REVIEW

Mechanisms Linking Obesity and Thyroid Cancer Developmentand Progression in Mouse Models

Won Gu Kim1,2& Sheue-yann Cheng1

Received: 7 November 2017 /Accepted: 20 December 2017 /Published online: 19 January 2018

AbstractRecent compelling epidemiological studies indicate a strong association of obesity with thyroid cancer. Obesity has been shownto promote thyroid cancer progression and exacerbate poor outcome in thyroid cancer patients. However, the molecular mech-anisms by which obesity increases thyroid cancer risk and facilitates cancer progression are not completely understood. Obesityinduces complex pathological changes including hyperglycemia, hyperinsulinemia, hyperlipidemia, oxidative stress, adipokines,and inflammatory responses. These changes can affect the development and progression of cancer through highly complexinteractions in vivo. The deleterious effect of obesity may differ according to the different cancer types. In view of the increasedincidence of thyroid cancer in parallel with the widespread occurrence of obesity in the past decades, it is imperative to clarifyhow obesity affects thyroid carcinogenesis. This review focuses on molecular mechanisms by which obesity aggravates thyroidcarcinogenesis as elucidated by mouse models of thyroid cancer.

Introduction

Thyroid cancer is the most common endocrine malignancy,and its incidence has risen rapidly in recent decades all overthe world [1–5]. The increased use of ultrasonography for thedetection of small papillary thyroid carcinoma (PTC) cannotfully explain this increase in thyroid cancer incidence [1].Previous epidemiological studies suggested that only abouthalf of this increase results from screening using ultrasonog-raphy for early detection while the rest could be attributable toenvironmental factors such as obesity and cigarette smoking[1, 3, 6–8].

The prevalence of obesity has been increasing, not only inadults but also in children and adolescents, in parallel with theincreases in thyroid cancer incidence in the USA and else-where [9–11]. Several epidemiological studies provide com-pelling evidence that obesity is associated with an increased

risk of thyroid cancer [9–14]. A recent meta-analysis foundthat the risk of thyroid cancer was 25% greater in overweightand 55% greater in obese individuals than their normal-weightpeers [13]. A pooled analysis of 22 prospective studiesshowed that each 5-unit increase of body mass index (BMI),young-adult BMI, adulthood BMI gain, and waist circumfer-ence (per 5 cm) were associated with 6, 13, 7, and 3% greaterrisks of thyroid cancer, respectively [14]. These associationswere consistently observed in all major pathological subtypesof thyroid cancer except medullary thyroid cancer [13, 14].Several studies also suggested that overweight and obesity aresignificantly associatedwithmore aggressive clinicopatholog-ical features in patients with thyroid cancer [15–17]. Thesefindings underscore the need to study molecular mechanismsunderlying the effects of obesity on thyroid carcinogenesis.

Obesity is known to cause an array of complex and diversemetabolic changes through accumulation of adipocytes.Adipose tissue is considered an endocrine organ that secretesvarious adipokines involved in metabolic regulation and in-flammatory processes [18]. Dysregulation of the endocrinefunction of adipose tissue leads to hyperglycemia, hyperlipid-emia, and insulin resistance. As illustrated in Fig. 1, obesity,due to excessive accumulation of adipose tissues, leads to theincreased secretion of adipokines, increased inflammatory re-sponses, and other metabolic changes that could impact thedevelopment and progression of many cancers. In this review,we highlight the molecular mechanisms by which obesity

* Sheue-yann Chengchengs@mail.nih.gov

1 Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, 37 Convent Drive, Room 5128,Bethesda, MD 20892-4264, USA

2 Division of Endocrinology and Metabolism, Department of InternalMedicine, Asan Medical Center, University of Ulsan College ofMedicine, Seoul 05505, South Korea

Hormones and Cancer (2018) 9:108–116https://doi.org/10.1007/s12672-017-0320-7

# Springer Science+Business Media, LLC, part of Springer Nature (outside the USA) 2018

aggravates thyroid carcinogenesis which has been uncoveedin studies using mouse models of thyroid cancer.

