Normal Cell-induced Modulation of the Neoplastic Phenotype Multiple Changes in Gene Expression Are Associated with

Specific regulatory pathways in neoplastic cells seem to be responsive to control signals provided by the normal cell/tissue environment. The pres ent experiments were designed to doline, at the molecular level, the growth-regulatory signals in neoplastic cells that are associated with the modulation of expression of the neoplastic phenotype by normal cell populations. When cultured in the presence of normal cell-conditioned medium, a highly malignant rat trachea! carcinoma-derived cell popula tion (IC-12) undergoes dramatic changes in morphology, and the anchor age-independent growth of these cells is inhibited. This phenomenon is termed normalization. The strategy adopted for elucidating the cellular/ molecular changes associated with the induction of these phenotypic alterations was to define the differences in inKNA expression patterns between IC-12 populations exhibiting the neoplastic phenotype (wild-type cells) and those exhibiting the normalized phenotype. For this purpose, the differential display technique and subsequent Northern blot analyses were used. Once specific, differentially expressed genes were identified, the temporal sequence of altered gene expression was determined by moni toring the levels of mRNA expression after the addition of normal cellconditioned medium. Some of the identified known genes are grouped into three general categories: (a) group I genes are those involved in cellular adhesion processes; (Al group II genes are those involved in signal transduction pathways; and (<•) group III genes are those involved in transcrip tion»)and translational processes. Genes that are differentially expressed during the normalization process seemed to exhibit characteristic tempo ral expression patterns after the addition of normal cell-conditioned me dium. Identification of these differentially expressed genes and their as sociated cellular functions provide insight into some of those regulatory pathways in neoplastic 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 likely to be critical upstream effectors regulating transcriptional regulatory events that result in the moderation of neoplastic behavior.