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Nat Rev Cancer. Author manuscript; available in PMC 2013 Oct 5.
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Molecular pathogenesis and mechanisms of thyroid cancer


Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer.

Thyroid cancer is a common endocrine malignancy that has rapidly increased in global incidence in recent decades1,2. In the United States, the average annual increase in thyroid cancer incidence of 6.6% between 2000 and 2009 is the highest among all cancers2. Although the death rate of thyroid cancer is relatively low, the rate of disease recurrence or persistence is high, which is associated with increased incurability and patient morbidity and mortality3.

There are several histological types and subtypes of thyroid cancer with different cellular origins, characteristics and prognoses4 (TABLE 1). There are two types of endocrine thyroid cells — follicular thyroid cells and parafollicular C cells — from which thyroid cancers are derived. Follicular thyroid cell-derived tumours, including papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), account for the majority of thyroid malignancies. PTC and FTC are collectively classified as differentiated thyroid cancer (DTC). Parafollicular C cell-derived medullary thyroid cancer (MTC) accounts for a small proportion of thyroid malignancies2. The primary molecular mechanism underlying MTC tumorigenesis is the aberrant activation of RET signalling (which is caused by RET mutations5), which are not present in follicular thyroid cell-derived tumours. The molecular pathogenesis of follicular thyroid cell-derived tumours is the focus of this Review.

Table 1
Thyroid tumours and their characteristics

Conventional surgical thyroidectomy with adjuvant ablation by radioiodine treatment has been the mainstay of treatment for follicular thyroid cell-derived cancer, but it is often not curative. The recent progress in understanding the molecular pathogenesis of thyroid cancer has shown great promise for the development of more-effective treatment strategies for thyroid cancer. This has mainly resulted from the identification of molecular alterations, including the genetic and epigenetic alterations of signalling pathways — such as the RAS–RAF–MEK–MAPK–ERK pathway (MAPK pathway) and the PI3K–AKT pathway — which is reshaping thyroid cancer medicine. This Review discusses the recent remarkable progress in understanding the molecular pathogenesis and mechanisms of thyroid cancer.

Common genetic alterations in thyroid cancer

Gene mutations

Numerous genetic alterations that have a fundamental role in the tumorigenesis of various thyroid tumours have been identified (TABLE 2). A prominent example is the T1799A transverse point mutation of BRAF, which results in the expression of BRAF-V600E mutant protein and causes constitutive activation of this serine/threonine kinase611. BRAFV600E mutation occurs in approximately 45% of PTCs12. There are also a few rare types of BRAF mutations identified in PTC, which mostly affect nucleotides around codon 600 and constitutively activate the BRAF kinase13,14. The requirement for BRAF-V600E to maintain tumour growth was initially demonstrated in a xenograft tumour model15. A previous comprehensive multicentre study demonstrated a strong association of BRAFV600E with poor clinicopathological outcomes of PTC, including aggressive pathological features, increased recurrence, loss of radioiodine avidity and treatment failures16. This was subsequently confirmed in numerous other studies, although, perhaps owing to variations in study design, some studies showed inconsistent results, as summarized and discussed in large meta-analyses that uniformly support the aggressive role of BRAFV600E mutation in PTC17,18. BRAFV600E-transgenic mice also developed aggressive PTC1921. Interestingly, some human PTC tumours have recently been found to exhibit intra-tumour heterogeneity in the BRAF genotype — with a minority of cells harbouring BRAFV600E and the majority harbouring wild-type BRAF22. This raises an interesting ‘chicken and egg’ puzzle of whether BRAF-V600E initiates PTC tumorigenesis or instead BRAFV600E occurs following the development of a thyroid tumour23. Although it is possible that BRAFV600E could be a secondary genetic event in PTC tumorigenesis as previously proposed24, an alternative possibility is that once PTC is initiated by BRAFV600E, secondary oncogenic alterations could take over to drive the tumorigenesis of PTC such that BRAF mutation is no longer selected for23.

Table 2
Gene mutations in thyroid tumours

Second in prevalence to BRAF mutations in thyroid cancer are RAS mutations. RAS is in its active state when bound with GTP. The intrinsic GTPase of RAS hydrolyses GTP and converts RAS into an inactive GDP-bound state, thus terminating RAS signalling. RAS mutations cause the loss of its GTPase activity, thus locking RAS in a constitutively active GTP-bound state. There are three isoforms of RAS: HRAS, KRAS and NRAS, and NRAS is predominantly mutated in thyroid tumours, mostly involving codons 12 and 61. Although RAS is a classical dual activator of the MAPK and PI3K–AKT pathways, RAS mutations seem to preferentially activate the PI3K–AKT pathway in thyroid tumorigenesis, as suggested by the preferential association of RAS mutations with AKT phosphorylation in thyroid cancers25,26. The common occurrence of RAS mutations in follicular thyroid adenoma (FTA), a presumed premalignant lesion, suggests that activated RAS may have a role in early follicular thyroid cell tumorigenesis. However, additional genetic alterations other than RAS mutation are apparently required to transform FTA into thyroid cancer. This is consistent with studies in which the expression of mutant HRAS was induced in normal thyroid cells in vitro, which resulted in only well-demarcated and differentiated colonies with phenotypes consistent with FTA27 and cell proliferation with normal differentiation28. More direct evidence has come from transgenic mouse studies in which conditional physiological expression of a KRAS mutant in the thyroid gland could not transform thyroid cells, but concurrent KRAS mutant expression and Pten deletion induced a rapid occurrence of aggressive FTC29.