Obesity in Mouse Models of Thyroid Cancer

A diet-induced obesity model has been widely used to evaluatethe effects of obesity on human diseases. The effect of obesityon thyroid carcinogenesis was studied using mouse models offollicular thyroid cancer (FTC). The mouse, which harbors aknock-in dominant negative mutation (denoted as PV) in theThrb gene, spontaneously develops metastatic FTC [19]. TheThrbPV/PV mice showed pathological progression of capsularand vascular invasion, lung metastases, and anaplastic changessimilar to human thyroid cancer [20]. Additionally, deletion ofone allele of the Pten gene (phosphatase and tensin homologdeleted from chromosome 10) into ThrbPV/PVmice reduced thetime required for spontaneous development and progression ofFTC in ThrbPV/PVPten+/− mice [21]. The loss of one allele ofthe tumor suppressor, the Pten gene, induces furtheroveractivation of phosphatidylinositol 3-kinase (PI3K) andprotein kinase B (AKT) signaling pathway in thyroid cancerof ThrbPV/PVPten+/− mice with more aggressive thyroid cancerand shorter survival than in ThrbPV/PV mice [21].

This double mutant mouse model has provided an oppor-tunity to evaluate the effects of diet-induced obesity on thecarcinogenesis of the thyroid [22] . Feeding ThrbPV/PVPten+/− mice with high fat diet (HFD) for 15 weeks successfullyinduced the phenotype of obesity in this mouse model withbody weight gain and increases of adiposity [22]. Virtually allThrbPV/PVPten+/− mice exhibited early-phase thyroid cancerdevelopments such as thyroid hyperplasia and capsular inva-sion (Fig. 2a), which were similarly detected in the doublemutant mice treated with HFD. Remarkably, anaplastic

transformation of thyroid cancer was promoted by HFD-induced obese ThrbPV/PVPten+/− mice (Fig. 2b) [22]. About62% of thyroid cancers in the HFD group underwent anaplas-tic transformation versus only 24% in the low fat diet (LFD)group (Fig. 2a). Microscopic examination of H&E-stainedtumor sections of representative HFD group samples indicateda loss of glandular differentiation and spindle cell anaplasia(Fig. 2b). The tumor weights of the HFD group (n = 26) weresignificantly higher than those of the LFD group (n = 25,p < 0.001), as shown in Fig. 2c. The survival of the HFDgroup was significantly shorter than the LFD group (p =0.02, Fig. 2d) [22].

Currently, it was not entirely clear the underlying molecularmechanisms by which obesity led to anaplasia. Anaplastictransformation occurs in the advanced stage of thyroid carcino-genesis, suggesting that additional Bhits^ could be acquiredduring cancer progression. Indeed, findings from next genera-tion sequencing supported the notion that anaplastic thyroidcancer was derived from well differentiated thyroid carcinomathrough accumulation of genetic abnormalities [23, 24]. InHFD-ThrbPV/PVPten+/− mice, serum leptin was elevated,resulting in the activation of JAK-STAT3 signaling [22].Several downstream effectors in JAK-STAT3 signaling, suchas c-MYC, were found to be also elevated [22]. It is known thatc-MYC induces cell de-differentiation. In human anaplasticthyroid cancer, c-MYC was shown over-expressed [25]. Onemechanism bywhich over-expression of c-MYCwas found viaactivation of super-enhancers through chromatin remodeling[26]. However, the over-expression of c-MYC could also bedue to gene amplification and/or other genetic aberrationevents. Such changes could be broadly considered as additionalBhits^ to affect anaplastic transformation, which is linked close-ly with the up-stream events initiated from obesity.

