Lessons from Malignant Reversion

Abstract

Many studies of tumorigenicity ask the question from the perspective of what turns a cell cancerous. Tuynder et al. ask the question from the opposite direction: What genes are associated with reversion of the malignant phenotype? The authors used two methods to select revertant cell lines: resistance to lethality associated with H-1 parvovirus infection and transfection of SIAH-1 (human homolog of Drosophila seven in absentia, which is a p53-regulated gene implicated in cell death and ubiquitination and degradation of target proteins). Revertants were characterized for growth in soft agar, as well as tumorigenicity in immunocompromised mice. Analysis of differential gene expression between the parent and revertants and then among the various cell lines tested showed that one of the most strongly downregulated genes was tpt1 [encoding translationally controlled tumor protein (TCTP)]. TCTP, a protein associated with control of cell growth, was decreased in both the H-1 revertants and the SIAH-1 revertants. Furthermore, application of antisense knock out to inhibit tpt1 expression produced cells with decreased tumorigenicity. Analysis of the morphology of MCF7 breast cancer cells in the three-dimensional growth matrix, matrigel, showed that SIAH-1 expression or antisense inhibition of tpt1 led to the reorganization of the cell mass into structures more similar to those seen in "normal" growth--that is similar to the morphology of 184 B5 cells, a standard for normal breast cell growth. Thus, TCTP may be a new target for controlling malignant phenotype. M. Tuynder, L. Susini, S. Prieur, S. Besse, G. Fiucci, R. Amson, A. Telerman, Biological models and genes of tumor reversion: Cellular reprogramming through tpt1 /TCTP and SIAH-1 . Proc. Natl. Acad. Sci. U.S.A. 99 , 14976-14981 (2002). [Abstract] [Full Text]