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E1A Oncogene-induced Sensitization of Human Tumor Cells to Innate Immune Defenses and Chemotherapy-induced Apoptosis in Vitro and in Vivo^{1 ,,2}

Departments of Medicine and Microbology-Immunology and the Cancer Center, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612 [J. L. C.]; Department of Medicine, National Jewish Medical and Research Center and Departments of Medicine, Immunology and the Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80206 [T. A. M., J. M. R.]; Department of Biostatistics, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010 [D. N. I.]; and Laboratory of DNA Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20812 [A. M. L.]

Expression of the adenoviral E1A oncogene induces susceptibility of neoplastic cells from different species to both immune-mediated and chemotherapy-induced cell death. These effects of E1A are easily measured in vitro using cytotoxicity assays. However, conventional in vivo assays of tumor development lack similar precision for measurement of oncogene-induced changes in tumor cell traits. E1A expression in p53 mutant human breast carcinoma cells sensitized them in vitro to diverse immunological injuries and apoptosis triggered by chemotherapeutic agents, as predicted from studies of rodent tumor cells. Nude mice, which possess innate cellular immune defenses against E1A-expressing tumor cells, were used in a quantitative tumor induction assay to test the in vivo correlations of E1A-induced immunosensitivity and chemosensitivity of human tumor cells. Two distinct, E1A-induced breast cancer cell traits could be measured in nude mice: (a) increased tumor latency and (b) reduced efficiency of tumor induction. These results were confirmed in studies of E1A-expressing human fibrosarcoma cells. The results demonstrate that E1A-induced conversion of human cells from a cytolytic resistant to a cytolytic susceptible phenotype, as detected in vitro, translates into reduced tumorigenicity of cells confronted with innate immune defenses and exposed to chemotherapeutic agents in nude mice. However, the data also show that E1A expression does not completely eliminate the tumorigenicity of either established human tumor cells or of cells immortalized by E1A. This experimental approach should be useful for studies of the effects of other oncogene-related tumor cell traits on tumorigenicity and could be used for preclinical studies of different treatment strategies for human tumors.

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