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The Natural Thyroid Diet

The Natural Thyroid Diet

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Figure 2. PPARy Gene Rearrangements in Follicular Thyroid Carcinoma. The breakpoints of two chromosomal rearrangements, t(2;3)(q13;p25) and t(3;7)(p25;q31), have been cloned from human follicular thyroid carcinomas. Each rearrangement encodes a chimeric fusion protein that contains identical domains (A-E) of the PPARy nuclear receptor.

well with the known tumor suppressor-like effects of wild-type PPARy in a variety of epithelial cells [40-44]. In general, wild-type PPARy stimulation inhibits thyroid cell growth [45, 46] and a reduction in PPARy expression has also been noted in a significant subgroup of thyroid cancers without PPARy rearrangement [32, 38]. The retinoblastoma tumor suppressor protein and cell cycle regulators may be involved [45, 47, 48].

Figure 3. Molecular Pathways in Follicular Thyroid Tumors. Schematic representation of major molecular pathways involved in follicular thyroid tumors. Some, but not all, components and inter-connections of these pathways are indicated. Mutations are note in red and by red dots. Abbreviations: TSHR, thyroid stimulating hormone receptor; Gas, guanine nucleotide stimulatory factor a; PLC, phospholipase C; IP3, inositol triphosphate; DAG, diacylglycerol; PKC, protein kinase C; AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; RAC1/RHO, rac1/rho GTP binding proteins; GFR, growth factor receptor; GF, growth factor; RET, ret tyrosine receptor kinase; NTK1, ntrk1 tyrosine receptor kinase; GTP, guanine diphosphate; GTP, guanine triphosphate; RAS, ras GTP binding protein; BRAF, braf serine/threonine kinase; MEK, mitogen activated protein kinase kinase; ERK, extracellular signal regulated kinase (mitogen activated protein kinase); PI3K, phosphoinositol-3-kinase; PTEN, pten dual specificity phosphatase; AKT, akt serine/threonine kinase; PKB, protein kinase B; BAD and BAX, proapoptotic bcl-2 family members; p53, p53 tumor suppressor protein; RB, rb retinoblastoma tumor suppressor protein; CDKs, cyclin-dependent kinases; peroxisome proliferator-activated receptor

RXR, retinoid X receptor; p/CAF, CBP/p300, p160, nuclear receptor co-activators; HAT, histone acetyl transferase; HDAC, histone deacetylase complex. TATA, tata box.

Figure 3. Molecular Pathways in Follicular Thyroid Tumors. Schematic representation of major molecular pathways involved in follicular thyroid tumors. Some, but not all, components and inter-connections of these pathways are indicated. Mutations are note in red and by red dots. Abbreviations: TSHR, thyroid stimulating hormone receptor; Gas, guanine nucleotide stimulatory factor a; PLC, phospholipase C; IP3, inositol triphosphate; DAG, diacylglycerol; PKC, protein kinase C; AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; RAC1/RHO, rac1/rho GTP binding proteins; GFR, growth factor receptor; GF, growth factor; RET, ret tyrosine receptor kinase; NTK1, ntrk1 tyrosine receptor kinase; GTP, guanine diphosphate; GTP, guanine triphosphate; RAS, ras GTP binding protein; BRAF, braf serine/threonine kinase; MEK, mitogen activated protein kinase kinase; ERK, extracellular signal regulated kinase (mitogen activated protein kinase); PI3K, phosphoinositol-3-kinase; PTEN, pten dual specificity phosphatase; AKT, akt serine/threonine kinase; PKB, protein kinase B; BAD and BAX, proapoptotic bcl-2 family members; p53, p53 tumor suppressor protein; RB, rb retinoblastoma tumor suppressor protein; CDKs, cyclin-dependent kinases; peroxisome proliferator-activated receptor

RXR, retinoid X receptor; p/CAF, CBP/p300, p160, nuclear receptor co-activators; HAT, histone acetyl transferase; HDAC, histone deacetylase complex. TATA, tata box.

