Development of in vivo experimental system for analyses of human cancer inductive microenvironment by using NOG mice

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We developed a reliable new experimental in vivo model system for assaying cancer inductive microenvironment by using NOD/SCID/γc^<null>(NOG) mice. Human pancreatic cancer cell lines were examined for their ability to form diverse metastatic foci in the livers of NOG mice. Using the NOG mouse model system, we established a highly metastatic cell line, liver metastasized-BxPC-3 (LM-BxPC-3). We identified forty-five genes that were either upregulated or down regulated >4-fold in the LMBxPC-3 cell line. Only S100A4 expression correlated with the ability to form liver metastases, as evaluated in our quantitative model of metastasis in NOG mice. These results suggested that new experimental systems using NOG mice gave us the reliable metastasis model to search for and develop new anti-cancer therapies and noveldrugs against this and other key molecules. We also examined the role of Thrombospondin-2 (TSP-2) on invasion and metastasis of human malignant melanoma cell line A375. We isolated three human malignant melanoma cell lines transfected with human TSP-2 (A375/TSP-2). Cellular invasive potential was evaluated using matrigel invasion / migration assay. The in vivo metastatic experiment was performed using the NOG mice in vivo experimental system, in which the tumor cells were inoculated via portal vein from the spleen. In the in vivo metastatic experiment, A375/TSP-2 showed obviously less liver metastatic foci. The weights of liver were measured as index for metastatic hepatomegary and disclosed statistically significant. The reduction of microvessel within metastatic lesions expressing TSP2 was also histologically confirmed. The results also demonstrated that the NOG mouse systems are useful to study cancer inductive microenvironments including angiogenesis or matrix protease conditions.