Chronic exposure to FGF2 converts iPSCs into cancer stem cells with an enhanced integrin/focal adhesion/PI3K/AKT axis

Mona Sheta; Ghmkin Hassan; Said M Afify; Sadia Monzur; Kazuki Kumon; Hagar A Abu Quora; Mahmoud Farahat; Maram H Zahra; Xiaoying Fu; Akimasa Seno; Masaharu Seno

doi:10.1016/j.canlet.2021.08.026

Chronic exposure to FGF2 converts iPSCs into cancer stem cells with an enhanced integrin/focal adhesion/PI3K/AKT axis

Cancer Lett. 2021 Aug 26:521:142-154. doi: 10.1016/j.canlet.2021.08.026. Online ahead of print.

Authors

Mona Sheta¹, Ghmkin Hassan², Said M Afify³, Sadia Monzur⁴, Kazuki Kumon⁴, Hagar A Abu Quora⁴, Mahmoud Farahat⁵, Maram H Zahra⁴, Xiaoying Fu⁶, Akimasa Seno⁴, Masaharu Seno⁷

Affiliations

¹ Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan; Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt.
² Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan; Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus, Syria.
³ Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan; Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Menoufia, Egypt.
⁴ Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan.
⁵ Department of Biomaterials, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
⁶ Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan; Department of Pathology, Tianjin University of Traditional Chinese Medicine, China.
⁷ Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan. Electronic address: mseno@okayama-u.ac.jp.

PMID: 34455015
DOI: 10.1016/j.canlet.2021.08.026

Abstract

We previously demonstrated the conversion of normal stem cells, including induced pluripotent stem cells (iPSCs), into cancer stem cells (CSCs) without genetic manipulation. Herein, we designed a meta-analysis to assess gene expression profiles in different breast cancer cell lines focusing on the secretory factors responsible for conversion. As a result, fibroblast growth factor 2 (FGF2) was found to be the best candidate in T47D and BT549 cells, of which conditioned medium was previously successful in inducing CSCs. When treated with 3.1 μg/ml FGF2, mouse iPSCs not only maintained survival without LIF for three weeks but also acquired growth ability independent of FGF2. The resultant cells exhibited expression of stemness and cancer stem cell markers, sphere-forming ability, differentiation, and tumorigenicity with malignancy. The primary cultures of the tumor confirmed the signatures of CSCs with two different phenotypes with or without GFP expression under control of the Nanog promoter. Bioinformatic analysis of gene expression profiles suggested constitutive autocrine activation of the FGF receptor, integrins, focal adhesions, and PI3K/AKT pathways. FGF2 could potently initiate cancer as a component of the inflammatory microenvironment.

Keywords: Cancer initiation; Cancer stem cells; Chronic inflammation; FGF2; iPSCs.