The response of embryonal carcinoma (EC) to the mouse blastocyst has been examined using a clonal assay for growth regulation. This in vitro assay is based on the ability of the blastocyst to abrogate colony formation by the cancer cell, and the results are similar to previous studies in which the blastocyst prevented tumor formation of EC cells. Other laboratories have shown that the environment of the early embryo forces some EC cells to participate in normal embryonic development. The current research is aimed at elucidating the role of cell-cell contact in this reaction and at determining whether the mechanism is based on metabolic cooperation via intercellular junctions or on plasma membrane interactions (i.e., recognition). The methods include cell cycle synchronization of EC, microsurgery to place EC cells in the blastocyst, rescue of cancer cells from the blastocyst by immunosurgery, microsurgery to create fistulas in blastocysts, isolation of cell types from the blastocyst, microculture techniques to prepare cytoplasmic and membrane preparation from blastocysts, electron microscopy of gap junctions, microinjection into cells, and electrophoretic and immunological studies of surface proteins. The possible role of metabolic cooperation will be studied by transfer of small molecules between cells and by use of variant cell lines incapable of metabolic cooperation. The possible role of cell surface recognition will be studied by testing isolated cells and membrane preparations of blastocysts for their growth regulatory activity in microculture. The goal is to understand the mechanisms which regulate normal stem cells in early embryogenesis and to apply these mechanisms to the regulation of malignant stem cells. The use of a tissue culture assay for growth regulation of EC provides a convenient probe of regulatory mechanisms in the blastocyst. Ultimately, the embryological approach might lead to alternatives to cytotoxic therapy for cancer. (A)
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