Preprint / Version 1

Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell

Authors

  • Mayuko Nishi Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan
  • Hidenori Akutsu Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan
  • Ayumi Kudoh Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan
  • Hirokazu Kimura Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan
  • Naoki Yamamoto Department of Microbiology, National University of Singapore, Singapore
  • Akihiro Umezawa Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan
  • Sam Lee Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
  • Akihide Ryo Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan

Keywords:

Cancer stem cell, p21Cip1, drug screening, senescence, tumor sphere formation

Abstract

Cancer stem cells (CSCs) retain the capacity to propagate themselves through self-renewal and to produce heterogeneous lineages of cancer cells constituting the tumor. Novel drugs that target CSCs can potentially eliminate the tumor initiating cell population therefore resulting in complete cure of the cancer. We recently established a CSC-like model using induced pluripotent stem cell (iPSC) technology to reprogram and partially differentiate human mammary epithelial MCF-10A cells. Using the induced CSC-like (iCSCL) model, we developed a phenotypic drug assay system to identify agents that inhibit the stemness and self-renewal properties of CSCs. The selectivity of the agents was assessed using three distinct assays characterized by cell viability, cellular stemness and tumor sphere formation. Using this approach, we found that withaferin A (WA), an Ayurvedic medicine constituent, was a potent inhibitor of CSC stemness leading to cellular senescence primarily via the induction of p21Cip1 expression. Moreover, WA exhibited strong anti-tumorigenic activity against the iCSCL. These results indicate that our iCSCL model provides an innovative high throughput platform for a simple, easy, and cost-effective method to search for novel CSC-targeting drugs. Furthermore, our current study identified WA as a putative drug candidate for abrogating the stemness and tumor initiating ability of CSCs. Keywords: Cancer stem cell, p21Cip1, drug screening, senescence, tumor sphere formation

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