyroid hormone from thyroglobulin; and increasing thyroid blood flow.9 TSH does not influence parafollicular C-cells; therefore, it does not affect medullary thyroid cancer cells, and all subsequent discussion of thyroid cancer in this article refers to differentiated thyroid cancer (papillary and follicular thyroid cancer), which develops from thyroid follicular cells. TSH exerts its effect by binding to the TSH receptor, a G protein–coupled receptor on the thyrocyte surface (Fig. 1). Classical TSH actions are mainly mediated through the Gas–adenylyl cyclase–protein kinase A–cyclic adenosine monophosphate (cAMP) second messenger system, with some actions through the Gaq/11-inositol phosphate/ diacylglycerol-protein kinase C pathway.10 It has also been recognized, however, that TSH can cross-talk with many other cell signaling pathways, including those known to be associated with thyroid cancer development, including the mitogen-activated protein (MAP) kinase system11 and phosphoinositide 3-kinase (PI3-K) system.11,12 Other factors may also play a role in regulating thyroid function, at least in experimental models. These include insulin, insulin-like growth factor 1, epidermal growth factor, transforming growth factor b, phorbol esters, fibroblast growth factor, and hepatocyte growth factor.10 TSH AND THYROID CANCER DEVELOPMENT
The role of TSH in thyroid biology makes it an appealing candidate as a possible cause of thyroid cancer. Evidence for this has accumulated over the past decade in animal models and human clinical studies. Animal Model Evidence
Follicular thyroid cancer has been assessed in mice using a knock in mutation to the thyroid hormone receptor-b gene (TRbPV)13–16 that causes a dominant negative
TSH in Differentiated Thyroid Cancer
Fig. 1. Simplified model of TSH signaling pathways. TSH binds to its transmembrane receptor, which is coupled to G-protein complexes. Binding of TSH to the receptor leads to transmembrane conformational change, such that GTP binds the Ga, which then dissociates from the complex so it can interact with second messenger targets. The Gas–adenylyl cyclase–PKA– cAMP pathway is depicted on the right. Here, the GTP-bound Gas activates the membraneassociated PKA. PKA amplifies the TSH signal by catalyzing the conversion of ATP to cAMP, which in turn activates PKA. Targets of PKA are effectors of many of the classical TSH-dependent actions of thyroid cells. PKA also stimulates with other second messenger systems important in thyroid cancer, including the PI3K/AKT and the MAP kinase systems. The Gaq/11-IP3/DAG-PKC pathway is depicted on the left. Here, the Gaq activates phospholipase C, which generates 2 second messengers, DAG and IP3. These in turn activate protein kinase C and release of stored Ca21, respectively, effecting other TSH-dependent cellular actions. Gbg also seems to directly stimulate PI3K, hence activating the PI3K/AKT system. AC, adenylyl cyclase; ATP, adenosine triphosphate; BL, basolateral; Ca21, calcium ions; cAMP, cyclic adenosine monophosphate; CREB, cAMP responsive element binding protein; DAG, diacylglycerol; GTP, guanosine triphosphate; H2O2, hydrogen peroxide; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; NIS, sodium iodide symporter; P13K, P13 kinase; PIP2, phosphatidylinositol 4,5-biphosphate; PLC, phospholipase C; SR, sarco/endoplasmic reticulum; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH, thyrotropin.
