Specific regulatory pathways in neoplastic cells seem to be responsive to control signals provided by the normal cell/tissue environment. The 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 normal cell populations. When cultured in the presence of normal cell-conditioned 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 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 mRNA 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 monitoring the levels of mRNA expression after the addition of normal cell-conditioned medium. Some of the identified known genes are grouped into three general categories: (a) group I genes are those involved in cellular adhesion processes; (b) group II genes are those involved in signal transduction pathways; and (c) group III genes are those involved in transcriptional and translational processes. Genes that are differentially expressed during the normalization process seemed to exhibit characteristic temporal expression patterns after the addition of normal cell-conditioned medium. Identification of these differentially expressed genes and their associated 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.

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Supported by NIH Grant CA34695 under Interagency Agreement No. 1884-1268-A1 with the United States Department of Energy and by the Laboratory Directed Research and Development Program of the Oak Ridge National Laboratory, managed by the Lockheed Martin Energy Research Corp. for the United States Department of Energy under Contract No. DE-AC05-96OR22464.

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