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

Abstract

While the multifunctional proteins of the transforming growth factor-beta (TGF-beta) family have a potent antiproliferative effect on thyroid follicular cell growth, increased expression of TGF-beta 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-beta 1, 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-beta 1 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-beta. We conclude that constitutively TGF-beta resistant cells may occur in thyroid glands and that persistent TGF-beta 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.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Thus, the activation index, expressed by the epithelial volume/colloid volume ratio, increases as the thyroid becomes more active, reflecting an increase in the epithelial volume and a decrease in the colloid volume (13). Measurement of total cell volume in cultures of primary thyrocytes or cell lines cultured in vitro can be performed using confocal laser-scanning microscopy after cells are loaded with octadecylrhodamine B (15,16).…”

Transforming growth factor-β1 and activin A generate antiproliferative signaling in thyroid cancer cells

“…On the other hand, the expression of TGF-b1 mRNA and protein are increased in tumors derived from epithelial cells when compared with normal cells, suggesting that these tumoral cells became unresponsive to TGF-b1's growth inhibitory action (Asmis et al 1996, Siegel & Massague 2003. In the thyroid, TGF-b promotes growth arrest in follicular cells derived from diverse animal species (Morris et al 1988, Tsushima et al 1988, Taton et al 1993, Depoortere et al 2000.…”

TGF-β-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-κB activation

“…Based on these data, the current hypothesis for progression from normal thyroid through neoplasia to malignancy is that a mutation creates a thyroid cell that grows faster and responds less to TGF-b. More TGF-b is produced to control thyroid growth, but selection occurs favoring the growth of the unresponsive cells (Asmis et al, 1996;Blaydes and Wynford-Thomas, 1996;Lazzereschi et al, 1997;Goretzki et al 2000). This model is, however, in stark contradiction to the pathological data from surgical specimens, which indicate a very low mitotic index.…”