NOD-scidIl2rg tm1Wjl and NOD-Rag1 null Il2rg tm1Wjl : A Model for Stromal Cell-Tumor Cell Interaction for Human Colon Cancer

Stromal cells and the extracellular environment are vital to human tumors, influencing growth and response to therapy. Human tumor cell lines lack stroma and transplantation into immunodeficient mice does not allow meaningful analyses of the effects of stroma on tumor cell growth. Studies of xenografts of primary human tumor fragments in nude mice and in early scid mouse models were constrained by poor tumor growth accompanied by host-versus-graft reactivity, dramatically altering tumor architecture and tumor microenvironment. In contrast, severely immunodeficient NOD-scid and NOD-Rag1 (null) strains carrying the IL2rg (null) mutation (NSG and NRG) support the growth of many types of human primary tumors. We compared the take rate, growth and architectural preservation of 10 clinically distinct primary human colon cancers in NOD-scid, NOD-Rag1 (null) , NSG and NRG mice and determined the contribution of mouse and human cells to the stroma during tumor proliferation and expansion in secondary hosts and tumor response to treatment with 5-fluorouracil (5-FU). NSG and NRG mice more readily support growth of human primary colon tumor fragments than do NOD-scid, NOD-Rag1 (null) mice and maintain tumor architectural integrity in the primary recipient and through subsequent transplant generations. The human colon tumors were responsive to treatment with 5-FU. Human stromal cells in the primary graft were replaced by mouse-derived fibroblasts in a dynamic process during subsequent passages. Human colon cancer xenografts propagated in NSG and NRG mice maintain structural fidelity while replacing human stromal cells with murine stromal cells.