Metformin Inhibits Growth of Thyroid Carcinoma Cells, Suppresses Self-Renewal of Derived Cancer Stem Cells, and Potentiates the Effect of Chemotherapeutic Agents

Chen, Guofang; Xu, Shuhang; Renko, Kostja; Derwahl, Michael

doi:10.1210/jc.2011-1754

Cited by 177 publications

(153 citation statements)

References 32 publications

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“…This finding is in good agreement with the results of an experimental study (14), in which an inhibitory effect of metformin on the growth of thyroid cells derived from nodular goiters was demonstrated. Metformin directly inhibits thyroid growth by activation of the AMPK/mammalian target of rapamycin (mTOR) pathway and antagonized the growth-stimulatory effect of insulin by inhibition of the MAPK pathway (14). Furthermore, in T2DM, metformin reduces insulin resistance and in turn hyperinsulinemia mainly by decreasing gluconeogenesis in the liver (24).…”

Section: Discussionsupporting

confidence: 92%

“…However, that study (13) did not explicitly focus on T2DM and also did not consider antidiabetic drug intake. Focusing on the relationship between metformin and thyroid volume, a recent experimental study (14) demonstrated an inhibitory effect of metformin on the growth of human thyroid cells. Thus, it is intriguing to hypothesize that an association between T2DM and goiter, if existent, might be modulated by metformin use.…”

Section: Introductionmentioning

confidence: 99%

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Metformin inhibits goitrogenous effects of type 2 diabetes

Ittermann

Markus

Schipf

et al. 2013

European Journal of Endocrinology

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Objective: Data on the association between type 2 diabetes mellitus (T2DM) and thyroid volume are sparse. An experimental study demonstrated an inhibitory effect of metformin on the growth of human thyroid cells. So far no study on humans has investigated potentially modulating effects of metformin on the association between T2DM and thyroid volume. Therefore, we investigated these effects in a population-based cohort study. Design and methods: We used data from the Study of Health in Pomerania and included 2570 individuals for cross-sectional and 1088 individuals for longitudinal analyses. T2DM was defined by physician-diagnosed self-report or intake of antidiabetic medication. Results: In the cross-sectional data, females with T2DM treated with antidiabetic medication other than metformin had a larger thyroid volume (bZ4.69; 95% CI 1.87 to 7.50) and a higher odds ratio (OR) for goiter (ORZ1.71; 95% CI 1.05 to 2.79) than females without T2DM, whereas in males, no such association was detected. In females or males treated with metformin, T2DM was not associated with thyroid volume or goiter. In longitudinal analyses, incident T2DM not treated with metformin was significantly associated with a higher risk for incident goiter in the total population (incidence rate ratio (IRR)Z1.70; 95% CI 1.10 to 2.91). Individuals with T2DM having changed from metformin to other antidiabetic agents during follow-up also had a higher risk for incident goiter than individuals without T2DM (IRRZ2.71; 95% CI 1.74 to 4.20). Conclusions: We demonstrate an inhibitory effect of metformin on prevalent and incident goiter. Antigoitrogenous effects of metformin add to the general benefits of metformin treatment of T2DM.European Journal of Endocrinology 169 9-15

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Metformin inhibits goitrogenous effects of type 2 diabetes

Ittermann

Markus

Schipf

et al. 2013

European Journal of Endocrinology

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“…Besides, in vitro study, our study showed that metformin exerted a growthinhibitory effect on primary thyrocytes and thyroid cancer cells by reducing hyperinsulinemia and by a direct cellular action, including inhibition of cell cycle progression and induction of apoptosis (Chen et al 2012). Metformin markedly diminished growth stimulation by insulin on differentiated human thyroid cells, anaplastic thyroid carcinoma cells, a doxorubicin-resistant thyroid carcinoma cell line and thyroid cancer stem cells.…”

Section: Metformin and Thyroid Carcinomamentioning

confidence: 65%

“…Metformin was found to antagonize the growthstimulatory effect of insulin in vitro (Chen et al 2012). With addition of metformin, the insulin-induced increase of cell proliferation was almost abolished.…”

Section: Metformin and Ir In Thyroid Nodulesmentioning

confidence: 94%

Metformin and thyroid disease

Meng

Chen

et al. 2017

Journal of Endocrinology

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An intriguing area of research in thyroidology is the recently discovered association of insulin resistance with thyroid functional and morphological abnormalities. Individuals with hyperinsulinemia have larger thyroid gland and a higher prevalence of thyroid nodules and cancer. Accordingly, patients treated with metformin have a smaller thyroid volume and a lower risk of incident goiter, thyroid nodule and cancer. Multiple studies in vitro and in vivo have demonstrated that metformin can inhibit the growth of thyroid cells and different types of thyroid cancer cells by affecting the insulin/IGF1 and mTOR pathways. Besides, metformin treatment was associated with a decrease in the levels of serum thyroid-stimulating hormone (TSH) in diabetic patients possibly by enhancing the effects of thyroid hormones in the pituitary and activating the adenosine monophosphate-activated protein kinase (AMPK). Based on this evidence, metformin appears to be a promising therapeutic tool in patients with thyroid disease. More clinical studies are necessary to evaluate the clinical significance of metformin for the treatment of thyroid diseases.

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“…in a serumfree medium, results in the formation of thyrospheres, although the size of the spheres is smaller than that of those generated in the presence of EGF and bFGF (Fig. 1) or in response to insulin and IGF1 and IGF2 stimulation (Malaguarnera et al 2011, Chen et al 2012. Spheres including thyrospheres are derived from a single stem cell that generates a self-copy of itself and differentiates into progenitor cells (Lan et al 2007, Deleyrolle & Reynolds 2009).…”

Section: Discussionmentioning

confidence: 99%

Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?

Xu¹,

Chen²,

Peng³

et al. 2013

Journal of Endocrinology

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Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are targets of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres, the ability of 17b-oestradiol (E 2 ) to induce the formation of thyrospheres and the expression of oestrogen receptors (ERs) and the effect of E 2 on the growth and expression of markers of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin and sodium iodide symporter (NIS)) were analysed. E 2 induced thyrosphere formation, albeit to a lower extent than other growth factors. Thyroid stem and progenitor cells expressed ERa (ESR1) and ERb (ESR2) with eight times higher expression levels of ERa mRNA compared with the differentiated thyrocytes. E 2 was a potent stimulator of the growth of thyroid stem/progenitor cells. In contrast, TSH-induced differentiation of progenitor cells, in particular, the expression of NIS, was significantly inhibited by E 2 . In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females.

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Metformin Inhibits Growth of Thyroid Carcinoma Cells, Suppresses Self-Renewal of Derived Cancer Stem Cells, and Potentiates the Effect of Chemotherapeutic Agents

Abstract: Metformin markedly diminished growth stimulation by insulin and showed an additive antimitogenic effect to chemotherapeutics agents. Therefore, our results suggest this drug as adjuvant treatment for thyroid cancer in type 2 diabetic patients.

Cited by 177 publications

References 32 publications

Metformin inhibits goitrogenous effects of type 2 diabetes

Metformin inhibits goitrogenous effects of type 2 diabetes

Metformin and thyroid disease

Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?

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