In
goiter, increased expression of
growth factors and their receptors occurs. We have inhibited the action of some of these
growth factors, alone and in combination, to determine which are important in goitrogenesis. Recombinant adenovirus vectors (RAds) expressing truncated, secreted forms of human Tie2 (RAd-sTie2) and
vascular endothelial growth factor receptor 1 (RAd-sVEGFR1) or a truncated, dominant-negative
fibroblast growth factor receptor 1 (RAdDN-FGFR1) were used.
Goiters in mice were induced by feeding an
iodide-deficient diet, containing
methimazole and
sodium perchlorate. RAds were administered to mice simultaneously with the goitrogenic regimen, which was continued for 14 d. RAd treatment did not significantly affect increases in TSH or reductions in
thyroid hormone or thyroid hyperactivity seen in
goitrogen-treated controls mice, suggesting no effect on pituitary or thyroid responses to
hypothyroidism. In control
goiters, a 4-fold increase in vascular volume accompanied a 2-fold increase in thyroid mass. Complete inhibition of these increases was found when animals were treated with the three RAds in combination. In thyroids from three RAd-treated animals, there was marked, significant inhibition of Tie2, FGFR1, VEGFR1,
FGF-2, and
VEGF expression, compared with control
goiters. When used individually, RAdDN-FGFR1 partially prevented
goiter and RAd-sVEGFR1 partially reduced vascular volume. Their effects were not additive. RAd-sTie2 did not reduce
goiter mass or vascular volume when used alone but was essential for complete
goiter inhibition.
VEGF and VEGFR1 expression was reduced in these thyroids. Limitation of physiologic organ growth is complex, requiring inhibition of multiple, interdependent
growth factor axes.