Although inhibition of wild-type PPARy by PAX8-PPAR7 appears to be functionally important, the CREB3L2-PPARy fusion protein appears to exhibit little inhibitory activity [30], suggesting that other mechanisms are also critical. PAX and CREB3L2 rearrangements have been noted in other cancers, supporting the idea that contributions of these domains in and are func tionally important. For example, the PAX3 and PAX7 genes are rearranged in alveolar rhabdomyosarcoma [49-51 ] and CREB3L2 is rearranged in fibromyxoid sarcoma [29]. Wild-type PAX8, a transcription factor required for normal thyroid follicular cell development [52], also possesses transforming activities in vitro [53].

Follicular adenomas with PAX8-PPARy rearrangement have been identified at apparent lower frequency than in follicular carcinomas [33, 34, 36] and it seems most reasonable to consider these early (precursor/in situ) follicular carcinomas [32] unless genetic and/or clinical distinctions from the follicular carcinomas can be documented. PPARy rearrangements are expected in at least some follicular adenomas because differential diagnosis of follicular adenomas from carcinomas is not precise. The possibility that PPARy rearrangements mark a subset of follicular carcinomas, some even before histologic evidence of invasiveness is apparent, suggests that molecular analyses of fine needle aspiration biopsies may be useful to detect these follicular cancers [54]. However, the exact diagnostic utility of rearrangements in diagnosis will not be clear until the biologic and molecular relatedness of follicular carcinomas and adenomas with PPARy rearrangement is better defined. Papillary (follicular variant) and Hurthle cell carcinomas with rearrangement have been observed infrequently [32, 34, 55], suggesting that these thyroid cancers arise via alternate transformation pathways (Figure 1).

Clinical and pathological characteristics of follicular carcinoma patients with rearrangements have been examined. Follicular carcinomas with rearrange ment tend to have well-defined foci of vascular invasion and capsular penetration but not lymph node metastases [32, 33]. They also tend to present at younger patient age than follicular carcinomas without PPARy rearrangement [32, 33] and progress and metastasize in some cases [23, 35]. Even so, few PPARy rearrangements have been detected in anaplastic thyroid carcinomas [34, 35], which are highly aggressive cancers thought to arise from follicular and papillary carcinomas. Further studies are required to define the biologic characteristics and patterns of progression of follicular thyroid tumors with rearrangement.

RET rearrangements

Somatic rearrangements in the gene encoding the RET receptor tyrosine kinase have been identified in a subset of thyroid cancers that exhibit follicular cell differentiation, characteristic papillary and/or nuclear morphologies, and a propensity for lymph node metastases. These are papillary thyroid carcinomas (Figure 1). Interestingly, the RET gene plays a fundamental role in multiple thyroid cancers. Whereas rearrangements of RET characterize papillary thyroid carcinomas [11, 14], germ-line RET point mutations characterize medullary thyroid carcinomas arising in the multiple endocrine neoplasia type 2 [56-59] and family medullary thyroid carcinoma syndromes. Thus, different RET mutations (rearrangements or point mutations) arising in different cellular contexts (follicular or C cell lineages) promote formation of different thyroid cancers (Figure 1). The RET rearrangements are discussed in detail in Chapter 12.

RET rearrangements in papillary carcinoma are thyroid-specific mutations and most often result from para-centric chromosomal inversions. For example, the RET gene at chromosome 10q11 is recombined frequently with other 10q loci such as H4 in PTC1 [60] and ELE1 in PTC3 [61, 62]. Several less frequent reciprocal translocations involving RET and other chromosomal loci have been described, particularly in papillary carcinoma patients exposed to radiation in the Chernobyl accident [63-65]. All known RET rearrangements result in expression of cytoplasmic, chimeric fusion proteins that contain the intracellular tyrosine kinase domain of RET fused to domains of non-RET (termed RET fusion genes or RFG) genes. The extracellular cadherin-like, cysteine-rich, and transmembrane domains of RET are not retained in the RFG-RET fusion proteins.

Experiments expressing RFG-RET fusion proteins in thyroid cell lines support a central role of the RAS-BRAF-MEK-ERK pathway in neoplastic transformation of follicular cells into papillary carcinomas (Figure 3). The RFG-RET fusion proteins stimulate follicular cell proliferation and inhibit differentiation [66-70]. Apoptosis may also be altered [71]. These biologic effects are mediated by ligand-independent dimer-ization [72, 73], cytoplasmic relocation [73], and constitutive activation of the RET tyrosine kinase. Adaptor molecules such as Shc, Frs2, Enigma, and Grb proteins interact with RET proteins [69, 74-78] and stimulate downstream RAS-BRAF-MAPK-ERK and other signal transduction pathways.

