Our objective is to examine the possibility that the growth of freshly isolated human colorectal carcinoma cells in appropriate organs of athymic nude mice correlates with the metastatic potential of these neoplasms. The development of metastases in organs distant from the primary neoplasm is the major obstacle to the treatment of human colorectal carcinoma. The treatment of established metastasis may be limited by their biologic heterogeneity, which results from the continuous evolution of tumors, and is responsible for the multiple differences that exist among tumor cells populating primary neoplasms, among different metastases, and even among cells of a single metastasis. Advances in the therapy of human colorectal cancer may occur once we improve our understanding of the basic biology of this disease. To date, most of the data on the biology of metastasis have been derived from studies with rodent neoplasms. It is now necessary to extend our investigations to relevant human tumor systems. We propose to measure the ability of human colorectal carcinoma cells from different sources (primary tumor, lymph node metastasis, distant metastasis) and different stages of disease (early- Dukes A and B, intermediate- Dukes C, and advanced- Dukes D) to grow in mouse liver and lung following intrasplenic and intravenous injection. The human origin of the neoplasms will be verified by karyotypic and isoenzyme analysis. Tumors that grow in the lungs and liver of the nude mouse will be cloned and the clones tested for heterogeneity of metastatic phenotype and organ site preference. The metastatic potential of liver or lung colonies derived from primary tumor cells in nude mice will be compared to the metastatic potential of hepatic or pulmonary metastases from the same patient. Tumor-associated and major histocompatibility antigens of experimental and clinical metastases will be assessed with autologous lymphocytes and T cell clones in proliferative and cytotoxic assays. Our goal is to determine whether measurement of metastatic potential of human colorectal cancers in nude mice improves the ability of the current clinico-pathologic staging system to predict development of metastatic disease.
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