Mutations or deletions of the tumour suppressor gene PTEN are the classical genetic alterations that activate the PI3K–AKT pathway and are the genetic basis for follicular thyroid cell tumorigenesis in Cowden’s syndrome30. Mutations of PIK3CA, which encodes the p110α catalytic subunit of PI3K, are also common in thyroid cancer, particularly FTC, PDTC and ATC25,26,3135. As in other human cancers36, activating PIK3CA mutations in thyroid cancer occur in exon 9 and exon 20. AKT1 mutations were found in metastatic thyroid cancers in one study, and their functional relevance remains to be established35.

Other important genes that are mutated in thyroid tumorigenesis include β-catenin (CTNNB1)37,38, TP5339,40, isocitrate dehydrogenase 1 (IDH1)41,42, anaplastic lymphoma kinase (ALK)43 and epidermal growth factor receptor (EGFR)44. The preferential occurrence of these mutations in PDTC and ATC, which are the most aggressive thyroid cancers, suggests that they may have a role in the progression and aggressiveness of thyroid cancer. In Hürthle-cell thyroid carcinoma (HCTC), mutations of NADH dehydrogenase (ubiquinone) 1α subcomplex 13 (NDUFA13; also known as GRIM19) are fairly common45. Unlike other types of thyroid cancers, HCTC does not harbour classical genetic alterations, such as BRAF and RAS mutations or RET–PTC 46,47, but commonly harbours DNA haploidization in recurrent disease47.

Gene amplifications and copy-number gains

Oncogenic gene amplification or copy-number gain are additional prominent genetic mechanisms in thyroid tumori-genesis (TABLE 3). This is particularly the case for genes encoding receptor tyrosine kinases (RTKs)26. Copy-number gains are also common for the genes encoding PI3K–AKT pathway members, including PIK3CA, PIK3CB, 3-phosphoinositide-dependent protein kinase 1 (PDPK1; also known as PDK1), AKT1 and AKT2 (REFS 25,26,32). Overall, genetic copy-number gains of these genes are more prevalent in ATC than in DTC, suggesting that these genetic alterations are important for the progression and aggressiveness of thyroid cancer. Copy-number gain of these genes in ATC could occur either through genetic amplification or chromosomal instability and aneuploidy. An important and expected consequence of these copy-number gains is the activation of downstream signalling pathways, as is suggested by the association of copy-number gains of genes encoding RTKs with increased phosphorylation of AKT and ERK in thyroid cancer26.

Table 3
Copy-number gains in thyroid cancer*

Many of the genes with copy-number gains are proto-oncogenes. A mechanism for them to contribute to thyroid tumorigenesis is through increased protein expression and consequent aberrant activation of the signalling pathways in which they are involved25,26,33. It is interesting to note that in DTCs, PIK3CA mutation is mutually exclusive with PIK3CA copy-number gain31,33, suggesting that either of these genetic alterations is sufficient to promote thyroid tumorigenesis through the PI3K–AKT pathway. However in aggressive undifferentiated ATC, PIK3CA mutations and amplifications often occur simultaneously in the same tumour26,33, which is a mechanism through which mutant PIK3CA can be amplified to drive the progression and aggressiveness of thyroid cancer.

Gene amplification or copy-number gain of the IQ-motif-containing GTPase-activating protein 1 (IQGAP1) is another important genetic event that has been recently discovered in thyroid cancer48. IQGAP1 is a multifunctional scaffold protein that has an important role in human tumorigenesis49. IQGAP1 amplification was found to increase protein expression and to be associated with invasiveness of thyroid cancer cells. Interestingly, coexistence of IQGAP1 copy-number gain and BRAFV600E mutation was particularly associated with a high incidence of recurrent PTC48.

Gene translocations

Gene translocation resulting in oncogenic rearrangements in thyroid cancer is best exemplified by RET–PTC. There are more than 10 types of RET–PTC translocation, as determined by the types of partner genes, and the most common types are RET–PTC1 and RET–PTC35052. RET is a proto-oncogene encoding an RTK. RET–PTC occurs as a consequence of genetic recombination between the 3′ tyrosine kinase portion of RET and the 5′ portion of a partner gene, such as the coiled-coil domain-containing gene 6 (CCDC6; also known as H4) in RET–PTC1 and nuclear receptor co-activator 4 (NCOA4; also known as ELE1) in RET–PTC3 (REFS 53,54). Spatial contiguity of RET and the partner gene in the nucleus is a structural basis for the formation of RET–PTC rearrangements55. The rearrangements result in ligand-independent dimerization and constitutive tyrosine kinase activity of RET. RET–PTC can occur in benign FTA and follicular variant PTC (FVPTC), but more commonly in classical PTC56. A recent study found a correlation between the presence of RET–PTC and a high growth rate of benign thyroid tumours57. However, the role of RET–PTC in early thyroid tumorigenesis is unclear. RET–PTC is a classical oncoprotein that activates the MAPK and PI3K–AKT pathways58,59. RET–PTC activates both pathways by recruiting signalling adaptors to phosphorylated Tyr1062 on the intracellular domain of the RET fusion protein60. It is thus not surprising that RET–PTC occurs in FTA and FVPTC; these are follicular thyroid tumours in which the PI3K–AKT pathway has a primary role in tumorigenesis61.

The paired box 8 (PAX8)–peroxisome proliferator-activated receptor-γ (PPARG) fusion gene (PAX8–PPARG) is another prominent recombinant oncogene in thyroid cancer, occurring in up to 60% of FTC and FVPTC6264. PAX8–PPARG also occurs in FTA64, although, like RET–PTC, its prevalence is low in benign thyroid tumours and its oncogenic role is unclear. PAX8–PPARγ exerts a dominant-negative effect on the wild-type tumour suppressor PPARγ and also transactivates certain PAX8-responsive genes65. Interestingly, the expression of PPARγ was dramatically reduced in FTC that developed in the TRβPV mouse model — which expresses a knock-in dominant-negative mutant of human thyroid hormone receptor-β (TRβ) — resulting in follicular thyroid tumorigenesis66. An AKAP9–BRAF fusion gene resulting in activation of the BRAF kinase also occurs in ionizing-radiation-induced PTC67, but not in sporadic PTC68. Unlike RET–PTC, the importance of AKAP9–BRAF in thyroid tumorigenesis is probably limited owing to its rarity.

