THE TUMOR-SUPPRESSOR GENE WT1 INHIBITS RAS-MEDIATED TRANSFORMATION

Wilms' tumor belongs to a small group of pediatric neoplasms that have served as paradigms of human cancers in which recessive mutations pla y a primary role in tumorigenesis. WT1 is a candidate tumor suppressor gene that is mutationally inactivated in a proportion of both familia l and sporadic Wilms' tumors. Recent studies demonstrated that WT1 can partially suppress growth of a Wilms' tumor cell line in vitro and in vivo. We investigated the ability of WT1 to inhibit the expression of the transformed phenotype in non-Wilms' tumor cells. The expression o f WT1 cDNA in ras-transformed NIH3T3 cells yielded large, flat cells t hat exhibited complete contact-inhibition. These morphologic changes w ere associated with decreased proliferation, suppression of clonogenic ity in soft agar and inhibition of tumor growth in nude mice. Moreover , expression of WT1 in non-transformed NIH3T3 cells resulted in simila r morphologic changes and profound resistance to transformation by an activated uas oncogene. These studies suggest that tumor inhibition by WT1 in these cells may be achieved by interference with the ras-media ted signalling pathway.