Obesity affects the secretion of adipokines, the hormonessecreted by adipocytes, with increased leptin and decreasedadiponectin levels being well known examples [27]. It isknown that leptin binds to its receptor, leading to the activa-tion of intracellular Janus kinase 2 (JAK2)-signal transducerand activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling system, therebypromoting the growth of cancer cells [28, 29]. On the otherhand, adiponectin inhibits the PI3K-AKT-mechanistic targetof rapamycin (mTOR) signaling through activation of adeno-sine monophosphate-activated kinase (AMPK), which playsan important role in intracellular energy metabolism and in-hibits the growth of cancer cells [28, 30]. Thus, the decrease ofadiponectin caused by obesity may play an important role inthe development and progression of cancer. These findingssuggest that the change in adipokine plays an important rolein thyroid cancer. A previous study revealed that leptin andleptin receptors were over-expressed in human PTCs and wereassociated with a more aggressive cancer phenotype [31].Studies also suggested that the expression of both leptin and

Fig. 1 Various pathways may explain the mechanism by which obesityinduces carcinogenesis and exacerbates cancer progression. Obesityincreases adipocytes, and the extent of systemic inflammation, andoxidative stress. Insulin resistance induced by obesity results inincreased serum insulin levels, augmented IGF-1 signaling, increasesserum leptin levels and suppresses serum adiponectin levels. Increasesin insulin resistance, IGF-1 signaling, oxidative stress, free fatty acid(FFA), inflammatory signaling, and changes in adiopkines and other mac-romolecules, may contribute to cancer progression, and metastasis

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its receptor was regulated by insulin epigenetically [32]. Anin vitro study using thyroid cancer cells demonstrated thatleptin induced cancer cell proliferation and migration andinhibited apoptosis [33, 34]. In ThrbPV/PVPten+/− mice, serumleptin levels were significantly increased by HFD-inducedobesity (Fig. 2e), whereas there was no signification differ-ence in serum adiponectin levels (Fig. 2f) [22]. Increased se-rum leptin levels were detected in obese ThrbPV/PVPten+/−

mice [22]. Moreover, over-activation of the JAK2-STAT3 sig-naling pathway and increased expression of STAT3 targetgenes were found in obese ThrbPV/PVPten+/− mice [22].These findings indicate that increased serum leptin levels are

involved in promoting the progression of thyroid cancer byactivating the JAK2- STAT3 signaling.

Recent studies compared the effects of leptin and orallyavailable leptin-derived peptide, OB3 in thyroid cancer cells[35]. OB3 has shown to be effective appetite suppression sim-ilarly as metformin in preclinical studies [36, 37]. Leptin stim-ulated thyroid cancer cell invasion through activation ofSTAT3 and MAPK pathway. However OB3 did not affectcancer cell proliferation and invasion [35]. Besides, OB3 re-ported to suppress leptin-induced signaling and progression ofovarian cancer cells [38]. These findings suggested that po-tential reduction of serum leptin levels by metformin or OB3

Fig. 2 HFD-induced obesity induces aggressive phenotype in ThrbPV/PVPten+/− mice. a Pathological changes in thyroid cancer progression inhigh-fat diet (HFD) group and low-fat diet (LFD) group. There was sig-nificant increase in anaplastic transformation after HFD-induced obesity.b Anaplastic transformations in HFD-induced obese ThrbPV/PVPten+/−

mice. H&E-stained thyroid tumor sections of LFD-treated ThrbPV/PVPten+/− mice are shown in panels a and a′at low magnification andhigh magnification, respectively. H&E-stained thyroid tumor sections ofHFD-treated ThrbPV/PVPten+/− mice are shown in panels b, c, d, and eand in b′, c′, d′, and e′ at low and high magnification, respectively.

