Development of cancer-initiating cells and immortalizedcells with genomic instability

• 作者: Ken-ichi Yoshioka Yuko Atsumi Hitoshi Nakagama Hirobumi Teraoka
• 来源期刊: 世界干细胞杂志：英文版（电子版）
• 学科: 医学
• 关键词: ARF/p53 MODULE Cancer stem cells Cancerinitiatingcells DIFFERENTIATION GENOMIC INSTABILITY H2AX
• 年，卷（期）: 2015,（2）
• 页码范围: 483-489
• 页数: 7页
• 分类号: R

摘要

Cancers that develop after middle age usually exhibitgenomic instability and multiple mutations. This is indirect contrast to pediatric tumors that usually developas a result of specific chromosomal translocations andepigenetic aberrations. The development of genomicinstability is associated with mutations that contributeto cellular immortalization and transformation. Canceroccurs when cancer-initiating cells （CICs）, also calledcancer stem cells, develop as a result of these mutations.In this paper, we explore how CICs develop as a resultof genomic instability, including looking at which cancersuppression mechanisms are abrogated. A recent in vitrostudy revealed the existence of a CIC induction pathwayin differentiating stem cells. Under aberrant differentiationconditions, cells become senescent and develop genomicinstabilities that lead to the development of CICs. Theresulting CICs contain a mutation in the alternativereading frame of CDKN2A （ARF）/p53 module, i.e. , ineither ARF or p53. We summarize recently establishedknowledge of CIC development and cellular immortality,explore the role of the ARF/p53 module in protectingcells from transformation, and describe a risk factorfor genomic destabilization that increases during theprocess of normal cell growth and differentiation and isassociated with the downregulation of histone H2AX tolevels representative of growth arrest in normal cells.