CONVERSION OF EMBRYONIC CELLS INTO TRANSFORMED CELLS

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That the intracellular controls which regulate the emergence of a normal definitive muscle, cartilage, or pigment cell may produce neoplastic cells when they malfunction has been discussed since Boveri's time over 60 years ago. To this end, the impact of TPA, EMS, pp60 v-src, and BrUdR on the differentiation programs of primary cultured myogenic, chondrogenic, and melanogenic cells is studied. These 4 pleiotropic molecules, each having a different initial intracellular target, share one remarkable property - they selectively, but reversibly block transcription of that subset of genes which define the treated cell's differentiation program. These conclusions derive from following (a) the synthesis of cell-specific proteins, and (b) the accumulation of these cell-specific mRNAs in the treated cells. The vulnerability of a normal cell's differentiation program to these agents cannot be ascribed to a generalized cytotoxicity reaction, but may be analogous to the transcriptional response of heat-shocked cells. The semi-autonomy of a cell's differentiation program in the context of the regulation of "household" molecules is striking. These experiments also provide unusually favorable models for the study of normal myofibrillogenesis and chondrogenesis, as well as the role of c-oncogenes in the regulation of proliferation and/or cell diversification. Our common model for normal cell diversification and transformation postulates that the lineage-dependent activation of cell-specific subsets of genes active in early compartments of a given lineage, are inactive in later compartments. To test this, 0-16 hour chick blastodisc cells were dissociated and cultured at low density. They demonstrate that hours prior to gastrulation, and well before putative "cell-cell, epithelial-mesenchymal inductive interactions", blastodisc cells have been channeled into different, transitory, founder cells for multi-, bi-, and unipotential lineages. These findings suggest that early and late stages of diversification reflect genetically pre-programmed intracellular changes, rather than changes primarily induced by exogenous molecules. These conclusions are also consistent with the proposition that the unique phenotypic properties of any given type of transformed cell must be pre-determined by the differentiation program of its normal progenitor cell.