The objective of this proposal is to correlate the immune response of the liver to development of hepatic metastasis. To accomplish this goal, a murine colon adenocarcinoma model (MCA-38) that metastasizes to the liver and simulates the natural history of human colorectal cancer has been developed. The colonization of the liver by liver derived MCA-38 tumor cells previously injected into the ileocolic vein of C57B1/6 mice be distinguished by 3 stages; """"""""covert"""""""" metastasis (day 1-10), """"""""overt"""""""" metastasis (day 11- 20) and """"""""extensive"""""""" metastasis (day 21-death). The survival and number of hepatic metastatic foci of 8-10 week old immunocompetent C57B1/6 mice, congenitally immunodeficient C57B1/6 mice (defective in NK cells, T cells, macrophages, etc.), and gnotobiotic C57B1/6 mice given liver derived MCA-38 will be determined. These results will be correlated to the pheno- and morpho-types of nonparenchymal liver cells in issue sections from these mice at each stage of metastases. Additionally, isolated nonparenchymal liver cell suspensions or their subpopulations from these same mice will be analyzed at each stage for phenotype expression, cytotoxicity, cytostasis and cytokine production (i.e. interleukin-1, interferon, tumor necrosis factor). Culture derived MCA-38 which does not metastasize in C57B1/6 mice will be tested for metastastic potential in congenitally immunodeficient mice. Since liver derived MCA-38 does not colonize in C57B1/6. nu/nu mice, experimental in vivo depletion of cells (anti-asialo GM1, irradiation, silica treatment) involved in natural immunity will be under taken to determine which cells in the liver contribute to the resistance to tumor invasion. Conversely, immunocompetent C57B1/6 mice will be depleted selectively with monoclonal antibodies to various T cells subsets (anti-Thy 1.21gG2a, anti-Lyt 2, anti-L3T4) to try and reproduce the immunologic mileau of the athymic nude mouse and thus understand the antimetastatic mechanism in the liver. Finally, the athymic nude mouse will be reconstituted with various T cell subsets. In conclusion, the use of this model system (MCA-38) may provide new and clinically relevant information on the interaction of the liver's defense system with tumor cells that invade the liver.