Aberrant gene methylation

Aberrant gene methylation is an epigenetic hallmark of human cancer — which is also common in thyroid cancer69 — that usually silences a gene when occurring in the promoter regions. BRAFV600E mutation was found to be associated with hypermethylation of several tumour suppressor genes, including tissue inhibitor of metalloproteinases 3 (TIMP3), SLC5A8, death-associated protein kinase 1 (DAPK1) and retinoic acid receptor-β (RARB)70. A recent DNA methylation microarray study revealed broad hypermethylation of genes throughout the genome driven by BRAF-V600E signalling in PTC cells71. Interestingly, this study also revealed a large range of genes throughout the genome that, driven by BRAF-V600E, became hypomethylated and hence overexpressed. These hypermethylated or hypomethylated genes have important established metabolic and cellular functions. Thus, alterations in gene methylation coupled to BRAF-V600E and probably to other oncoproteins represent a prominent epigenetic mechanism in thyroid tumorigenesis.

Promoter methylation of PTEN is also common in FTC and ATC7274, which is consistent with the loss of expression of PTEN that is found in a subset of these thyroid cancers73,75,76. PTEN methylation is associated with genetic alterations of the PI3K–AKT pathway in thyroid tumours, including mutations of various isoforms of RAS, PIK3CA mutation and amplification, and PTEN mutations72. This is consistent with a model in which aberrant activation of the PI3K–AKT pathway, driven by activating genetic alterations, causes aberrant methylation and hence silencing of PTEN, which in turn leads to failure to terminate the PI3K–AKT signalling and creates a self-amplifying loop72.

Despite the identification of these common genetic alterations in thyroid cancers, it is important to note that approximately 30–35% of DTCs do not harbour known genetic alterations, and so further investigation is required to identify the underlying genetic backgrounds.

Altered signalling pathways in thyroid cancer

The MAPK signalling pathway

The MAPK pathway has a fundamental role in the regulation of cell proliferation and survival and in human tumorigenesis (FIG. 1). The importance of this pathway has been well established in thyroid tumorigenesis, particularly for PTC77,78. In thyroid cancer, the MAPK pathway is driven by activating mutations, including BRAF and RAS mutations, by RET–PTC and, in some cases, by the recently discovered ALK mutations43.

Figure 1
The MAPK and related pathways in thyroid cancer

MAPK-mediated thyroid tumorigenesis involves a wide range of secondary molecular alterations that synergize and amplify the oncogenic activity of this pathway, such as genome-wide hypermethylation and hypomethylation71. Additionally, upregulation of various well-established oncogenic proteins can occur. These include chemokines79,80, vascular endothelial growth factor A (VEGFA)81, MET82,83, nuclear factor-κB (NF-κB)84, matrix metalloproteinases (MMPs)79,84,85, prohibitin86, vimentin87, hypoxia-inducible factor 1α (HIF1α)88, prokineticin 1 (PROK1; also known as EG-VEGF)89, urokinase plasminogen activator (uPA) and its receptor (uPAR)90,91, transforming growth factor-β1 (TGFβ1)9294 and thrombospondin 1 (TSP1)93. These proteins are all established players in human tumorigenesis through a variety of mechanisms that drive cancer cell proliferation, growth, migration and survival, as well as tumour angiogenesis, invasion and metastasis.

Many of these proteins are key constituents of the unique extracellular matrix (ECM) microenvironments that have been proposed to be important in the pathogenesis of thyroid cancer driven by oncoproteins such as BRAF-V600E95. It is now clear that the ECM micro-environment does not only function as a structural support for the cellular elements of cancer, but it also has a profound impact on the behaviours of cancer cells, including their viability, proliferation, adhesion and motility. Thyroid cancer cells and stromal cells, such as fibroblasts and macrophages, produce proteins that form paracrine and autocrine signalling loops. For example, BRAF-V600E-mediated MAPK pathway activation promotes the release of TSP1 into the ECM where it interacts with and modulates other proteins. These include integrins and non-integrin cell-membrane receptors, matrix proteins, cytokines, VEGFA and MMPs, which in turn activate signalling in thyroid cancer cells and promote tumour progression and metastasis93,95. Another example is the tumour-promoting cytokine TGFβ1, which is released into the ECM owing to the activation of the BRAF-V600E–MAPK pathway92,94. Cytokines can create an inflammatory microenvironment that may produce reactive oxygen species and oxidative stress, which may in turn stimulate the MAPK pathway and augment thyroid tumorigenesis96. Thus, secondary molecular alterations in the tumour ECM microenvironment, triggered by the aberrant signalling of the MAPK pathway, have an important role in the pathogenesis of thyroid cancer.

In terms of stromal cells in the tumour micro-environment, an important role of tumour-associated macrophages is that they produce cytokines such as TGFβ1. The role of stromal fibroblasts in thyroid tumori-genesis seems to be affected by the expression patterns of the two fibroblast growth factor receptor 2 (FGFR2) isoforms, FGFR2-IIIb and FGFR2-IIIc, in cancer cells and fibroblasts: co-implantation of thyroid cancer cells and fibroblasts expressing the same type of FGFR2 isoform did not affect xenograft tumour progression, whereas co-implantation of thyroid cancer cells and fibroblasts that respectively expressed FGFR2-IIIb and FGFR2-IIIc resulted in increased tumour progression97. These results highlight the importance and complexity of cellular and molecular constituents in determining the impact of the microenvironment on thyroid cancer cell behaviour.