frameshift in TRb.17 These mice develop a thyroid hormone resistance syndrome with an elevated non-suppressible TSH, and homozygotes (TRbPV/PV) manifest spontaneous metastatic follicular thyroid cancer.13 In this model, TSH receptor pathway signaling is necessary for thyroid cancer development, because when TRbPV/PV mice are crossed with knockout mice for the TSH receptor (TSHR–/–), offspring do not develop thyroid cancer.14 In wild-type mice (ie, no thyroid hormone resistance), however, when TSH is elevated by treatment with propylthiouracil, no metastatic thyroid cancer ensues.14 Treatment of heterozygous thyroid hormone–resistant mice (TRbPV/1; who do not ordinarily develop cancer) with propylthiouracil generates asymmetric follicular thyroid cancer with frequent metastases.16 Therefore, TSH is necessary but not sufficient to produce follicular cancer in mice; additional activation
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of permissive cell signaling pathways is required. In these mice, activating the PI3-K/AKT cascade seems crucial in disease development.15,18,19 Animal model evidence also exists for TSH signaling influencing papillary thyroid cancer. Using a mouse model with knock in of BRAFV600E (LSL- BRAFV600E/TPOCre) that produced early and aggressive papillary cancer, Franco and colleagues20 found that crossing mice with TSHR–/– mice led to marked delay in cancer development, with subsequent tumors being indolent. The effect of TSH on cancer development was mediated through the classical Gas pathway, because inhibiting Gas function had similar effects to the TSHR–/– experiments. Suppressing TSH with levothyroxine therapy did not revert the BRAFV600E phenotype, indicating that TSH signaling was most important in thyroid cancer initiation. Clinical Evidence
Boelaert and colleagues21 first reported higher serum TSH concentration predicted human thyroid cancer in 2006 (Fig. 2). Since then, many cross-sectional studies have assessed clinical data for an association between serum TSH concentration and thyroid cancer. Most, but not all, studies confirm the association.22,23 In doseresponse meta-analysis, the relationship was present from subnormal levels through the normal range and above.23 The effect seemed largest at lower TSH levels, with a 3-times greater odds ratio of thyroid cancer between a TSH of 4 mU/L compared with 0 mU/L, although the odds ratio still doubled between 2.2 and 7 mU/L. Major problems remain, however, with interpreting results of the diagnostic studies: (1) all are cross-sectional and (2) there is often incomplete assessment of potential confounding. Without adequately addressing these issues, it remains unclear whether serum TSH is a cause or simply a predictor of human thyroid cancer. Being a predictor of thyroid cancer diagnosis may have clinical applications (discussed later) but would be
Fig. 2. Prevalence of thyroid cancer from Boelaert and colleagues,21 according to the serum TSH concentration measured at presentation in 1183 subjects with normal serum free thyroxine concentrations, indicating increased prevalence in those with higher TSH. *, P 5 .05; **, P 5 .01; ***, P 5 .001, compared with TSH
MBBS, FRACP, MPH
a,b,c,
*
KEYWORDS Thyrotropin Thyroid cancer Recombinant human TSH Thyroid hormone TSH KEY POINTS Thyrotropin (TSH) is the major growth factor and regulator of the thyroid. Further research is required to definitely show that higher serum TSH causes human thyroid cancer, whether prediagnostic serum TSH predicts ultimate prognosis, and how best to use serum TSH in determining which patients with thyroid nodules should undergo biopsy. TSH is important in the management of thyroid cancer, with TSH stimulation of thyroid cells (either by thyroid hormone withdrawal or recombinant human [rh]-TSH) facilitating radioiodine uptake and detection of occult persistent thyroid tissue via release of serum thyroglobulin. The development of rh-TSH was an important advance in thyroid cancer management, permitting TSH stimulation to occur without hypothyroidism, albeit at greater financial cost. Further work is required to prove that rh-TSH is equivalent to thyroid hormone withdrawal in patients with metastatic disease. A risk-benefit approach to TSH targets in thyroid cancer management may maximize clinical benefit of this therapy while minimizing complications.
