In the preclinical studies for anticancer drugs, in vitro and in vivo models derived from clinical tumor specimens are considered to provide more accurate prediction data for clinical efficacy of candidate agents as compared to models using conventionally established cancer cell lines. A pivotal role of this department is the establishment of cancer organoids, cell aggregates consisted of variously differentiated cells including cancer stem cells, and tumor-harboring animal models (cancer tissue/cell-transplanted immune-deficient mice). These in vitro and in vivo models are used for exploration/screening of molecular target drugs.
The research activities of this department are also focused on studies of recapitulation of multi-step carcinogenesis for diverse organs through an in vitro approach. Whereas both genetic and environmental factors cooperate for tumorigenesis in vivo, we have demonstrated that combination introduction of cancer-related genetic alterations in cultured murine primary epithelial cells, so called organoids, could lead to the development of adenocarcinoma in the dorsal skin of immunedeficient mice. Notably, tumor initiation and subsequent step-wise progression from normal cells via pre-cancerous lesions to carcinoma could be accurately recapitulated for various vital organs in a cell-autonomous manner. By taking this approach, genetic and/or environmental interactions toward tumorigenesis could be conveniently investigated in vitro, which would likely accelerate elucidation of the molecular mechanisms underlying carcinogenesis. Although heterogeneously p53-knockout or activated Kras-introduced organoids did not form carcinomas, in vitro treatment of genotoxic carcinogens could induce carcinoma-like tissues. We will elucidate the molecular mechanisms of carcinogensis by environmental factors using these organoid models.