Transgenic mouse lines engineered to express RFG-RET fusion proteins in the thyroid document their ability to promote formation of papillary carcinoma-like tumors in vivo [79-82]. However, these transgenic lines do not all develop thyroid tumors with high penetrance or short latency and few, if any, develop tumors that metastasize without co-expression of additional mutations, arguing that multiple alterations are required for expression of the full papillary carcinoma phenotype [66, 67, 83].

RET rearrangements have been detected in 15-25% of papillary carcinomas and have been considered specific based on RTPCR and Southern blot experiments [70, 84-91]. RET rearrangements appear to arise early in papillary carcinoma because they are most common in low stage and the occult/micropapillary tumors [89, 92-94]. Papillary carcinomas with RET rearrangements may also present at younger patient age than papillary carcinomas without RET rearrangements [87, 95, 96], in a manner that resembles PPARy rearrangements in follicular carcinoma. Other strong clinico-pathologic correlates of RET rearrangement include classic papillary (not follicular variant) morphology [97, 98] and the presence of lymph node spread [86, 87, 96, 98]. The ELE1-RET (PTC3) fusion protein may be more frequent in the aggressive tall cell [17] and solid [16, 20] papillary carcinoma subtypes. A significant fraction of papillary carcinomas with RET alterations appear to progress to poorly differentiated thyroid carcinoma [99] but few RET rearrangements have been detected in anaplastic thyroid cancers [84, 89].

A few recent reports have noted RET rearrangements, somewhat unexpectedly, in benign and malignant Hurthle cell tumors [18, 19] and in thyroid hyalinizing trabec-ular adenomas [100, 101]. These Hurthle cell carcinomas with RET rearrangements appear to have increased tendency for lymphatic spread [102], supporting a biologic connection to papillary carcinoma as well. Thus, one intriguing possibility is that the Hurthle cell tumors with RET rearrangement are actually papillary carcinomas with additional morphologic and perhaps biologic features. An alternate possibility that must be excluded is that the RET rearrangements are present in a small fraction of the tumor cells because a only combined high cycle RTPCR and nucleotide probe hybridization have so far demonstrated their presence.

NTRK1 rearrangements

Somatic rearrangements in the gene encoding the NTRK1 receptor tyrosine kinase have been identified in 5-15% of papillary thyroid carcinomas (Figure 1). These are discussed further in Chapter 12. In essence, NTRK1 rearrangements bear strong resemblance to RET rearrangements in several respects. First, both NTRK1 and RET are receptors for neurotrophic ligands [103] and are not normally expressed in follicular epithelial cells. Second, both NTRK1 and RET rearrangements were identified by transfection of papillary carcinoma DNA into NIH3T3 cells [11, 14, 85]. Third, both NTRK1 and RET rearrangements arise frequently from subtle intra-chromosomal inversions. Fourth, both NTRK1 and RET rearrangements lead to expression of fusion proteins with constitutive tyrosine kinase activation. For example, rearrangements at 1q21 often fuse the NTRK1 tyrosine kinase domain to other proteins such as TPM and TPR [104-106]. Fifth, both NTRK1 and RET rearrangements may be more frequent in younger patients and in patients with lymph node metastases [95, 96, 107]. Last, the NTRK1 and RET fusion proteins activate related signal transduction pathways in thyroid follicular cells [66, 108-111] (Figure 3). Expression of the NTRK1 fusion proteins in the thyroid of transgenic mice leads to follicular hyperplasia- and papillary carcinoma-like proliferations [112].

RAS mutations

Somatic point mutations in RAS genes have been detected frequently in both non-thyroid [113] and thyroid (Figure 1) cancers. This contrasts the thyroid-specific gene rearrangements involving PPARy,RET, and NTRK1. RAS mutations are most common in follicular versus papillary and Hurthle cell tumors [33, 91, 114-120] and have been detected in 20-50% of follicular adenomas and carcinomas [33, 91, 119-122]. The presence of RAS mutations in both follicular adenomas and carcinomas is consistent with a model in which many RAS-initiated follicular carcinomas develop from adenoma (morphologic) precursors. Experimental evidence supports this contention in that mutated RAS is insufficient to induce a fully transformed phenotype in vitro [66, 123-126] or follicular carcinoma in vivo [127, 128]. N-RAS mutations appear to predominate over K-RAS and H-RAS mutations in follicular thyroid tumors and mutations in codon 61 of N-RAS may be the most prevalent [33, 119, 120, 129]. The possibilities that K-RAS mutations are more frequent in papillary compared to follicular thyroid tumors [114, 115, 130], radiation-associated carcinomas [114], and/or aggressive thyroid cancers [130] require further investigation, particularly in view of the primary role of K-RAS mutations in pancreatic ductal carcinomas [10, 131] that are highly aggressive.