Funding Source: Cancer Council Queensland. Conflict of Interest: Nil. a Department of Internal Medicine & Aged Care, Royal Brisbane & Women’s Hospital, Level 3, Dr James Mayne Building, Herston, Queensland 4029, Australia; b Department of Endocrinology, Royal Brisbane & Women’s Hospital, Level 1, Dr James Mayne Building, Herston, Queensland 4029, Australia; c Department of Population Health, QIMR Berghofer Medical Research Institute, Herston Road, Herston, Queensland 4029, Australia * Department of Internal Medicine & Aged Care, Level 1, Dr James Mayne Building, Royal Brisbane & Women’s Hospital, Herston, Queensland 4029, Australia. E-mail address: [email protected] Endocrinol Metab Clin N Am 43 (2014) 367–383 http://dx.doi.org/10.1016/j.ecl.2014.02.012 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
368
McLeod
INTRODUCTION
Over the past decade, knowledge of the potential role of TSH in the development of differentiated thyroid cancer has expanded. In addition, the therapeutic role of TSH has continued to evolve. This review synthesizes current knowledge of TSH in both the development and management of differentiated thyroid cancer. TSH BIOLOGY History
The crucial role of the anterior pituitary in thyroid growth and function was recognized in the early twentieth century, initially with studies in amphibians,1–3 followed by demonstration in mammals.4,5 TSH was identified as a distinct hormone secreted from the anterior pituitary shortly after,6 although it took until 1971 before its structure was elucidated.7 Physiology of TSH
TSH is the major regulator and growth factor of the thyroid. The approximately 28-kDa glycoprotein heterodimer is secreted under negative feedback from thyroid hormone, which occurs at both the levels of the pituitary and the hypothalamus (inhibiting secretion of TSH-releasing hormone, which as the name suggests, prompts release of TSH from the anterior pituitary).8 TSH controls the processes that lead to increased thyroid hormone production and secretion from follicular thyroid cells. These include increasing the number, size, and secretory activity of thyrocytes; increasing the activity of the sodium-iodide symporter (NIS); increasing the organification of iodide; increasing the cleavage and release of preformed thyroid hormone from thyroglobulin; and increasing thyroid blood flow.9 TSH does not influence parafollicular C-cells; therefore, it does not affect medullary thyroid cancer cells, and all subsequent discussion of thyroid cancer in this article refers to differentiated thyroid cancer (papillary and follicular thyroid cancer), which develops from thyroid follicular cells. TSH exerts its effect by binding to the TSH receptor, a G protein–coupled receptor on the thyrocyte surface (Fig. 1). Classical TSH actions are mainly mediated through the Gas–adenylyl cyclase–protein kinase A–cyclic adenosine monophosphate (cAMP) second messenger system, with some actions through the Gaq/11-inositol phosphate/ diacylglycerol-protein kinase C pathway.10 It has also been recognized, however, that TSH can cross-talk with many other cell signaling pathways, including those known to be associated with thyroid cancer development, including the mitogen-activated protein (MAP) kinase system11 and phosphoinositide 3-kinase (PI3-K) system.11,12 Other factors may also play a role in regulating thyroid function, at least in experimental models. These include insulin, insulin-like growth factor 1, epidermal growth factor, transforming growth factor b, phorbol esters, fibroblast growth factor, and hepatocyte growth factor.10 TSH AND THYROID CANCER DEVELOPMENT
The role of TSH in thyroid biology makes it an appealing candidate as a possible cause of thyroid cancer. Evidence for this has accumulated over the past decade in animal models and human clinical studies. Animal Model Evidence
Follicular thyroid cancer has been assessed in mice using a knock in mutation to the thyroid hormone receptor-b gene (TRbPV)13–16 that causes a dominant negative
TSH in Differentiated Thyroid Cancer
Fig. 1. Simplified model of TSH signaling pathways. TSH binds to its transmembrane receptor, which is coupled to G-protein complexes. Binding of TSH to the receptor leads to transmembrane conformational change, such that GTP binds the Ga, which then dissociates from the complex so it can interact with second messenger targets. The Gas–adenylyl cyclase–PKA– cAMP pathway is depicted on the right. Here, the GTP-bound Gas activates the membraneassociated PKA. PKA amplifies the TSH signal by catalyzing the conversion of ATP to cAMP, which in turn activates PKA. Targets of PKA are effectors of many of the classical TSH-dependent actions of thyroid cells. PKA also stimulates with other second messenger systems important in thyroid cancer, including the PI3K/AKT and the MAP kinase systems. The Gaq/11-IP3/DAG-PKC pathway is depicted on the left. Here, the Gaq activates phospholipase C, which generates 2 second messengers, DAG and IP3. These in turn activate protein kinase C and release of stored Ca21, respectively, effecting other TSH-dependent cellular actions. Gbg also seems to directly stimulate PI3K, hence activating the PI3K/AKT system. AC, adenylyl cyclase; ATP, adenosine triphosphate; BL, basolateral; Ca21, calcium ions; cAMP, cyclic adenosine monophosphate; CREB, cAMP responsive element binding protein; DAG, diacylglycerol; GTP, guanosine triphosphate; H2O2, hydrogen peroxide; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; NIS, sodium iodide symporter; P13K, P13 kinase; PIP2, phosphatidylinositol 4,5-biphosphate; PLC, phospholipase C; SR, sarco/endoplasmic reticulum; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH, thyrotropin.
