The long-term objectives of the proposed project are to determine whether and how intercellular communication is involved in the process of carcingoenesis.
Specific aims are: (i) to extend the hypothesis that gap-junctional intercellular communication block is involved in the tumor promotion stage of carcingoenesis, especially in epithelial cell transformation and in vivo carcinogenesis; (ii) to search for mesenger molecules which pass through gap junctions and which regulate cell growth during carcinogenesis; (iii) to identify critical oncogenes whose expressions are modulated by intercellular communication; (v) to examine the role and mechanisms of selective lack of gap-junctional communication between transformed and nontransformed cells. Changes in intercellular communication will be examined during the process of in vitro cell transformation and of in vivo carcinogenesis be measuring intercellular transfer of microinjected fluoresecent dye, while expression of gap junction genes will be measured tal approaches are proposed: (i) For in vitro studies, mainly human and mouse epidermal cells will be used. (ii) For in vivo studies, rat liver and mourse skin two-stage carcinogenesis models will be used. (iii) Modulation of expression of specific oncogenes by or viral oncogenes. (iv) Involvement of cell contact- mediated non-junctional intercellular communication in gene expression control and cell transformation will be studied using a coculture system of rat hepatocytes together with rat liver epithelial cells or BALB/c 3T3 cells. (v) Identification of possible second messengers which pass through gap junctions will be pursued by filtration assay using artificial membranes containing gap junctions; candidate molecules include members of two signal transduction pathways i.e., cyclic nucleotides and inositol phosphates. (vi) For the search of cell-cell recognition molecules that may regulate intercellular communication, glycoproteins will be considered as possible candidates. Possible involvement of extracellular matrix will be also studied. (vii) In order to examine the role of selective intercellular communication between transformed and surrounding normal cells, chemicals which can modulate intercellular communication will be used.
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