Growth factor receptor signalling in thyrocytes of normal and neoplastic origin

Sammanfattning: Cellular growth and function are controlled by stimulatory and inhibitory factors actingthrough specific receptors. The present thesis focuses on the role of growth factors, theirreceptors and signalling pathways in normal and neoplastic thyroid epithelial cell biology.Decreased sensitivity towards the growth inhibitory transforming growth factor-β(TGF-β) has been described in various types of carcinomas. This is thought to bemediated by inactivation of TGF-β receptors or the downstream signalling Smad proteins.Effects of TGF-β were evaluated in six anaplastic thyroid carcinoma cell lines andcompared to normal thyrocytes. One tumour cell line did not respond to TGF-β.Interestingly, this was not a result of loss or downregulation of TGF-β receptors or Smadmolecules.Hepatocyte and epidermal growth factors (HGF and EGF) are potent mitogens forthyroid epithelial ceils. FRTL-5 cells, commonly used as a model system of normalthyrocytes, were found unresponsive to HGF despite the expression of functional HGFreceptors (Met) and a seemingly normal intracellular signal transduction. Met was foundoverexpressed and constitutively activated in a ligand independent fashion in a majority ofthe investigated anaplastic thyroid carcinoma cell lines. The same cell lines showed a basalactivation of the EGF receptor (EGFR), perhaps as a result of concomitant expression of transforming growth factor-α, one of the EGFR ligands. Upon inhibition of EGFRsignalling Met was downregulated and its tyrosine phosphorylation was diminished,suggesting a cross talk between the two receptors. Furthermore, inhibition of EGFR signalling decreased tumour cell proliferation.In summary, evidence of a novel mechanism for TGF-β insensitivity in anaplasticthyroid carcinoma cells is presented. The results also indicate that FRTL-5 cells are oflimited use for studies of normal thyrocyte biology. Moreover, anaplastic thyroidcarcinoma cells have the capacity to overexpress constitutively activated Met, which maybe due to aberrant activation of the EGFR signalling system.