Establishment of an appropriate metastasis model and a novel treatment for advanced human colorectal cancer using RAG2/common-γ double knockout mice

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The aim of this study is to establish an animal medel for immunothrerapeutic treatment of human colon cancer. Our results demonstrate that most of human colorectal cancer tissues remain alive in RAG2/common-γ knockout (DKO) mice, moreover, some of them invade into the muscular layer and lymphovascular channel in the flank, unlike with the ordinary immuno-compromised mice, nude mice and scid mice. These mice showed more foci of liver metastases than other mice after intrasplenic injection of the human colon cancer cell line, HT-29. Adaptation, invasion and liver metastasis of human colon cancer into several mice organs were more prevalent in DKO mice. Human colorectal cancer tissue implanted in the subcutaneous tissue of DKO mice showed the similar sensitivity to anti-cancer drugs in the HDRA method. Phenotypes of human colorectal cancer in DKO mice were kept as same as those before implantation. The effect of standard chemotherapeutics on MHC class I and CEA expression in colorectal cancer cell lines was determined. All anti-cancer drugs examined, when given at IC_50 values, induced expression of MHC class I in the human colon cancer cell line, COLO201. However, expression of CEA mRNA was only induced upon exposure to 5-FU. Regarding the in vivo studies in mice, the tumor size of colon26 was reduced only in response to treatment with CDDP, which also mediated the highest induction of MHC class I expression. These results indicate that cancer-specific immunotherapy may be synergistically effective when used in combination with systemic chemotherapy.