Representative samples of anaplastic loci indicated by arrows are appar-ent at low magnification in panels b, c, d, and e (×20). The foci areselected shown at high magnification in the corresponding panels b′, c′,d′, and e′ (×80). c The weights of thyroid tumors in HFD group and LFDgroup, presented as mean ± SE. The difference was analyzed by Student’st test. d The survival of ThrbPV/PVPten+/−mice was shorter in HFD groupthan LFD group. The Kaplan-Meier curves were compared by the log-rank test. e, f The serum leptin and adiponectin concentrations in wild-type and ThrbPV/PVPten+/− mice treated with LFD or HFD. [24]

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could be useful to suppress leptin-induced stimulation in can-cer progression.

JAK-STAT3 Signaling in Obese Mouse Modelsof Thyroid Cancer

Activation of the JAK-STAT3 signaling pathway has beenshown to be associated with increased invasion and metastasisin various types of cancer [39]. In normal cells STAT3 signal-ing is tightly controlled by a negative feedback mechanisminvolving the suppressors of cytokine signaling (SOCS) andtyrosine phosphatases, whereas in cancer cells constitutiveactivation of STAT3 is common [39]. Overexpression ofSTAT3 signaling is also associated with lymphatic metastasisof thyroid cancer [40, 41]. The role of JAK-STAT3 signalingin the anaplastic transformation of FTC was confirmed bytreating ThrbPV/PVPten+/− mice with the STAT3 selective in-hibitor, S3I-201 [42]. This inhibitor, which was identifiedthrough structure-based virtual screening of the NationalCancer Institute libraries, has shown its effectiveness in theinhibition of STAT3 activity in both in vitro and in vivo stud-ies [43]. S3I-201 treatment significantly reduced the thyroidtumor weight of obese ThrbPV/PVPten+/−mice (thyroid cancerincidence Fig. 3a). The median survival of obese ThrbPV/PVPten+/− mice treated with S3I-201 was significantly longer(1 month) than vehicle-treated mice (Fig. 3b). Moreover, thisinhibitor suppressed the phosphorylation of tyrosine 705(Y705), critical for STAT3 activation (Fig. 3c). Inhibition ofSTAT3 activity led to the suppression of downstream targetgenes such as Ccnd1, Myc, Bcl2, Mcl1, and Socs3, thus con-tributing to the delayed tumor growth and survival [42]. Thereduced expression of Ccnd1, Myc, and Bcl2 can inhibit can-cer cell proliferation and promote cancer cell survival [44].Detailed molecular analysis also revealed that inhibition ofSTAT3 reduces the expression of cell cycle regulators to in-hibit thyroid tumor cell proliferation without evidence of anychange in thyroid function [42]. Inhibition of the STAT3 sig-naling pathway also delayed thyroid cancer progression. Asshown in Fig. 3d, the anaplasia phenotype in vehicle-treatedthyroid tumors reverted to a less progressed vascular invasion(panel d). While we saw metastases in the lung of vehicle-treated obese ThrbPV/PVPten+/− mice (panel c′), none wereobserved in the lung of inhibitor-treated mice ((panel d′),Fig. 3d). These findings further strengthen the notion thatelevated leptin could promote carcinogenesis via JAK-STAT3 signaling in obese ThrbPV/PVPten+/− mice.

Therapeutic Potential of Metformin in ObesityAssociated with Thyroid Cancer

With well-established efficacy and safety profiles, metforminis the most widely used anti-diabetes drug for treatment ofpatients with type II diabetes. Metformin has shown anti-

cancer activities in both in vitro and in vivo studies for manycancers [45]. The molecular basis by which metformin actsbeneficially for patients remains inconclusive. Both direct andindirect effects of metformin have been proposed for anti-cancer properties, such as a direct inhibition of the AMPK/mTOR signaling pathway and/or an indirect lowering of glu-cose, insulin, and anti-inflammatory effects [46, 47]. Clinicalstudies have shown that metformin has anti-proliferative ef-fects in early breast cancer and suppresses precancerous le-sions in colorectal cancer [48–50]. Results of meta-analysessuggest a possible role for metformin in the primary preven-tion of cancer, as well as survival benefits of metformin’s usein cancer patients [51–53]. A recent meta-analysis also sup-ports the use of metformin as an adjuvant therapeutic agent,especially in patients with colorectal and prostatic cancer whohave undergone radical radiotherapy [54].

