Endocrine Abstracts

Background: Metformin plays anti-tumoral roles in human cancers including breast and thyroid. However, its effects on metastatic lesions are undetermined. We studied the effects of metformin on bone metastasis of thyroid cancer.

Method: Luciferase-tagged anaplastic FRO and follicular FTC 133 thyroid cancer cells were used. In vivo effects of metformin were evaluated in both ectopic tumor model and bone metastasis model generated by intratibial injection.

Result: Metformin treatment significantly reduced viabilities of FRO and FTC133 thyroid cancer cells in vitro. However, oral administration of metformin to ectopic tumor model showed limited therapeutic effect only. To evaluate the effects of metformin in bone metastasis model, luciferase-tagged FRO or FTC133 cells were injected into tibia in nude mice and metformin was administrated via drinking water. Bioluminescence imaging showed that tumor growth was significantly decreased from 2 to 4 wks in metformin-treated tumors than controls in both FRO and FTC133 cell injected groups. In FRO cell group, total tumor volume per bone volume (TmV/BV) was significantly reduced in metformin-treated group than control by 30% at 4 weeks. The number of osteoclasts per bone was significantly decreased and the reactive bone formation was significantly reduced in metformin-treated group than in control group. To investigate the molecular mechanisms, the effect of metformin on osteoblasts in tumor microenvironment were studied. Conditioned medium of FRO (FRO-CM) was harvested and treated into murine osteoblastic cells with or without metformin. RT-PCR analysis showed that treatment of FRO-CM increased RANKL and decreased OPG while, treatment of metformin reversed FRO-CM mediated changes of OPG/RANKL ratio.

Conclusion: The anti-cancer effects of metformin on thyroid cancer were more sensitive in bone metastasis rather than in ectopic tumor model, owing to the regulatory actions of metformin on metastatic niche of bone.