Endocrine Abstracts

We have recently shown that human thyroid follicular cells in culture secrete large amounts of active plasminogen activators (PAs). Thyroid cells also secrete large amounts of vascular endothelial growth factors (VEGFs) and express their receptors, the VEGFRs. PAs, as serine proteases, are known to process growth factors, particularly VEGFs into active forms. In endothelial cells, VEGFs stimulate PA production. We examined the effect of inhibiting VEGF signalling on thyroid follicular cell PA activity and function. One VEGFR inhibitor, [[4-(4′-chloro-2′-fluoro)phenylamino]-6,7-dimethylquinazoline](CFPD) potently inhibited the secretion of active PA by the cells. This inhibitor also increased their ¹²⁵I uptake. It had no adverse effects on thyroid cell viability. Other putative VEGFR inhibitors e.g. SU5416 did not have any detectable effects on the cells. Levels of p42/44 MAPK were high in unstimulated cells suggesting autocrine stimulation of MAPK. CFPD inhibited endogenous MAPK in the cells possibly by inhibiting VEGFR. CFPD did not prevent MAPK stimulation by EGF, insulin, TPA or FGF suggesting that its effects were specific to the VEGFR. Long term effects of CFPD showed that EGF effects on MAPK phosphorylation were however inhibited by CFPD. Consistent with this CFPD was able to completely block the stimulatory effects of EGF on PA production and its inhibitory effects on ¹²⁵I uptake. In FRTL5 cells, CFPD also inhibited endogenous phosphor MAPK levels but as in the primary cultures, it had no significant effects on their growth. FRTL5 cells do not secrete active PAs and CFPD did not regulate FRTL5 ¹²⁵I uptake. We conclude that VEGFs may have an autocrine role in thyroid follicular cells to stimulate PA production and decrease ¹²⁵I uptake. Most of these effects are due to activation of p42/44 MAPK. This pathway does not appear to be essential for follicular cell growth.