Regulatory Effects of TGF-? Superfamily Members on Normal and Neoplastic Thyroid Epithelial Cells
Thyroid growth and function is partly regulated by growth factors binding to receptors on the cell surface. In the present thesis, the transforming growth factor-? (TGF-?) superfamily members have been studied for their role in regulation of growth and differentiation of both normal and neoplastic thyroid epithelial cells.TGF-?1 is a negative regulator of thyrocyte growth and function. However, the importance of other TGF-? superfamily members has not been fully investigated. TGF-?1, activin A, bone morphogenetic protein (BMP)-7 and their receptors were found to be expressed in porcine thyrocytes. In addition to TGF-?1, activin A was also found to be a negative regulator of thyroid growth and function, and both stimulated phosphorylation and nuclear translocation of Smad proteins. Furthermore, TGF-?1 and epidermal growth factor (EGF) demonstrated a synergistic negative effect on thyrocyte differentiation. Simultaneous addition of the two factors resulted in a loss of the transepithelial resistance and expression of the epithelial marker E-cadherin. This was followed by a transient expression of N-cadherin.Despite the extremely malignant character of anaplastic thyroid carcinoma (ATC) tumor cells, established cell lines are still responsive to TGF-?1. A majority of the cell lines were also found to be growth inhibited by BMP-7. BMP-7 induced cell cycle arrest of the ATC cell line HTh 74 in a dose- and cell density-dependent manner. This was associated with upregulation of p21CIP1 and p27KIP1, decreased cyclin-dependent kinase (Cdk) activity and hypophosphorylation of the retinoblastoma protein (pRb). TGF-?1, and to some extent also BMP-7, induced the expression of N-cadherin and matrix metalloproteinase (MMP)-2 and -9. Stimulation of HTh 74 cells with TGF-?1 increased the migration through a reconstituted basement membrane indicating an increased invasive phenotype of the cells.Taken together, these data show that TGF-? superfamily members not only affect growth and function of normal thyroid follicle cells but may also, in combination with EGF, play a role in cell dedifferentiation. This study additionally suggests that the TGF-? superfamily members may be important for the invasive properties of ATC cells.
Source Type:Doctoral Dissertation
Keywords:MEDICINE; Dermatology and venerology,clinical genetics, internal medicine; Clinical genetics; Genetics; activin; BMP; cadherin; carcinoma; cell cycle arrest; dedifferentiation; EGF; growth inhibition; invasion; Smad; TGF-?; thyroid; Genetik; patologi; Pathology
Date of Publication:01/01/2002