In two studies, the use of metformin was associated withbetter prognostic factors and treatment outcomes in diabeticpatients with thyroid cancer [55, 56]. One of these studiesshowed that primary tumor size is smaller in patients treatedwith metformin, suggesting it inhibits tumor growth [55].The other cohort study reported significantly lower recur-rence of differentiated thyroid cancer in diabetic patientstreated with metformin [56]. Several in vitro studies revealedthat metformin inhibits cell proliferation in thyroid cancercells including PTC, medullary, and anaplastic thyroid can-cer (ATC) cells [55, 57–60]. Metformin inhibits cancer cellgrowth by activation of AMPK and downregulation of themTOR signaling pathway in PTC and FTC cell lines [55]. InATC cell lines, metformin showed anti-mitogenic effects byinhibition of cell cycle progression and induction of apopto-sis [57]. Metformin also potentiated the effects of chemo-therapeutic agents such as doxorubicin and cisplatin in ATCcells [57]. These observations suggest the possibility of clin-ical use of metformin as an adjuvant treatment for patientswith ATC.

The beneficial effects of metforminwere also demonstratedin vivo in HFD-induced obese ThrbPV/PVPten+/− mice. HFD-induced obesity promoted the anaplastic transformation ofthyroid cancer in ThrbPV/PVPten+/−mice [22]. HFD promotedtumor progression from extensive hyperplasia (Fig. 4a, panela) and early vascular invasion (panel b) in the thyroid of LFD-ThrbPV/PVPten+/− mice to the more advanced stages of vascu-lar invasion (panel e) and anaplasia (panel f) [61]. Treatmentwith metformin from the age of 6 to 21 weeks reduced tumorprogression from vascular invasion (Fig. 4a, panel b) to hy-perplasia (panel d) in LFD-ThrbPV/PVPten+/− mice [61]. Moreimpressively, metformin markedly reduced the tumor pheno-types from vascular invasion (Fig. 4a, panel e) and anaplasia(panel f) to capsular invasion (panel h) in HFD-ThrbPV/PVPten+/− mice [61]. The beneficial effects of metformin onthe pathological changes are clearly evident in reduced capsu-lar invasion (Fig. 4b) and blocked occurrence of vascular

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invasion (Fig. 4c) and anaplastic transformation (Fig. 4d) inHFD-ThrbPV/PVPten+/− mice [61] . These beneficial effects ofmetformin on thyroid cancer progression support the use ofmetformin as an adjuvant therapy for patients with refractorythyroid cancer or ATC.

Metformin acts through three different mechanisms to de-lay thyroid carcinogenesis of HFD-ThrbPV/PVPten+/− mice.

The first is that metformin inhibits the activation of theSTAT3 signaling pathway in this mouse model. One studyfound that the activation of leptin-JAK2-STAT3 signaling ac-counts for the HFD-induced promotion of thyroid cancer pro-gression in ThrbPV/PVPten+/− mice [22]. Another showed thatmetformin treatment reduces the HFD-induced activation ofSTAT3 signaling by decreasing the extent of phosphorylation

Table 1 Summary ofphenotypical changes in a mousemodel of thyroid cancer

Animal model Intervention Phenotype Reference

ThrbPV/PVPten+/− HFD-induced obesity Large tumor size, shorter survival,more anaplastic change

22

ThrbPV/PVPten+/− STAT3 inhibitor, S3I-201 Delay tumor growth and survival,inhibit lung metastasis

42

ThrbPV/PVPten+/− Metformin Reduce capsular invasion, vascularinvasion, and anaplasia

