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World J Stem Cells. Mar 26, 2015; 7(2): 483-489
Published online Mar 26, 2015. doi: 10.4252/wjsc.v7.i2.483
Development of cancer-initiating cells and immortalized cells with genomic instability
Ken-ichi Yoshioka, Yuko Atsumi, Hitoshi Nakagama, Hirobumi Teraoka
Ken-ichi Yoshioka, Yuko Atsumi, Hitoshi Nakagama, Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Hirobumi Teraoka, Department of Pathological Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-0034, Japan
Author contributions: Yoshioka K and Atsumi Y generated the figures and wrote the manuscript; Nakagama H and Teraoka H contributed to the writing of the manuscript.
Supported by Funding from the National Cancer Center Research and Development Fund Grant, No. 23-C-10; Grants-in-Aid for Scientific Research MEXT KAKENHI, No. 20770136; and Grants-in-Aid for JSPS Fellows.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ken-ichi Yoshioka, PhD, Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. kyoshiok@ncc.go.jp
Telephone: +81-3-3542-2511 Fax: +81-3-3543-9305
Received: July 23, 2014
Peer-review started: July 25, 2014
First decision: August 28, 2014
Revised: September 29, 2014
Accepted: November 7, 2014
Article in press: November 10, 2014
Published online: March 26, 2015
Processing time: 239 Days and 20.8 Hours
Abstract

Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations and epigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells (CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A (ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2AX to levels representative of growth arrest in normal cells.

Keywords: ARF/p53 module; Cancer stem cells; Cancer-initiating cells; Differentiation; Genomic instability; H2AX

Core tip: Cancer usually develops in conjunction with genomic instability and multiple genetic mutations. Only a small number of cells, called cancer-initiating cells (CICs), are the progenitors of cancerous tissue; but how genomic instability and genetic mutations prompt CICs to develop is still unclear. Recent investigations have uncovered the existence of a pathway that could be responsible. This review explores how that pathway might induce the development of CICs, the tumor suppression mechanisms that must be abrogated in order for malignancies to occur, and the role of the alternative reading frame of CDKN2A (ARF)/p53 module/p53 module in protecting normal cells from oncologic transformation.