The PI3K–AKT signalling pathway

The PI3K–AKT pathway also has a fundamental role in thyroid tumori-genesis61,98 (FIG. 2). Early evidence to support the role of this pathway in thyroid tumorigenesis came from the finding that Cowden’s syndrome (which is caused by germline mutations of PTEN) was associated with FTA and FTC99. A functional role for the PI3K–AKT pathway in sporadic thyroid tumorigenesis was initially revealed by the finding of increased expression and activation of AKT in thyroid cancers, particularly FTC100102. Among the three AKT isoforms, AKT1 and AKT2, but not AKT3, were found to be robustly expressed and activated in thyroid cancer, suggesting a particularly important role for these two isoforms in thyroid tumorigenesis101.

Figure 2
The PI3K–AKT and related pathways in thyroid cancer

In the TRβPV transgenic mouse model — in which the PI3K–AKT pathway is activated, which involves the interaction of TRβPV with the p85α regulatory subunit of PI3K — FTC spontaneously developed103,104, and the activation and nuclear localization of AKT1 was observed105. Human tumour studies suggested that the invasiveness and metastasis of FTC promoted by the PI3K–AKT pathway particularly involved the activation and nuclear localization of AKT1 (REF. 102). This is consistent with the occurrence of AKT1 mutations in metastatic thyroid cancers35. Furthermore, Akt1 ablation delayed or prevented tumour progression, vascular intravasation and distant metastasis of FTC in TRβPV mice106. The role of AKT2 in thyroid tumorigenesis has also been demonstrated in vivo, as the occurrence of thyroid tumours was reduced in Pten+/−Akt2−/− mice107. Thus, whereas the MAPK pathway has a central role primarily in PTC, the PI3K–AKT pathway has such a role primarily in FTC and its invasion and metastasis. This is consistent with genetic alterations in the PI3K–AKT pathway occurring most frequently in FTC, whereas those in the MAPK pathway occur most frequently in PTC17,18,61,78,98. The inhibition of thyroid cancer cell proliferation by PI3K–AKT pathway inhibitors was dependent on the presence of genetic alterations in the PI3K–AKT pathway108,109, suggesting that thyroid cancer cells harbouring such genetic alterations have become dependent on the over-activation of this pathway.

Vascular invasiveness and capsular invasiveness are defining histopathological features of FTC110. Genetic alterations in the PI3K–AKT pathway are far more common in FTC than in its precursor, FTA31,33. It is therefore conceivable that overactivated PI3K–AKT signalling promotes the conversion of FTA to FTC by conferring tumour cell invasiveness. There are also secondary molecular alterations, albeit limited in number so far, that are robustly induced by PI3K–AKT signalling and that have an important role in the pathogenesis of FTC; these include alterations of the WNT–β-catenin111, HIF1α112,113, FOXO3 (REF. 114) and NF-κB114 pathways.

The NF-κB signalling pathway

The NF-κB pathway has an important role in the regulation of inflammatory responses that are linked to tumorigenesis115 (FIG. 1). Increased NF-κB activation in thyroid cancer cell lines and tissues has long been documented116118. Recent studies demonstrate that the NF-κB pathway controls proliferative and anti-apoptotic signalling pathways in thyroid cancer cells119,120. The NF-κB pathway is involved in upregulating the expression of several oncogenic proteins that are also upregulated by the MAPK pathway. Furthermore, RET–PTC, RAS and BRAF-V600E — members of the MAPK pathway — can cause activation of the NF-κB pathway in thyroid cancers119. Interestingly, NF-κB signalling was upregulated by expression of BRAF-V600E121,122, but not by expression of a constitutively active mutant of MEK in NIH3T3 cells123, suggesting a direct coupling of BRAF-V600E to the NF-κB pathway. Through a mechanism that is not yet specifically defined, BRAF-V600E was shown to cause IκB degradation (and consequent activation of NF-κB) independently of MEK–ERK signalling in thyroid cancer cells84. This dual coupling of BRAF-V600E to the NF-κB pathway and to the MEK–ERK pathway is consistent with the finding that simultaneously suppressing the two pathways using NF-κB and MEK inhibitors synergistically inhibited the proliferation of thyroid cancer cells harbouring a BRAF-V600E mutation124.

The RASSF1–MST1–FOXO3 signalling pathway

RASSF1 is a member of the RAS association domain family, which, in response to apoptotic signalling, associates with and activates mammalian STE20-like protein kinase 1 (MST1; also known as STK4)125. Activated MST1 phosphorylates Ser207 in the forkhead domain of the forkhead transcription factor FOXO3. This phosphorylation disrupts the interaction of FOXO3 with 14-3-3 proteins in the cytoplasm and promotes FOXO3 translocation to the nucleus, where it promotes the transcription of pro-apoptotic genes126 (FIG. 1). Thus, this RASSF1–MST1–FOXO3 pathway has an important tumour-suppressive role by promoting apoptosis.

Hypermethylation of the promoter of RASSF1A is common and is associated with its silencing in thyroid cancers127,128. This occurs even in benign FTA, albeit to a lesser extent, suggesting that impairment of the RASSF1–MST1–FOXO3 pathway is involved in early thyroid tumorigenesis128.

