RAS oncogene activation induces proliferation in normal human thyroid epithelial cells without loss of differentiation

Neoplastic transformation of rodent thyroid epithelial cell lines by mutant RAS genes has been widely studied as an experimental model of oncogene-ind uced loss of tissue-specific differentiation. However, separate evidence st rongly implicates RAS mutation as an early event in human thyroid tumour de velopment at a stage prior to loss of differentiation. To resolve this cont roversy we examined the short- and long-term responses of normal human thyr oid epithelial cells to mutant RAS introduced by micro-injection and retrov iral transduction respectively. In both cases, expression of RAS at a level sufficient to induce rapid proliferation did not lead to loss of different iation as shown by expression of cytokeratin 18, E-cadherin, thyroglobulin, TTF-1 and Pax-8 proteins. Indeed, RAS was able to prevent, and to reverse, the loss of thyroglobulin expression which occurs normally in TSH-deficien t culture medium. These responses were partially mimicked by activation of RAF, a major RAS effector, indicating involvement of the MAP Kinase signal pathway. The striking contrast between the effect of mutant RAS on differen tiation in primary human, compared to immortalized rodent, epithelial cultu res is most likely explained by the influence of additional co-operating ab normalities in the latter, and highlights the need for caution in extrapola ting from cell line data.