Evaluation of mechanisms whereby normal cells modulate expression of the neoplastic phenotype

It has been noted that the emergence of neoplastic populations in vivo as well as expression of the neoplastic phenotype may be influenced by regulatory factors associated with normal cell/tissue environment. Here we utilized a model system in which expression of the neoplastic phenotype of a highly aggressive, metastasizing, undifferentiated rat tracheal carcinoma-derived cell line designated IC-12 was normalized following establishing cocultures of these neoplastic cells and normal primary rat tracheal epithelial cells. A series of experiments were carried out to reveal the mechanisms whereby normal cells modulate expression of the neoplastic phenotype, and to define the associated molecular/cellular changes occurring in neoplastic cells. It was determined that while establishment of gap junction communication was not involved as a mechanism associated with the normal cell- induced modulation of the neoplastic phenotype, interactions of IC-12 cells with a specific factor (a laminin-related protein) produced by normal epithelial cells induced morphologic changes in IC-12 cells and inhibited their anchorage independent growth. Associated with this normalization process there were changes in a number of critical regulatory signals in affected neoplastic cells. Changes in the cell surface expression of integrins, as well as altered mRNA expression of genes involved in cellular adhesion processes, in signal transduction pathways, and in transcriptional/translational processes were noted. Understanding those regulatory pathways in neoplastic cells which are amenable to influence exhibited by the normal cell/tissue environment may provide important insights into the dynamics of neoplastic development and furthermore, define a mechanistic basis for the development of novel approaches for therapeutic intervention during tumor development.