frameshift in TRb.17 These mice develop a thyroid hormone resistance syndrome with an elevated non-suppressible TSH, and homozygotes (TRbPV/PV) manifest spontaneous metastatic follicular thyroid cancer.13 In this model, TSH receptor pathway signaling is necessary for thyroid cancer development, because when TRbPV/PV mice are crossed with knockout mice for the TSH receptor (TSHR–/–), offspring do not develop thyroid cancer.14 In wild-type mice (ie, no thyroid hormone resistance), however, when TSH is elevated by treatment with propylthiouracil, no metastatic thyroid cancer ensues.14 Treatment of heterozygous thyroid hormone–resistant mice (TRbPV/1; who do not ordinarily develop cancer) with propylthiouracil generates asymmetric follicular thyroid cancer with frequent metastases.16 Therefore, TSH is necessary but not sufficient to produce follicular cancer in mice; additional activation
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of permissive cell signaling pathways is required. In these mice, activating the PI3-K/AKT cascade seems crucial in disease development.15,18,19 Animal model evidence also exists for TSH signaling influencing papillary thyroid cancer. Using a mouse model with knock in of BRAFV600E (LSL- BRAFV600E/TPOCre) that produced early and aggressive papillary cancer, Franco and colleagues20 found that crossing mice with TSHR–/– mice led to marked delay in cancer development, with subsequent tumors being indolent. The effect of TSH on cancer development was mediated through the classical Gas pathway, because inhibiting Gas function had similar effects to the TSHR–/– experiments. Suppressing TSH with levothyroxine therapy did not revert the BRAFV600E phenotype, indicating that TSH signaling was most important in thyroid cancer initiation. Clinical Evidence
Boelaert and colleagues21 first reported higher serum TSH concentration predicted human thyroid cancer in 2006 (Fig. 2). Since then, many cross-sectional studies have assessed clinical data for an association between serum TSH concentration and thyroid cancer. Most, but not all, studies confirm the association.22,23 In doseresponse meta-analysis, the relationship was present from subnormal levels through the normal range and above.23 The effect seemed largest at lower TSH levels, with a 3-times greater odds ratio of thyroid cancer between a TSH of 4 mU/L compared with 0 mU/L, although the odds ratio still doubled between 2.2 and 7 mU/L. Major problems remain, however, with interpreting results of the diagnostic studies: (1) all are cross-sectional and (2) there is often incomplete assessment of potential confounding. Without adequately addressing these issues, it remains unclear whether serum TSH is a cause or simply a predictor of human thyroid cancer. Being a predictor of thyroid cancer diagnosis may have clinical applications (discussed later) but would be
Fig. 2. Prevalence of thyroid cancer from Boelaert and colleagues,21 according to the serum TSH concentration measured at presentation in 1183 subjects with normal serum free thyroxine concentrations, indicating increased prevalence in those with higher TSH. *, P 5 .05; **, P 5 .01; ***, P 5 .001, compared with TSH
