SCID-hu mice for the study of human cancer metastasis

Cancer metastasis involves dynamic and multistep in vivo processes. While g eneration of metastatic clones requires genetic alterations in cancer cells , subsequent selection of the clones is heavily influenced by interactions with the surrounding tissue microenvironment. To reproduce the complex cell ular interactions that occur in human patients is, however, difficult, and has not been achieved using currently available in vitro systems or convent ional animal models. The SCID-hu mouse is generated by surgical implantatio n of human fetal tissues into mutant mice of the severe combined immunodefi cient (SCID) phenotype. The unique feature of this model is that the implan ted human tissues maintain their normal architecture and function. Therefor e implanted human tissues will provide relevant microenvironments for the g rowth and metastasis of human cancer cells. The SCID-hu mouse model, which was specifically designed for the study of human cancer biology, enables ex perimental investigation of cellular events involved in cancer metastasis o n the basis of interactions between human cancer cells and the human tissue microenvironment. It has been demonstrated that various types of human can cer cell lines generate tumors in implanted human bone marrow and lung, org ans frequently involved in metastasis in patients, upon intravenous inocula tion. Tumorigenic activity in SCID-hu mice faithfully reflects the clinical features of the original cancer. Tumor formation and selection of high tum origenic variants occur in a species-specific manner. Furthermore, it was s hown that metastatic tumor formation is regulated by both cancer cells and conditions in the host organs. Conditioning of animals by either whole-body irradiation or interleukin Icl treatment prior to cancer cell inoculation induced metastatic tumor formation by certain small cell lung cancer (SCLC) cell lines specifically in human bone marrow. A novel gene has been identi fied by comparing gene expression profiles between high and low tumorigenic SCLC cells in human lung. This gene is preferentially expressed in low met astatic lines, and transfection of the gene into highly metastatic cells re sults in suppression of metastasis. Recent studies have shown that the gene product is involved in the apoptosis induction pathway. Collectively, our results indicate that the SCID-hu mouse will serve as a unique platform tec hnology with which to investigate cellular events involved in human cancer metastasis, as well as to identify genes playing important roles in the gro wth and metastasis of human cancer, in the context of interactions between human cancer cells and human tissue environments.