Oncotarget

Research Papers:

Metformin blocks progression of obesity-activated thyroid cancer in a mouse model

Jeongwon Park, Won Gu Kim, Li Zhao, Keisuke Enomoto, Mark Willingham and Sheue-Yann Cheng _

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Oncotarget. 2016; 7:34832-34844. https://doi.org/10.18632/oncotarget.8989

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Abstract

Jeongwon Park1, Won Gu Kim1,2, Li Zhao1, Keisuke Enomoto1, Mark Willingham1, Sheue-Yann Cheng1

1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

2Current Address: Division of Endocrinology, Department of Internal Medicine Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, South Korea, Seoul 138-736

Correspondence to:

Sheue-yann Cheng, e-mail: chengs@mail.nih.gov

Keywords: thyroid carcinogenesis, obesity, metformin, mouse models

Received: February 16, 2016    Accepted: April 16, 2016    Published: April 26, 2016

ABSTRACT

Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (ThrbPV/PVPten+/−mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. ThrbPV/PVPten+/−mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD-ThrbPV/PVPten+/−mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD-ThrbPV/PVPten+/−mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD-ThrbPV/PVPten+/−mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer.


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