Annual Report 2019

Department of Animal Experimentation

Toshio Imai, Ryoichi Masui, Masako Ochiai

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 the candidate agents compared to models using conventionally established cancer cell lines. A pivotal role of this Department is the establishment of cancer organoids, cell aggregates consisting 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 efficacy evaluation and pharmacodynamic biomarker discovery of molecular target drugs. A goal is to set up flexible models which have greater accuracy than previous ones using established cancer cell lines.

The 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 basic 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 demonstrated that through combined introduction of cancer-related genetic alterations in cultured murine primary epithelial cells, so-called organoids, could lead to development of adenocarcinomas in the dorsal skin of immunodeficient mice. Notably, tumor initiation and subsequent stepwise progression from normal cells via precancerous 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 Trp53-knockout organoids did not form carcinomas, in vitro treatment of genotoxic carcinogens, e.g., acrylamide (AA) and 7,12-dimethylbenz(a)anthracene (DMBA), could induce carcinoma/carcinoma-like tissues. These results resembled those induced in AA-or DMBA-treated mouse models, and it was suggested that such in vitro chemical carcinogenesis models would contribute to reduction of animal experimentation. In addition, we will elucidate molecular mechanisms of early stages of carcinogenesis by environmental factors using these organoid models.

Future prospects

 Staff of the Department of Animal Experimentation should be united in their resolve to establish wide-ranging cancer animal model panels, which could be selected depending on their intended use.

List of papers published in 2019

Journal

1. Naruse M, Masui R, Ochiai M, Maru Y, Hippo Y, Imai T. An organoid-based carcinogenesis model induced by in vitro chemical treatment. Carcinogenesis, 2020

2. Ochiai M, Yoshihara Y, Maru Y, Tetsuya M, Izumiya M, Imai T, Hippo Y. Kras-driven heterotopic tumor development from hepatobiliary organoids. Carcinogenesis, 40:1142-1152, 2019

3. Maru Y, Onuma K, Ochiai M, Imai T, Hippo Y. Shortcuts to intestinal carcinogenesis by genetic engineering in organoids. Cancer Sci, 110:858-866, 2019

4. Matsuura T, Maru Y, Izumiya M, Hoshi D, Kato S, Ochiai M, Hori M, Yamamoto S, Tatsuno K, Imai T, Aburatani H, Nakajima A, Hippo Y. Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis. Carcinogenesis, 2019