Metformin Is Associated with a Favorable Outcome in Diabetic Patients with Cervical Lymph Node Metastasis of Differentiated Thyroid Cancer

Jang, Eun Kyung; Kim, Won Gu; Kwon, Hyemi; Choi, Yun Ju; Jeon, Min Ji; Kim, Tae Yong; Shong, Young Kee; Kim, Won; Kim, Eui Young

doi:10.1159/000437365

Cited by 25 publications

(27 citation statements)

References 28 publications

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“…Recent studies suggest that metformin treatment could reduce tumor cell invasion in pancreatic cancer [35]. Metformin treatment of diabetetic patients is associated with low recurrence of cervical lymph node metastasis of differentiated thyroid cancer [36]. Indeed, we found that FN protein abundance was higher in thyroid tumors of HFD- Thrb PV/PV Pten +/− mice than in LFD- Thrb PV/PV Pten +/− mice (Figure 4B-I, panel a, lanes 4-6 versus lanes 1-3; quantitative data: Figure 4B-II-a, bar 3 versus bar 1).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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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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Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…Despite recent research suggesting an improved survival associated with the use of anti-diabetic medications, their use as adjuvant therapy in patients undergoing surgery for pancreatic cancer remains unclear. [21][22][23] Using a large, nationally representative sample of patients, the current study sought to investigate the impact of metformin use on OS among patients who had undergone Fig. 1 Kaplan-Meier curves of metformin users vs. non-users surgical resection of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer

Cerullo

Gani

Chen

et al. 2016

Journal of Gastrointestinal Surgery

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Preclinical evidence has demonstrated anti-tumorigenic effects of metformin. The effects of metformin following pancreatic cancer, however, remain undefined. We sought to assess the association between metformin use and survival using a large, nationally representative sample of patients undergoing surgery for pancreatic cancer. Patients undergoing a pancreatic resection between January 01, 2010, and December 31, 2012, were identified using the Truven Health MarketScan database. Clinical data, including history of metformin use, as well as operative details and information on long-term outcomes were collected. Multivariable Cox proportional hazards regression analysis was performed to assess the effect of metformin use on overall survival (OS). A total of 3393 patients were identified. The mean age of patients was 54.2 years (SD = 9.1 years). Roughly one half of patients were female (n = 1735, 51.1 %); 49.1 % (n = 1665) presented with a Charlson comorbidity index of 3 or greater (CCI ≥3); and 19.6 % (n = 664) had diabetes. At the time of surgery, 60.0 % (n = 2034) of patients underwent a pancreaticoduodenectomy, 35.7 % (n = 1212) a partial/distal pancreatectomy, while 4.3 % (n = 147) had a total pancreatectomy. On pathology, 1057 (31.2 %) had lymph node metastasis. Metformin use was identified in 456 patients (13.4 %) and was more commonly administered among patients without locally advanced disease (14.3 vs. 11.6 %, p = 0.038). While OS was comparable between patients within the first year of surgery (OS at 1 year 65.4 % [95 % confidence interval (CI) 63.4-67.3 %] vs. 69.2 % [95 % CI 64.2-73.4 %]), patients who received metformin demonstrated an improved OS beginning at 18 months following surgery. On multivariable analysis adjusting for patient and clinicopathologic characteristics, metformin use was independently associated with a decreased risk of mortality (hazard ratio [HR] = 0.79, 95 % CI 0.67-0.93, p = 0.005). Metformin use was associated with an improved overall survival among patients undergoing pancreatic surgery for pancreatic cancer. Further work is necessary to better understand its role in modifying cancer-specific and overall health outcomes.

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“…Besides lowering the thyroid cancer risk, metformin treatment has been associated with longer disease-free survival in T2DM patients with cervical lymph node metastasis of DTC (Jang et al 2015). In a retrospective study involving 240 DTC individuals, diabetic patients who were treated with metformin had smaller thyroid cancer size, higher complete response rate and longer progression-free survival in comparison to nonmetformin-treated diabetic patients and non-diabetic thyroid cancer patients matched by age, gender and BMI (Klubo-Gwiezdzinska et al 2013).…”

Section: Differentiated Thyroid Cancer (Dtc) Epidemiologymentioning

confidence: 99%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

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Metformin Is Associated with a Favorable Outcome in Diabetic Patients with Cervical Lymph Node Metastasis of Differentiated Thyroid Cancer

Cited by 25 publications

References 28 publications

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

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

Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

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