61

Fig. 3 The effects of STAT3 inhibitor, S3I-201, in HFD-treated obeseThrbPV/PVPten+/− mice. a Survival curves for HFD-ThrbPV/PVPten+/−

mice treated with S3I-201 or vehicle. Intraperitoneal injection three timesa week from 8 weeks of age until they had to be euthanized because ofsickness. Data are presented by Kaplan-Meier methods and analyzed bylog-rank test. The p values are indicated. b Thyroid weights of vehicle-treated or S3I-201-treated wild-type or ThrbPV/PVPten+/−. cWestern blotanalysis of protein abundance of leptin receptor, phosphorylated -JAK2(Y1007/1008), total JAK-2, phosphorylated STAT3 (Y705), total-

STAT3, and GAPDH as a loading control after treatment with vehicleor S3I-201 in wild-type and ThrbPV/PVPten+/− mice. d Representativeexamples of hematoxylin and eosin (H&E)-stained thyroid sections fromwild-type mice treated with vehicle (panel a) and S3I-201 (panel b) andlung sections treated with vehicle (panel a′) and S3I-201 (panel b′) andthyroid tumor sections from ThrbPV/PVPten+/− treated with vehicle (panelc) and S3I-201 (panel d) and lung sections treated with vehicle (panel c′)and S3I-201 (panel d′). The arrows indicate vascular invasion (panel d)and anaplasia (panel c). [36]

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of STAT3 at tyrosine 705, which is critical for STAT3 activa-tion, in these mouse thyroid tumor tissues [61]. The secondmechanism is that metformin inhibits the extracellular signal-regulated kinase (ERK) signaling pathway. Leptinmediates itseffects via not only STAT3 signaling, but also ERK signaling[62]. That metformin treatment attenuates the HFD-inducedactivation of ERK signaling is made evident by the reducedphosphorylation of ERK proteins in thyroid tumors [61]. Thethird mechanism by which metformin delays thyroid carcino-genesis is through its effect on cytoskeletal structure, cancercell motility, and migration via inhibition of the epithelial-mesenchymal-transition (EMT) and fibronectin (FN)-integrinsignaling pathway in HFD-ThrbPV/PVPten+/− mice [61].Metformin treatment significantly decreases the expressionof vimentin, a type III intermediate filament protein and amajor cytoskeletal component in mesenchymal cells [61].FN and its receptors such as integrins α6, β1, and β3 wereabundant in thyroid tumors from HFD-ThrbPV/PVPten+/−

mice, and metformin treatment markedly reduced the proteinlevels of FN and integrins [61]. Currently, the detailed molec-ular basis underlying the metabolic effects of metformin arenot completely understood. However, these findings suggestthat metformin could act could act in vivo in ways other than

inhibiting the AMPK and mTOR pathways. These newly dis-covered pathways mediated bymetformin could play a criticalrole in thyroid cancer.

Perspectives and Future Directions

The in vivo molecular evidence presented in this review clearlydemonstrates that obesity could impact thyroid carcinogenesisin a mouse model of thyroid cancer, ThrbPV/PVPten+/− mice.HFD-induced obesity accelerates the growth and progressionof thyroid cancer, notably shortening survival and promotinganaplastic transformation. These changes were elucidated viathe HFD-induced elevated leptin to act through the JAK2-STAT3 signaling pathway. Preclinical targeting of the STAT3by using a STAT3-specific inhibitor, S3I-201, further validatedthe relevance and the critical role of the leptin downstreameffector in obesity-activated thyroid carcinogenesis. ThatSTAT3 could be a potential target raised the possibility thatthe findings from the mouse model could be translated to clin-ical practice. Oral STAT3 inhibitors and anti-sense STAT3(AZD9150) are emerging as potential anti-cancer agents andare being tested in various phases of clinical trials for solidtumors, refractory hematological malignancies, lung, and head

