Acquired and naturally occurring resistance of thyroid follicular cells to the growth inhibitory action of transforming growth factor-beta 1 (TGF-beta 1).
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.
Asmis
L M
LM
Department of Medicine, University Clinic of Internal Medicine, Bern, Switzerland.
Kaempf
J
J
Von Gruenigen
C
C
Kimura
E T
ET
Wagner
H E
HE
Studer
H
H
D000818:Animals; D002415:Cats; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006042:Goiter / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D013954:Thyroglobulin / Q000032:analysis; D013961:Thyroid Gland / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016212:Transforming Growth Factor beta; D007633:Keratins; D013954:Thyroglobulin