MULTIPLE CHANGES IN GENE-EXPRESSION ARE ASSOCIATED WITH NORMAL CELL-INDUCED MODULATION OF THE NEOPLASTIC PHENOTYPE

Specific regulatory pathways in neoplastic cells seem to be responsive to control signals provided by the normal cell/tissue environment. Th e present experiments were designed to define, at the molecular level, the growth-regulatory signals in neoplastic cells that are associated with the modulation of expression of the neoplastic phenotype by norm al cell populations. When cultured in the presence of normal cell-cond itioned medium, a highly malignant rat tracheal carcinoma-derived cell population (IC-12) undergoes dramatic changes in morphology, and the anchorage-independent growth of these cells is inhibited. This phenome non is termed normalization. The strategy adopted for elucidating the cellular/molecular changes associated with the induction of these phen otypic alterations was to define the differences in mRNA expression pa tterns between IC-12 populations exhibiting the neoplastic phenotype ( wild-type cells) and those exhibiting the normalized phenotype, For t his purpose, the differential display technique and subsequent Norther n blot analyses were used, Once specific, differentially expressed gen es were identified, the temporal sequence of altered gene expression w as determined by monitoring the levels of mRNA expression after the ad dition of normal cell-conditioned medium. Some of the identified known genes are grouped into three general categories: (a) group I genes ar e those involved in cellular adhesion processes; (b) group II genes ar e those involved in signal transduction pathways; and (c) group III ge nes are those involved in transcriptional and translational processes, Genes that are differentially expressed during the normalization proc ess seemed to exhibit characteristic temporal expression patterns afte r the addition of normal cell-conditioned medium. Identification of th ese differentially expressed genes and their associated cellular funct ions provide insight into some of those regulatory pathways in neoplas tic cells that are amenable to regulation by normal cells. An analysis of the temporal sequence of altered gene expression provides further information that allows the identification of those genes that are lik ely to be critical upstream effecters regulating transcriptional regul atory events that result in the moderation of neoplastic behavior.