Vascular endothelial growth factor (VEGF) is a vascular endothelial cell specific mitogen and a major regulator of angiogenesis. VEGF secretion is activated in some thyroid cancers and that VEGF secretion is stimulated by TSH. So we postulated that TSH may promote growth and invasion in some thyroid cancers by stimulating VEGF secretion and angiogenesis.

We investigated the TSH effect for the VEGF secretion, endothelial cell proliferation and invasion in vitro with the primary cultured normal thyroid cell (NT-1) and thyroid cancer cell line (TPC-1). And to evaluate the relationship between TSH and VEGF, angiogenesis and tumor growth in vivo, we xenografted human dermal matrix inoculated with thyroid cells into nude mice or directly injected subcutaneously. For the study, mice were made hypothyroid (Group 1) by antithyroid hormone p.o, hyperthyroid (Group 2) by L-thyroxine injection and euthyroid (Group 3). One week after the treatment, significant difference were noted in T3, T4 and TSH level between each group, but the VEGF level showed significant difference in group 1 only compared with group 2 and 3. NT-1 or TPC-1 were seeded in the upper chamber of Transwell and HUVEC were cultured in lower chamber, and added different concentration of TSH. NT-1 and TPC-1 secreted VEGF under basal condition, but the level were similar. TPC-1 cells secreted significantly more VEGF than NT-1 after TSH (1, 10, 100 mIU/dl) stimulation, which were also parallel with the concentration of TSH. In low concentration of TSH (0, 1 mIU/dl), there were no difference of HUVEC proliferation between NT-1 and TPC 1. In high concentration of TSH (10, 100 mIU/dl), however, TPC-1 enhanced HUVEC proliferation than NT-1 significantly (p<0.05). Similar findings were noted in thyroid cell invasion. Invasion was higher in TPC-1 than in NT-1 in high concentration of TSH (10, 100 mIU/dl). In vivo study using the dermal matrix showed that number of blood vessels ingrowth were higher in Group 1 (25/HPF) than Group 2 (16/HPF) or Group 3 (17/HPF). But there was no difference between Group 2 and Group 3. Level of TSH and VEGF were also increased significantly in Group 1 compared with in Group 2 and Group 3. The size of tumor did not showed significant difference between each group during observation. The tumor from Group 1 (6.2 gm) were larger compared with Group 2 (5.1 gm) or Group 3 (5.6 gm), but this difference was not significant statistically (p>0.05). The number of blood vessels in tumor were also more increased in Group 1 and were commonly located in the peripheral portion of tumor.

We conclude that thyroid cancer cell line secrete the VEGF and TSH secretion is more enhanced by the stimulation of TSH. And increased VEGF promote the vascular endothelial cell proliferation, invasion and angiogenesis in thyroid cancer.