Development of New Risk Assessment Methods with iPSCs

Title of Research:
13_S01-01-4

Development of the Novel Method with iPSCs to Assess ChemicalCompounds for the Risk of CSC Induction
Principal Investigator:
Masaharu Seno, PhD (Professor, Graduate School of Natural Science and Technology, Okayama
University) 3.1.1 Tsushima-Naka, Kita, Okayama 700-8530, Japan.
Collaborators:
Tomonari Kasai, PhD, Akifumi Mizutani, PhD, Jyunko Masuda, PhD, Akimasa Seno, PhD, Aun Ko
Ko Oo, PhD, Hideki Minematsu, MS, Eman Ahmed Taha, MS (Graduate School of Natural Scienceand Technology, Okayama University)
Yoshiaki Iwasaki, MD, PhD (Center of Healthcare, Okayama University)
Summary of Research:
The risk assessment for the cancer development caused by chemical compounds has long
been made by mutagenicity or repeated dose toxicity study, by which it generally takes long timeto get results. However, cancer is currently recognized consisting of heterogeneous population ofcells and cancer stem cells (CSCs). This is altering the idea that a cancer tissue consists of ahomogeneous population of clonal cells continuously proliferating due to the oncogenic mutations.
It appears necessary to develop a novel method to identify chemical compounds that may induce
cancer stem cells. In this study, we established a simple method to assess the risk of chemicalcompounds inducing CSCs employing mouse iPSCs, which have been reprogrammed from theembryonic fibroblast derived from a transgenic mouse carrying the Nanog promoter integrated
with GFP gene. This method allows the assessment in 8 days by judging the increase of spheres
and the fluorescence of GFP enhanced by Nanog gene expression. We evaluated 147 chemicalcompounds and 30 were judged as positive. Further, we tried to analyze the molecular mechanism
inducing CSCs from miPSCs by microarray, CpG methylation, lipid component, bioinformatics andso on. As the results, the relationship of some chemokine and its receptors, some specificcytoplasmic signal transduction pathway, inflammatory factors were implied to be importantlyinvolved. Collectively, it should be possible to find out the key relationships between the cancer
risks and the mechanism of action of chemical compounds in the future.
Timeline:
March 1, 2012 – February 28, 2018Topics:
Poster presentation entitled “Development of the Novel Method with iPSCs to Assess ChemicalCompounds for the Risk of CSC Induction” at 2017 Annual Meeting of LRI.
Publications:
Nair N, Calle AS, Zahra MH, Prieto-Vila M, Oo AKK, Hurley L, Vaidyanath A, Seno A, Masuda J,Iwasaki Y, Tanaka H, Kasai T, Seno M. A cancer stem cell model as the point of origin ofcancer-associated fibroblasts in tumor microenvironment. Sci Rep. 2017;7(1):6838.
Ninomiya T, Ohara T, Noma K, Katsura Y, Katsube R, Kashima H, Kato T, Tomono Y, Tazawa H,Kagawa S, Shirakawa Y, Kimura F, Chen L, Kasai T, Seno M, Matsukawa A, Fujiwara T. Irondepletion is a novel therapeutic strategy to target cancer stem cells. Oncotarget.
2017;8(58):98405-98416.
OoA, Calle AS, Nair N, Mahmud H, Vaidyanath A, Yamauchi J, Khayrani AC, Du J, Alam MJ, Seno
A, Mizutani A, Murakami H, Iwasaki Y, Chen L, Kasai T, Seno M. Up-Regulation of PI 3-Kinases
and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNAHypomethylation Mediated by the Cancer Microenvironment. Translational Oncology.
2018;11(3), 653-663.
Seno A, Seno M. Commonly expressed genes among cancer stem cells induced from hiPSCs andDevelopment of New Risk Assessment Methods with iPSCs
obtained from cancer tissues or cell lines. Tumor and Microenvironment. 2018 in press.