Recent studies have correlated the clinical and pathologic features with RAS mutation status. Thyroid carcinoma patients with RAS mutations may present at older age and with larger tumors [33] and may more frequently have less differentiated, high stage cancers [130, 132-134]. Careful pathologic evaluation of classic from follicular variant papillary carcinomas has noted another potentially interesting pattern. Follic-ular variants seem to contain more N-RAS (75%) and H-RAS (25%) mutations and few if any RET rearrangements, whereas classic papillary carcinomas seem to contain more RET rearrangements (30-35%) and few if any RAS mutations [98]. Follicular variants papillary carcinomas also had statistically lower rates of lymph node metastases and higher rates of tumor encapsulation and vascular invasion (follicular carcinomalike features) compared to classic papillary carcinomas [98]. Thus, the existence of a morphologic and molecular "hybrid" thyroid cancer with some features of papillary and follicular carcinoma needs to be further explored.

Mouse modeling experiments have documented that RAS mutations are important role in tumorigenesis and tumor maintenance[128, 131, 135, 136] and RAS proteins transduce multiple stimuli from the thyroid follicular cell surface (Figure 3) as discussed further in Chapter 7.

BRAF mutations

Somatic point mutations in the BRAF gene have been identified recently in thyroid and other cancers [137]. BRAF encodes a serine/threonine kinase downstream of RAS and it transduces signals from multiple stimuli (Figure 3). A mutation that alters valine 599 to glutamic acid (V599E) in the BRAF kinase domain has been identified in 35-45% of papillary thyroid carcinomas [70, 90, 91, 120, 138-140] and in some undifferentiated/anaplastic thyroid carcinomas [90, 138]. BRAF mutations have been detected in few other benign or malignant thyroid tumors [70, 90, 91] and seem not to co-exist with RAS point mutations or RET rearrangements [70, 91, 138], thereby defining an additional sub-pathway in papillary carcinoma (Figure 1).

Papillary thyroid carcinoma patients with BRAF mutations tend to present at older age [90], at higher stage [90, 138], and with more frequent distant metastases compared to papillary carcinoma patients without BRAF mutation. Thus, mutated BRAF may define an aggressive papillary carcinoma form. In agreement with this possibility, mutated BRAF exhibits enhanced kinase activity and increased transformation efficiency compared to wild-type BRAF in vitro [137].

Thyroid stimulating hormone receptor and G protein mutations

Iodide uptake and thyroid hormone biosynthesis and metabolism are coordinately regulated with proliferation in thyroid follicular epithelial cells. These differentiated thyroid functions are controlled by the thyroid stimulating hormone receptor (TSHR) and its downstream signaling molecules (Figure 3) such as cyclic AMP and phospholi-pase C [141-143]. Somatic mutations in molecular components of the TSHR pathway have been detected in 60% or more of benign TSH-independent (autonomous/hyper-functioning) thyroid nodules. The remaining 40% of autonomous nodules are postulated to contain undefined alterations in the same TSHR system [144]. Approximately 90% of mutations involve TSHR, often in the third intracellular loop or transmembrane regions of this seven-spanning membrane receptor [145, 146]. 5-10% of the mutations involve the G protein subunit Gsa/gsp activated by TSHR ligands [147]. Thus, constitutive stimulation of the TSHR pathway underlies most autonomous thyroid tumors [148].