Activation of the RASSF1–MST1–FOXO3 signalling pathway promoted thyroid cancer cell apoptosis21. Interestingly, this study demonstrated that BRAF-V600E, but not wild-type BRAF, directly interacted with the carboxyl terminus of MST1 and inhibited its kinase activities, resulting in decreased FOXO3 transactivation. This was independent of MEK–MAPK signalling. This suggests that, in addition to the classical coupling to MEK–MAPK, negative regulation of RASSF1–MST1–FOXO3 is a mechanism that is involved in BRAF-V600E-driven thyroid tumorigenesis. This unique mechanistic model explains the finding that thyroid cancers that developed in BRAFV600EMst1−/− transgenic mice were more aggressive than those that developed in BRAFV600E mice21. The direct interaction of BRAF-V600E with MST1 to prevent RASSF1-mediated MST1 activation also provides an explanation for the mutually exclusive occurrence of BRAFV600E mutation and RASSF1A hypermethylation in thyroid cancer128, as either event may be sufficient to inactivate RASSF1–MST1–FOXO3 signalling. Therefore, BRAF-V600E is coupled independently to three major pathways: MEK–MAPK, RASSF1–MST1–FOXO3 and NF-κB, and thus represents a unique and powerful oncogenic mechanism in thyroid tumorigenesis (FIG.1). The activation of the PI3K–AKT pathway, such as that induced by PTEN inactivation, can also downregulate the activities of the RASSF1–MST1–FOXO3 pathway in FTC114. This involves AKT-mediated phosphorylation of FOXO family members, which causes their translocation from the nucleus to the cytoplasm, where they are sequestered by 14-3-3 proteins, thus reducing the transcription of pro-apoptotic genes129 (FIG. 2).

The WNT–β-catenin signalling pathway

The WNT–β-catenin pathway has a well established role in the regulation of cell growth and proliferation, as well as in stem cell differentiation, and its constitutive activation is commonly found in human cancers130. β-catenin, when upregulated by upstream WNT signalling, is translocated into the nucleus and transcribes various tumour-promoting genes. In thyroid cancer, activation of WNT–β-catenin signalling is often caused by activating mutations of CTNNB1 (which encodes β-catenin), particularly in PDTC and ATC37,38. Furthermore, the expression of β-catenin was higher in ATC than in DTC131. Thus, the WNT–β-catenin pathway seems to have a particularly important role in thyroid tumour aggressiveness.

Aberrant activation of WNT–β-catenin signalling often occurs as a consequence of the activation of the PI3K–AKT pathway in thyroid cancers132,133. This occurs through glycogen synthase kinase 3β (GSK3β), which is directly phosphorylated — and hence inactivated — by AKT134. As GSK3β promotes the degradation of β-catenin, its inactivation results in the upregulation of WNT–β-catenin signalling (FIG. 2). Interestingly, RET–PTC can activate the WNT–β-catenin pathway by activating the PI3K–AKT pathway and also by directly phosphorylating β-catenin in thyroid cancer cells58.

The HIF1α pathway

It has long been known that hypoxia is a strong stimulus of cancer metabolism, growth and progression. HIF1α is a key mediator of the response to hypoxia, in which it binds to HIF1β (also known as ARNT) to form the HIF1 transcription factor that induces the expression of various genes associated with cell metabolism and tumour angiogenesis135. Angiogenesis, which is a key step in the progression of solid tumours, is a common response to intratumoural hypoxia. This process is promoted by VEGFA, the expression of which is strongly upregulated by HIF1. HIF1α is not expressed in normal thyroid tissues but is expressed in thyroid cancers, particularly in aggressive types, such as ATC, and this is consistent with a role in thyroid cancer progression112,136. The oncogene MET, which is another target of HIF1, is also abundantly expressed in association with upregulated HIF1α in thyroid cancer136. Interestingly, HIF1 can be upregulated in thyroid cancer by both the PI3K–AKT112,113 and the MAPK pathways88, thus contributing to the effects of these two pathways on thyroid tumour progression.

The thyroid-stimulating hormone receptor signalling pathway

Through activation by thyroid-stimulating hormone (TSH), the TSH receptor (TSHR) has a fundamental role in the regulation of thyroid cell proliferation, differentiation and function, as well as in the development of the thyroid gland137. TSHR is a guanine-nucleotide-binding G-protein-coupled receptor that triggers two intracellular signalling pathways: G-mediated adenylyl cyclase–cyclic AMP (cAMP) signalling and the Gq- or G11-mediated phospholipase Cβ–inositol 1,4,5-trisphosphate–intracellular Ca2+ signalling. FTC spontaneously developed in TRβPV mice, but when these mice were crossed with Tshr−/− mice, no thyroid cancer developed138. This study thus elegantly demonstrates the requirement of TSHR signalling in thyroid carcinogenesis in this mouse model. Similar findings were reported in another mouse model in which thyroid-specific knock-in of BrafV600E (LSL-BrafV600Ethyroid peroxidase (Tpo)-Cre) caused the development of aggressive PTC, and crossing these mice with Tshr−/− mice resulted in a failure to develop thyroid cancer139. In this study, thyroid-specific deletion of Gnas (which encodes G) in LSL-BrafV600ETpo-Cre mice attenuated thyroid tumour formation. Interestingly, there is a clinical association of higher serum levels of TSH with a higher risk for malignancy of thyroid nodules in humans140142.

However, it is not clear whether TSHR signalling is required directly for the initiation of thyroid cancer or whether it is simply required, as would be expected physiologically, for the TSHR-dependent generation of thyroid cells, from which an oncogene-driven thyroid cancer would originate. Overactivation of TSHR signalling, such as that achieved through activating mutations in TSHR or G, is well known to cause benign hyperfunctional FTA143,144. These tumours are almost never malignant, which suggests that TSHR signalling may be protective against malignant transformation of thyroid cells. Consistently, low serum levels of TSH are associated with common genetic variants that predispose to an increased risk of thyroid cancer145,146. It therefore seems that the TSH–TSHR system has a dichotomous role in the development of thyroid cancer: it may suppress malignant transformation of thyroid cells and hence suppress the occurrence of thyroid cancer, but it may promote the growth and progression of thyroid cancer once it has been initiated by oncogenic alterations.