Fig. 4 Effects of metformin on thyroid cancer progression of LFD- orHFD-ThrbPV/PVPten+/−mice. a Representative examples of hematoxylinand eosin (H&E)-stained thyroid sections from the vehicle-treated LFD(panels a and b), metformin-treated LFD (panels c and d), vehicle-treatedHFD (panels e and f), metformin-treated HFD (panels g and h) groups ofThrbPV/PVPten+/− mice. The magnification is ×166. Arrows indicatepathological features of vascular invasion (panel e), capsular invasion(panels d and h) and anaplasia (panel f). The detailed pathological features

are enlarged in a higher magnification of ×332. b–d Pathologic analysisof the vehicle-treated LFD (n = 25), metformin-treated LFD (n = 13),vehicle-treated HFD (n = 26), and metformin-treated HFD (n = 18)groups of ThrbPV/PVPten+/− mice. The prevalence of each pathologicfeature in mice treated with vehicle or metformin is shown as percentageof occurrence for capsular invasion (b), vascular invasion (c), and ana-plasia (d). *Represents no occurrence. [55]

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and neck cancers [63–69]. Currently, there are no ongoing trialsfor STAT3 inhibitors in obesity-activated thyroid cancer.However, the successful trials of STAT3 inhibitors in the can-cers just mentioned could pave the way for future testing ofSTAT3 inhibitors on thyroid cancer exacerbated by obesity.

The finding that metformin could delay obesity-activatedthyroid cancer progression provides an extraordinary opportu-nity for a novel treatment modality for thyroid cancer. At pres-ent, five active phase III clinical trials are using metformin as asingle or combination treatment strategy in breast, endometrial,prostatic cancer, colorectal, and hepatocellular carcinoma(https://clinicaltrials.gov). Two clinical trials in colorectal(NCT02614339) and hepa toce l lu l a r ca rc inoma(NCT03184493) are in the clinical setting of adjuvant therapyafter the initial cancer treatment. The other clinical trial is for thecombination treatment with standard chemotherapy in ad-vanced or recurrent endometrial cancer (NCT02065687).Interestingly, two active phase III clinical trials usingmetforminare for preventing progression of low-risk prostatic cancer(NCT01864096) and progression of breast cancer in patientswith atypical hyperplasia or in situ breast cancer (NCT01905046). However, no ongoing clinical trial is evaluatingtherapeutic effects of metformin on thyroid cancer. Two activeclinical trials are for the purpose of mitigating the side effects ofradioactive iodine treatment by the use of metformin in patientswith differentiated thyroid cancer (NCT0309847) and evaluat-ing the effects of metformin use on volume change of benignthyroid nodules (NCT03183752). Taken together, the currenttrials testing metformin as a therapeutic for other cancers andthe preclinical positive findings thus far from the mouse modelsuggest that metformin could be beneficial for obesity-activatedthyroid cancer. Future studies are needed to bring metformin tothe forefront of treatment modalities for thyroid cancer.

The present review highlights the contribution of the leptin-JAK2-STAT3 signaling pathway to the development and pro-gression of obesity-activated thyroid cancer. This, however, isonly one aberrant pathway that is affected by obesity. Obesitycauses a barrage of changes in the human body associated withcancer development, including alterations in insulin/IGF-1 sig-naling, fatty acids/lipid signaling, oxidative stress, adipokines,and inflammation. It would be useful to dissect the contribu-tions of these different signaling pathways in obesity-activatedthyroid carcinogenesis. By doing so, a better picture of howobesity impacts thyroid carcinogenesis would emerge.Importantly, these molecular mechanisms thus identified couldbe used as the basis for discovering and applying novel thera-peutic targets for cancer treatment associated with obesity.

Acknowledgments We regret any reference omissions due to length lim-itation. We wish to thank all colleagues and collaborators who have con-tributed to the work described in this review. The research described in thisreview by the authors and their colleagues at the National Cancer Institutewas supported by the Intramural Research Program of the Center forCancer Research, National Cancer Institute, National Institutes of Health.

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