Autonomous thyroid tumors usually exhibit hyperplastic morphology and transgenic mice and other animal models with an activated TSHR-Gsa/gsp-cAMP axis [149, 150] develop follicular hyperplasia and hyper-functioning thyroid tumors, supporting a fundamental role of the TSHR system. Furthermore, nodular hyperthyroidism in non-autoimmune autosomal dominant hyperthyroidism [151] and the McCune-Albright Syndrome [152] have been associated with germ-line mutations in TSHR-Gsa/gsp axis. Although chronic stimulation of the TSHR pathway promotes formation of benign thyroid nodules, this seems to provide little increased risk of thyroid cancer. Additional cellular alterations [153], potentially including the down-regulation of are apparently required.

B-catenin and p53 mutations

Stage at presentation is a key prognostic factor in thyroid carcinoma. Mutations in the genes encoding B-catenin, a component of the Wnt signaling pathway [155], andp53, an important tumor suppressor and a sensor of genome stability, have been identified most often in advanced stage thyroid cancer. Mutations in exon 3 of B-catenin have been detected in 25-60% of poorly differentiated and anaplastic thyroid carcinomas [156, 157], and the expression of B-catenin protein is often reduced or re-localized from the plasma membrane to the cytoplasm and nucleus in these [156-158] and some follicular and papillary [157-160] thyroid carcinomas. p53 mutations have been identified mostly in poorly differentiated and anaplastic thyroid carcinomas [161-164] and they appear to interfere with differentiated functions in thyroid cells [165, 166] and promote thyroid cancer invasion and metastases in transgenic mouse models [83, 167]. The p53 pathways are discussed in detail in Chapter 8.

Aneuploidy and other chromosomal aberrations

A low level of chromosomal instability is observed in benign thyroid tumors and well-differentiated thyroid cancers such as papillary carcinoma, a moderate level of chromosomal instability is observed in follicular carcinoma, and higher levels of chromosomal instability are observed in Hurthle cell, poorly differentiated/anaplastic, and metastatic carcinomas. Thus, increased chromosomal instability and aneuploidy correlate generally with increased thyroid cancer aggressiveness. On the other hand, microsatellite instability is relatively infrequent in thyroid cancer [168-174]. Exposure to ionizing radiation increases genetic instability and thyroid carcinoma prevalence as discussed in Chapter 11.

Analyses of human thyroid tumors with conventional cytogenetics and fluorescence in situ hybridization have identified additional recurrent chromosomal abnormalities. Hyperplastic nodules from thyroid goiters often contain one or two clonal numerical changes, including trisomies of chromosomes 7, 10, 12, 17, and/or 22, whereas follicular adenomas more frequently contain three or more numerical chromosomal alterations and/or balanced chromosomal rearrangements [25, 175-178]. However, it should be kept in mind that karyotypes frequently present an incomplete picture of chromosomal content because the cultures may frequently appear diploid as the result of contaminating normal cells. All suspected genetic alterations must be verified in primary thyroid tumor tissues.

The chromosomal regions 2p21 and 19q13 are rearranged in approximately 10% and 20%, respectively, of thyroid follicular adenomas with clonal cytogenetic aberrations. Both the 2p21 [26, 175, 179] and 19q13 [24, 175, 180] loci fuse with multiple different partner chromosomes in different follicular adenomas. The 2p21 and 19ql3 breakpoints have been mapped using follicular adenoma cell lines that contain t(2;7)(p21;p15), t(2;20;3)(p21;q11;p25), t(5;19)(q13;13), or t(1;19)(p35;q13).The 2p21 breakpoint appears to involve a novel candidate gene termed THADA [181, 182] and the 19q13 breakpoint a novel transcription factor gene termed ZNF331/RITA [183-185]. It will be informative to define the cell biologic and biochemical mechanisms of these new thyroid rearrangements.

Additional genetic imbalances have been defined in follicular thyroid tumors using loss of heterozygosity studies and comparative genomic hybridization techniques. Genetic gains predominate over losses in follicular adenomas, whereas genetic losses predominate over gains in follicular, Hurthle, and anaplastic thyroid carcinomas. The most consistent losses in follicular cancers involve chromosomes 2p [186-189], 2q [186-188], 3p [169, 174, 187-191], 7q [188, 192, 193], 9 [174, 187, 188, 194, 195], 10q [196-198], 11q [187, 189, 195, 197, 199, 200], 13q [187, 188, 196, 197], 17q [201], 18q [174, 187, 197], and 22q [187, 188, 195, 202, 203] regions. In addition to these losses, Hurthle cell carcinomas harbor deletions at 1q, 8q, 9q, 14q, and 17p [174, 194, 201]. The possibility that at least some of these genomic loci contain genes important in thyroid tumor pathogenesis is reinforced by the fact that three regions (2q13, 3p25 and 7q31) have been shown to be involve follicular carcinoma rearrangements [12, 30]. Thus, functionally important loci may be targeted by multiple genetic mechanisms.