Progressive molecular alterations

Progressive accumulation of genetic alterations

The accumulation of genetic alterations during thyroid tumour progression is probably best exemplified by genetic alterations to members of the PI3K–AKT pathway61. Mutations in members of this pathway, including those in RAS (particularly NRAS), PIK3CA and PTEN, as well as PIK3CA amplifications, increasingly occur from FTA to FTC and to ATC26,3133,147. Hypermethylation of the PTEN promoter also progressively increases in frequency from FTA to FTC and to ATC72. The coexistence of these genetic and epigenetic alterations also increasingly occurs from low-grade to high-grade thyroid tumours31,33. Genetic or epigenetic defects of PTEN can occur simultaneously with activating mutations of other genes in the PI3K–AKT pathway; in such cases, the PI3K–AKT pathway can presumably remain maximally activated26,33,72. Indeed, deletion of Pten accelerated the progression of FTC in TRβPV mice114.

The coexistence of multiple genetic alterations to members of the MAPK pathway also occurs, as exemplified by the simultaneous presence of BRAFV600E mutation, RAS mutations and RET–PTC in aggressive recurrent PTC and ATC26,148,149; these alterations are otherwise mutually exclusive in well-differentiated thyroid cancers7,9. It is thus compelling to propose that the process of thyroid cancer progression is one of progressive accumulation of multiple genetic alterations, which synergistically cooperate to amplify their oncogenicity.

Cooperation of the MAPK and PI3K–AKT pathways

The MAPK and PI3K–AKT pathways are primarily involved in differentiated PTC and FTC, respectively, and the simultaneous activation of both pathways becomes more frequent as the grade of thyroid tumours increases26,3133,35. One study analysed 24 genetic alterations in the major genes of the MAPK and PI3K–AKT pathways in 48 ATC samples and found that the majority (81%) of the samples harboured genetic alterations that could potentially activate both pathways26. The coexistence of phosphorylated ERK and AKT was also common in ATC but not in DTC26. Thus, genetic alterations that activate the MAPK and PI3K–AKT pathways are an important mechanism that drives the progression of thyroid cancer. In this model, as illustrated in FIG. 3, when a genetic alteration occurs in the MAPK pathway it drives tumorigenesis of the thyroid cell towards PTC; when a genetic alteration occurs in the PI3K–AKT pathway it drives tumorigenesis towards FTA and FTC. As genetic alterations accumulate and both pathways become activated, the tumour progresses into PDTC and ATC, which is a process that may be further accelerated by additional or secondary genetic alterations, including mutations in TP53, CTNNB1 and ALK.

Figure 3
Model of the progression of thyroid tumorigenesis driven by the MAPK and PI3K–AKT pathways

This model is supported by studies of transgenic mice in which the deletion of Pten and knock-in of KrasG12D (to activate both MAPK and PI3K–AKT pathways), but not either genetic manipulation alone, caused the development of aggressive thyroid cancer29. Similarly, this phenomenon is observed in melanoma. Transgenic mice with induced expression of BRAFV600E in melanocytes to activate the MAPK pathway alone developed only melanocytic hyperplasias, but the expression of BRAFV600E with Pten deletion (to also activate the PI3K–AKT pathway) caused melanoma with a rapid onset of metastasis150. Thus, dual activation of the MAPK and PI3K–AKT pathways may be a common mechanism for promoting tumour progression.

Impairment of the iodide-handling machinery

The main and unique function of follicular thyroid cells is to use iodide to synthesize thyroid hormone151,152 (FIG. 4). In this process, iodide is transported into the cell through the sodium–iodide symporter (NIS) that is located in the basal membrane. At the apical membrane, pendrin transports iodide out of the cell into the lumen of the thyroid follicle. In the lumen of the thyroid follicle, iodide undergoes oxidation by TPO and is incorporated into tyrosine residues of thyroglobulin (TG), which is later cleaved through proteolysis to produce thyroid hormones. This process is upregulated by TSH-mediated activation of TSHR. This is the biological basis for the conventional radioiodine treatment of thyroid cancer, but the iodide-handling machinery is often impaired, particularly in advanced thyroid cancers, thus making radioiodine treatment ineffective.

Figure 4
Iodide-handling machinery in the thyroid cell and its silencing by BRAF-V600E

Aberrant activation of the MAPK pathway has a crucial role in the impairment of the iodide-handling machinery17. BRAFV600E mutation is associated with the loss of radioiodine avidity and with radioiodine treatment failure in PTC16,35,153155. Consistently, BRAFV600E mutation is highly prevalent (78–95% of cases) in recurrent radioiodine-refractory PTC16,35,149,155, in contrast with the lower prevalence of BRAFV600E mutation (45% of cases) in primary PTC12. Numerous studies have reported an association of BRAFV600E mutation with decreased or absent expression of thyroid iodide-handling genes: NIS, TSHR, TPO, TG and SLC26A4 (which encodes pendrin) in thyroid cancer82,153,154,156160. A direct role of BRAFV600E in the downregulation of thyroid hormone synthesis pathway genes was demonstrated by showing that induced expression of BRAF-V600E in thyroid cells impaired the expression of almost all of these genes, which was restored by ceasing the expression of BRAF-V600E or by suppressing the MAPK pathway with a MEK inhibitor161. Similarly, in thyroid cells expressing RET–PTC1, NIS expression was increased following treatment with a MEK inhibitor162. Suppression of BRAF-V600E in mouse models of thyroid cancer also restored the expression of thyroid iodide-handling genes and radioiodine uptake163. This aberrant gene silencing by BRAF-V600E may involve alterations to histone acetylation at gene promoters164,165. An autocrine loop involving TGFβ is another mechanism92: BRAF-V600E promotes the secretion of TGFβ, which, through the activation of SMADs and consequent impairment of the thyroid-gene transcription factor PAX8, is a potent repressor of NIS in thyroid cells166.

