IN-VITRO RECONSTRUCTION OF TUMOR INITIATION IN A HUMAN EPITHELIUM

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