Acquired and naturally occurring resistance of thyroid follicular cells to the growth inhibitory action of transforming growth factor-β1 (TGF-β1)

While the multifunctional proteins of the transforming growth factor-β (TGF-β) family have a potent antiproliferative effect on thyroid follicular cell growth, increased expression of TGF-β in proliferating thyroid cells and in thyroid tumours has recently been described, suggesting a secondary counter-regulatory role of these proteins. We have studied further this apparent paradox in vitro using FRTL-5 cells, 5 continuous cell strains from feline multinodular goitres (MNG) and 29 primary cultures prepared from human MNG. While dose dependent inhibition of FRTL-5 cell growth was confirmed, a variable fraction of these cells was naturally resistant towards TGF-β1, thus explaining the large interassay variability of growth inhibition (36 to 98% within 2 days, n=19). After 40 days of continuous exposure, FRTL-5 cells became fully refractory towards TGF-β1 inhibition, due to the selective growth of naturally resistant subclones, as demonstrated for example by microscopic observation of three-dimensionally growing collagen-embedded cell clusters. The refractoriness could still be demonstrated even after several cell passages. In addition, 2 out of 5 feline thyroid cell strains obtained from feline MNG and 18 out of 29 primary cultures from human MNG showed a high degree of refractoriness towards TGF-β. We conclude that constitutively TGF-β resistant cells may occur in thyroid glands and that persistent TGF-β refractoriness may secondarily be acquired. Resistant cells may escape regular growth control mechanisms and hence may contribute to the notorious heterogeneity of thyroid growth and to nodular transformation.