Activation of the PI3K–AKT pathway was also shown to downregulate the iodide-handling machinery in thyroid cells both in vitro and in vivo167,168. Inhibition of the PI3K–AKT pathway induced NIS expression and iodide uptake in human thyroid cancer cells164,169. In addition to NIS, suppression of the PI3K–AKT pathway also induced the expression of TSHR, TPO and TG in human thyroid cancer cells, which was enhanced by treatment with histone deacetylase inhibitors, and radioiodine uptake was correspondingly robustly induced164. This could be augmented by co-treatment with TSH164. The involvement of both MAPK and PI3K–AKT pathways in the silencing of thyroid iodide-handling genes is consistent with the accumulation of genetic alterations in both pathways as thyroid tumours progress, during which there is an increasing loss of radioiodine avidity.

Translational promises in thyroid cancer

Remarkable advances in the translation of molecular findings in thyroid cancer to the clinic have occurred recently170. For example, because of its cancer specificity, the detection of BRAFV600E mutation in fine-needle aspiration biopsy (FNAB) samples was initially tested for the evaluation of thyroid nodules171,172, which has now found increasing clinical use170,173. The diagnostic utility of detecting RET–PTC using FNAB has also been intensively investigated170. The combinatorial use of genetic markers identified in FNAB samples, including BRAF mutation, RAS mutations, RET–PTC and PAX8–PPARG, has been shown to improve the diagnostic accuracy for thyroid nodules that are otherwise diagnostically indeterminate by conventional cytology assessment, although this diagnostic approach may need further improvement174,175. Applying genomic information to address clinical issues of thyroid neoplasia has also shown promise. For example, a gene-expression classifier (with high sensitivity and negative predictive power) is being used in the clinic to assist the diagnostic evaluation of indeterminate thyroid nodules176.

The prognostic application of BRAFV600E mutation has also become part of the clinical management of PTC170,173. A large, multicentre study demonstrated a strong association of BRAFV600E mutation with patient mortality from PTC177. Large studies have demonstrated that BRAFV600E is strongly associated with poor clinico-pathological outcomes even in conventionally low-risk patients16,178181. BRAFV600E detected in FNAB samples preoperatively predicted poor clinicopathological outcomes of PTC180,182,183 and even predicted lymph node metastasis (as determined by prophylactic central neck dissection in patients without preoperative evidence of lymph node metastasis)183. It is thus recommended that preoperative testing of BRAFV600E in FNAB samples be used for assisting risk stratification and defining surgical and medical treatments for patients with PTC170. Owing to their association with a worse prognosis of PDTC, RAS mutations are also promising prognostic markers for this type of thyroid cancer184186. It has been recently shown that RAS mutations are also associated with poor clinicopathological outcomes of FTC187 but this needs to be evaluated further.

Many components of the MAPK and PI3K–AKT pathways, from RTKs in the cell membrane to the various downstream signalling relay molecules, such as BRAF, MEK, AKT and mTOR, are therapeutic targets that are being actively tested for the treatment of thyroid cancer170. Novel small-molecule protein-kinase inhibitors have shown promise in clinical trials on thyroid cancer, including axitinib188, sorafenib189191, motesanib192 and pazopanib193. A promising therapeutic strategy is genetic-based targeting of thyroid cancer194, as supported by many preclinical studies demonstrating the selective inhibition of BRAFV600E-mutant thyroid cancer cells by various MEK inhibitors124,195199 and BRAF-V600E-specific inhibitors200,201. The latter include PLX4032 (also known as vemurafenib), which has been recently approved by the US Food and Drug Administration (FDA) for the treatment of BRAFV600E-positive melanoma202. Some of these MEK and BRAF-V600E inhibitors are currently being clinically tested for thyroid cancer. Therapeutic targeting of the PI3K–AKT pathway may also be genetically guided, as genetic alterations that activate this pathway confer thyroid cancer cells with remarkably increased sensitivities to AKT and mTOR inhibitors108,109. This therapeutic strategy for thyroid cancer may prove to be useful and should be tested clinically, as encouraged by a recent clinical trial showing that mutations in the PI3K–AKT pathway significantly increased the response rate of breast and gynaecological cancers to inhibitors of the PI3K–AKT pathway203.

The involvement of multiple signalling pathways in aggressive thyroid cancer suggests that it may be necessary to target them simultaneously for effective treatment. Indeed, single agent clinical trials of various kinase inhibitors in thyroid cancer have generally shown only partial responses. Several recent preclinical studies testing the combination of MEK or BRAF-V600E inhibitors with PI3K, AKT or mTOR inhibitors showed synergistic effects in inhibiting the proliferation and promoting apoptosis of thyroid cancer cells124,199,204,205. Synergistic effects of simultaneously targeting the MAPK and PI3K–AKT pathways were even more pronounced in cells that harboured genetic alterations in both pathways199. It has been recently demonstrated that simultaneously inhibiting the MAPK, PI3K–AKT and histone deacetylase pathways could more robustly induce the expression of thyroid iodide-handling genes (and thus increase radioiodine uptake) in thyroid cancer cells compared with inhibiting each pathway alone, and this could be enhanced by co-treatment with TSH164. Therefore, to restore radioiodine avidity by simultaneously targeting multiple signalling pathways is another promising area of translational research on thyroid cancer.

