TUMOR PROGRESSION AND THE IMMUNOBIOLOGY OF METASTASIS

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We recently postulated that one mechanism by which tumors progress to a heterogeneous malignant state is via undermethylation of DNA. DNA hypomethylation may result in the expression of genes that were previously not expressed. The treatment of tumor cells with 5-azacytidine has resulted in the selection of clones with varying phenotypes including tumor-immunogenic, nonmetastatic clones from metastatic tumors, metastatic clones from nonmetaststic tumors, and TK+ clones from cell populations that are spontaneously TK-. We continue to investigate the role of under methylation in the generation of the malignant phenotype. The second phase of our study is to assess the usefulness of immunogenic variants in the adoptive immunization of animals bearing metastatic tumors. Our current therapeutic protocol includes surgery, elimination of suppressor cells, adoptive transfer with primed spleen cells, and II-2 administration. These protocols have resulted in considerable prolongation of survival of animals challenged with a tumor considered to be the most aggressive murine tumor known. New experiments will utilize both active and adoptive immunization of animals using both the aggressive tumor and some additional less malignant (metastatic) tumors. Finally, we are also undertaking a series of studies to attempt to identify the antigen expressed by the immunogenic variants using antibodies in the hope of eventually using genetic probes to identify the genes responsible for antigen expression. (IP)