Metformin Delays Progression of Thyroid Tumor Metastases in Mice

Mitochondrial glycerophosphate dehydrogenase (mGPDH) is overexpressed in differentiated thyroid cancer (DTC) tissue, and metformin, which downregulates mGPDH, is associated with slowed growth in metastatic DTC tumors in mice, according to research presented at the 86^th Annual Meeting of the American Thyroid Association (ATA), held September 21–25 in Denver, Colorado.

Together, the findings bolster the case that metformin delays thyroid cancer progression, and provide a candidate biomarker for future studies of metformin’s efficacy against thyroid malignancies.

“The molecular target of metformin, mGPDH, is overexpressed in thyroid cancer and may serve as a biomarker of response to metformin treatment in thyroid cancer,” said lead study author Joanna Klubo-Gwiezdzinska, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.

Previous research has established that mGPDH is a molecular target of metformin, an oral pharmacotherapy for type 2 diabetes. Other research has suggested that metformin is associated with thyroid cancer remission rates among patients with diabetes.

The study authors therefore studied mGPDH expression in papillary and follicular thyroid cancer (PTC and FTC) in vitro, and metformin’s impact on tumor mGPDH expression and progression in mice.

Using immunohistochemical staining in 48 human thyroid tissue samples (16 FTCs, 24 PTCs, and 8 normal thyroid controls), the authors found that thyroid cancer tissue significantly overexpressed mGPDH compared with normal thyroid tissue (P < .001). There were no differences in mGPDH scores between PTCs and FTCs, Dr. Klubo-Gwiezdzinska noted.

Metformin induced a metabolic shift toward glycolysis in thyroid cancer cell lines, causing energetic stress and growth inhibition, the study authors found.

Using mice prone to developing lung and liver metastases when human FTC cells are injected into their tail veins, the researchers randomly assigned mice to be administered either with water (via gavage; n = 21) or metformin (via water gavage; n = 21).

Metformin treatment was associated with decreased metastatic tumor expression of mGPDH in mice-and with delayed metastatic tumor progression.

“After four weeks of treatment with metformin, the tumor burden was significantly smaller in animals treated with metformin as bioluminescence increased 59.8+/- 56.7 times in metformin group and 160.7+/-243.3 times in controls” (P = .047), she reported.

Subsequent analysis of lung and liver tissue in the mice showed that metformin was associated with a lower liver metastasis rate (36% vs 89% in controls; P = .023), and that mGPDH staining intensity in metastatic tumors was significantly lower in metformin-treated mice (P = .0148).

“Treatment with metformin delays progression of thyroid cancer metastases in vivo and is associated with downregulation of mGPDH in metastatic lesions,” Dr. Klubo-Gwiezdzinska concluded.

Reference

Klubo-Gwiezdzinska J, Gaskins K, Vasko V, et al. Oral abstract 17. The molecular target of metformin-mitochondrial glycerophosphate dehydrogenase (mGPDH) is overexpressed in papillary and follicular thyroid cancer and its down-regulation by metformin is associated with growth inhibitory effects in a metastatic thyroid cancer mouse model. Thyroid. 2016;26(suppl 1).