Concluding remarks

Remarkable progress in understanding the molecular pathogenesis of thyroid cancer has been made in recent years, as exemplified by the elucidation of the fundamental role of signalling pathways, such as the MAPK and PI3K–AKT pathways. Activation of these pathways, often in close connection and cooperation, constitute the primary oncogenic mechanism that promotes the development and progression of thyroid cancer. Central to this mechanism are the many powerful oncogenic alterations that drive these pathways. Important secondary molecular derangements driven by the overactivation of these pathways have also been increasingly uncovered, which synergize and amplify oncogenic signalling in thyroid tumorigenesis. This understanding of the molecular pathogenesis of thyroid cancer has now opened unprecedented opportunities for the development of novel clinical strategies for the management of thyroid cancer.

At a glance

  • Thyroid cancer is a common endocrine malignancy, and exciting progress has occurred in recent years in understanding its molecular pathogenesis.
  • Genetic and epigenetic alterations are the driving forces of thyroid cancer. Examples of these alterations include mutations in BRAF (BRAFV600E), RAS, PIK3CA, PTEN, TP53, β-catenin (CTNNB1), anaplastic lymphoma kinase (ALK) and isocitrate dehydrogenase 1 (IDH1), translocations (RET–PTC and paired box 8 (PAX8)–peroxisome proliferator-activated receptor-γ (PPARG)) and aberrant gene methylation.
  • At the core of the molecular pathogenesis of thyroid cancer is the uncontrolled activity of various signalling pathways, including the MAPK, PI3K–AKT, nuclear factor-κB (NF-κB), RASSF1–mammalian STE20-like protein kinase 1 (MST1)–forkhead box O3 (FOXO3), WNT–β-catenin, hypoxia-inducible factor 1α (HIF1α) and thyroid-stimulating hormone (TSH)–TSH receptor (TSHR) pathways.
  • The progression of thyroid cancer is a process of accumulation of genetic and epigenetic alterations with corresponding progressive derangements of signalling pathways. These are accompanied by numerous secondary molecular alterations, both in the cell and in the tumour microenvironment, which, acting in cooperation, amplify and synergize their impacts on thyroid tumorigenesis.
  • Aberrant silencing of thyroid iodide-handling genes and consequent loss of radioiodine avidity of thyroid cancer promoted by BRAF-V600E is a unique molecular pathological process in thyroid cancer, which causes the failure of radioiodine treatment.
  • The recent molecular findings provide unprecedented opportunities for further research and clinical development of novel molecular-based treatment strategies for thyroid cancer.


This work is supported by the US National Institutes of Health (NIH) R01 grants CA113507 and CA134225 to the author. The author thanks A. K. Murugan, Y. Trink and D. Liu for their help in preparing the figures and references. The author also thanks the numerous colleagues and investigators in this field whose outstanding work made it an extremely enjoyable experience to write this Review. The author wishes to apologize to those whose work is not cited owing to space limitations.


Differentiated thyroid cancer(DTC). Collectively includes both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), which are histologically differentiated, by comparison with poorly differentiated thyroid cancer (PDTC) and undifferentiated anaplastic thyroid cancer (ATC)
Radioiodine treatmentA classical treatment for patients with thyroid cancer. It is used after total thyroidectomy and consists of treating patients with the radioiodine isotope 131I, which emits high-energy β-particles and takes advantage of the unique function of thyroid follicular cells to accumulate iodide as a substrate for the synthesis of thyroid hormone
MAPK pathwayThis pathway has a fundamental role in the regulation of cell growth, proliferation, apoptosis and metabolic activities, through regulating the expression of various genes
PI3K–AKT pathwayThis pathway also has a fundamental role in the regulation of cell growth, proliferation, apoptosis and metabolic activities, through regulating the expression of various genes
PtenA tumour suppressor gene, the protein product of which converts phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-trisphosphate (PIP2), counteracting the conversion of PIP2 to PIP3 by PI3K and thus terminating PI3K–AKT signalling
Cowden’s syndromeAlso known as Cowden’s disease or multiple hamartoma syndrome. A rare, autosomally inherited disorder that is caused by mutations or defects in the tumour suppressor gene PTEN and is characterized by multiple tumour-like growths called hamartomas and an increased risk of certain cancers, such as breast cancer and follicular thyroid cancer
Copy-number gainA genetic abnormality in which the copy number of a chromosomal region or gene is more than the normal two copies (one paternal allele and one maternal allele), which occurs through the amplification of a local region of DNA within a chromosome, or through aneuploidy, in which multiple copies or fragments of identical chromosomes are present
Receptor tyrosine kinases(RTKs). These are typically growth-promoting transmembrane receptors that transduce extracellular signalling into intracellular signalling through the activation of their cytoplasmic kinase domain in response to extracellular signals such as ligand-binding
Gene translocationA genetic rearrangement in which a chromosomal fragment is translocated to another chromosome where it is not normally located, which may create a recombinant gene product with new function or uncontrolled function (compared with the original gene product)
Follicular thyroid tumoursCollectively includes follicular thyroid adenoma (FTA), follicular thyroid cancer (FTC) and follicular variant papillary thyroid cancer (FVPTC); they share common dense follicular cell architectures
Gene methylationAn epigenetic covalent addition of a methyl group to the fifth carbon of the cytosine residue in a CpG dinucleotide, typically in CpG islands (that is, CpG-rich regions) in the 5′-flanking promoter regions of genes. Such methylation is usually closely associated with chromatin remodelling and silencing of the corresponding genes. Capsular invasiveness, A phenomenon in which thyroid cancer invades the connective tissue capsule that surrounds the tumour, which is a defining feature of progression to malignancy from a benign thyroid tumour


Competing interests statement

The author declares competing financial interests: see Web version for details.


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