Summary

Knowledge of the molecular events that govern human thyroid tumorigenesis has grown considerably in the past ten years. Key genetic alterations and new onco-genic pathways have been identified. Molecular genetic aberrations in thyroid carcinomas bear noteworthy resemblance to those in acute myelogenous leukemias. Thyroid carcinomas and myeloid leukemias both possess transcription factor gene translocations in thyroid carcinoma and and CBF-related translocations (amongst others) in myeloid leukemia [204]. PPARy and RARa are closely related members of the same nuclear receptor subfamily, and the and fusion proteins both function as dominant negative inhibitors of their wild-type parent proteins [12, 205, 206]. Thyroid carcinomas and myeloid leukemias [207-210] also both harbor NRAS mutations (15-25% of both cancers) and receptor tyrosine kinase mutations - RET mutations in thyroid carcinomas and FLT3 mutations in myeloid leukemias [211, 212]. The NRAS and tyrosine receptor kinase mutations are not observed in the same thyroid carcinoma or leukemia patients [209, 213], suggesting that multiple initiating pathways exist in both. Lastly, thyroid carcinomas [214] and myeloid leukemias [209, 215] possess p53 mutations at relatively low frequency (10-15%) in patients who tend to be older and have more aggressive, therapy resistant disease. Such parallels are unlikely to occur by chance alone and argue that common mechanisms underlie these diverse epithelial and hematologic cancers.

The comparison of thyroid carcinomas and myeloid leukemias may highlight areas of thyroid cancer investigation worthy of further focus. For example, few collaborating mutations have been defined in thyroid carcinomas even though they play a clear role in myeloid leukemias [212, 216], as exemplified by RARa rearrangements [217, 218] and FLT3 mutations [219] that together dictate the promyleocytic leukemia phenotype. Functional interactions between collaborating mutations are possible at multiple levels, and it is tempting to speculate that some thyroid carcinomas might develop through an unique combination or co-activation of RET and RAS and/or RET and PPARy (and/or other) signaling systems. In fact, the ELE1-RET (PTC3) fusion protein contains the ELE1 nuclear receptor co-activator domain [220, 221] and it appears to physically associate with and inhibit wild-type in some papillary carcinomas [222].

The similarities of the fusion proteins in thyroid carcinoma and myeloid leukemia suggest that a more directed search for fusion genes in non-thyroid carcinomas is warranted. In fact, novel fusion genes have been identified recently in aggressive mid-line [223, 224], secretory breast [225], and renal cell [226-232] carcinomas, although the epithelial nature of the latter is not well-documented. Interestingly, these cancers all tend to present more frequently in adolescence and young adulthood in a manner similar to thyroid and myeloid [233] malignancies that have fusion genes. The analyses of cancers that present earlier in life may enhance fusion gene recognition in other carcinoma types.

Definition and biologic characterization of the precursor cells that give rise to thyroid carcinoma will also be important. Myeloid leukemias are thought to arise from stem/progenitor cells that acquire disturbed self-renewal and differentiation capacities but retain characteristics of the myeloid lineages. Although the presence of comparable stem/progenitor cells in the thyroid are not defined, distinct thyroid cancer lineages and patterns of differentiation exist and candidate stem/progenitor cells such as the p63-immunoreactive solid cell nests [234] are apparent.

A last important area is development of molecular-based therapies for thyroid carcinoma patients resistant to standard radio-iodine treatment. Treatments for such cancers are limited and pathways defined by thyroid cancer mutations are prime targets for pharmacologic interventions with molecular inhibitors. Tyrosine kinase inhibitors [235-239] and nuclear receptor ligands [240-242] have proven dramatically effective in some myeloid leukemia patients. Various molecular inhibitors are being investigated now in thyroid cancer models [45, 243-249]. Such developments predict that the thyroid cancer model will continue to provide biologic insights into human carcinoma biology and that improved pathologic diagnosis and treatment for thyroid cancer patients sit on the not too distant horizon.

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