Development and assessment of new risk assessment methods

Title of Research:
13_S01-01-2

Development of novel method to assess chemical compounds forthe risk of cancer stem cell induction with iPS cells
Principal Investigator:
Masaharu Seno, Graduate School of Natural Science and Technology Okayama University
Collaborators:
Tomonari Kasai, Graduate School of Natural Science and Technology Okayama University
Shuichi Furuya, Okayama University Research Administration office
Akifumi Mizutani, Graduate School of Natural Science and Technology Okayama University
Junko Masuda, Graduate School of Natural Science and Technology Okayama University
Summary of Research:
Cancer stem cells are considered to be significantly responsible for growth, metastasis,invasion and recurrence of all cancer. We propose the risk assessment of chemical compounds fortheir potential of induction of cancer stem cells, while those for carcinogenic activity have been
evaluated by mutagenicity test, repeated dose toxicity study, estimating with statistical analysis,and so on.
Cancer stem cells are typically characterized by continuous proliferation self-renewal as well as
by differentiation potential, while stem cells are considered to differentiate into tissue specificphenotype of mature cells under the influence of microenvironment. Cancer stem cells can betraced back to the stem cells under specific influences of microenvironment, so called ‘cancerous
niche’, which induces malignant tumors. We have very recently demonstrated the induction ofcancer stem cells from mouse iPS cells culturing in the conditioned medium derived from cancer
cells, although the details of the mechanisms of differentiation is not very well known as of yet.
In this study, we aim at the development of novel method to evaluate the risk of chemicalcompounds for the potential to induce cancer stem cells from iPS cells in vitro in a short period.
Briefly, mouse iPS cells are suspended in the conditioned medium. The cells are further
replenished with the growth medium with the compounds to be assessed.
We are currently observing the fluorescence intensity of GFP, of which expression is under thecontrol of Nanog promoter, and the shape of colonies everyday for a period of 8 days. Based onthese observations, 20 from 75 compounds assessed in the procedure were selected asprospectively positive candidates for converting mouse iPS cells to cancer stem cells. The
modification of the method for efficient availability and high sensitivity is under way. We areplanning further assessment for the mechanism through which the compounds are inducing thegeneration of cancer stem cells. The mechanism inducing cancer stem cells is needed to bestudied in detail.
Timeline:
March 2012-February 2015
Topics:Development of novel method to evaluate chemical compounds as the possible inducer of cancer
stem cells using iPS cells. The 28th Annual Meeting of the Japanese Society for Alternatives toAnimal Experiments. (Dec. 2015, Yokohama)
Publications:
Analysis of the mechanism in the induction of cancer stem cells by signaling inhibitors. BMB 2015
(Dec. 2015, Kobe)
Development of a simple risk assessment of chemical compounds in the induction of cancer stem
cells in vitro. The 28th Annual Meeting of the Japanese Society for Alternatives to Animal
Experiments. (Dec. 2015, Yokohama)4