In vitro reconstruction of tumour initiation in a human epithelium.

Knowledge of tumour initiation in human epithelia is limited by sample availability and difficulty in experimental manipulation of human cells. The thyroid is a useful model since, in addition to multiple tumour stages, it presents two distinct 'pathways' of tumorigenesis: 'follicular' tumours, in which ras oncogene mutations occur at high frequency and 'papillary' tumours, associated with ret (or trk) activation. We have used these observations to reconstruct early thyroid tumorigenesis, using amphotropic retroviral vectors. When introduced into normal thyroid epithelial cells, mutant ras induces self-limiting growth of well-demarcated, differentiated colonies--a phenotype consistent with follicular adenoma. Activated ret on the other hand induces smaller, poorly-demarcated colonies with a morphology consistent with early papillary tumours. Mutant p53--which occurs only in the latest stages of thyroid cancer--was without effect. Our results provide the first direct experimental evidence in a human epithelium for alternative initiating oncogenes and their determination of the subsequent 'direction' of tumour development.