Annual Report 2017

Department of Animal Experimentation

Toshio Imai, Naoko Higashijima, Ryouichi Masui, Masako Ochiai, Yoshitaka Hippo, Masashi Izumiya

Introduction

 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 the Department of Animal Experimentation 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 goal is to set up flexible models that have greater accuracy than previous ones using established cancer cell lines.

Our team and what we do

 We willingly contribute to establish useful in vitro and in vivo models including cancer organoids and PDX models for translational research and to screen and evaluate prospective candidates for molecular-targeted new drugs.

Research activities

 The research activities of the Department of Animal Experimentation are 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 immune-deficient mice. Notably, tumor initiation and subsequent step-wise progression from normal cells via pre-cancerous lesions to carcinoma could be accurately recapitu-lated for various vital organs in a cell-autonomous manner. By taking this approach, genetic and/or environmental interactions toward tumorige-nesis could be conveniently investigated in vitro, which would likely accelerate elucidation of the molecular mechanisms underlying carcinogenesis. Although activated Kras-introduced or heterogeneously p53-knockout organoids did not form carcinomas, in vitro treatment of genotoxic carcinogens could induce carcinoma-like tissues. We will elucidate the molecular mechanisms of the early stages of carcinogenesis by environmental factors using these organoid models.

Future prospects

 The staff of the Department of Animal Experimentation is united in our resolve to establish wide ranging cancer animal model panel, which could be selected depending on the intended use.

List of papers published in January 2017 - March 2018

Journal

1. Kangawa Y, Yoshida T, Maruyama K, Okamoto M, Kihara T, Nakamura M, Ochiai M, Hippo Y, Hayashi SM, Shibutani M. Cilostazol and enzymatically modified isoquercitrin attenuate experimental colitis and colon cancer in mice by inhibiting cell proliferation and inflammation. Food Chem Toxicol, 100:103-114, 2017