Development of cancer-initiating cells and immortalized cells with genomic instability.
Development of cancer-initiating cells and immortalized cells with genomic instability.
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DOI：
10.4252/wjsc.v7.i2.483
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发表时间：
2015-03
影响因子：
4.1
通讯作者：
Ken‐ichi Yoshioka;Yuko Atsumi;H. Nakagama;H. Teraoka
中科院分区：
文献类型：
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作者：
Ken‐ichi Yoshioka;Yuko Atsumi;H. Nakagama;H. Teraoka
中年以后发生的癌症通常表现出基因组的不稳定性和多重突变。这与通常由于特定染色体易位和表观遗传畸变而发展的儿科肿瘤形成直接对比。基因组不稳定性的发展与有助于细胞永生和转化的突变有关。当癌起始细胞（CICs），也称为癌症干细胞，由于这些突变而发展时，癌症就发生了。在本文中，我们探讨了CICs是如何作为基因组不稳定的结果而发展的，包括研究哪些癌症抑制机制被废除。最近的一项体外研究表明，在干细胞分化过程中存在CIC诱导通路。在异常分化条件下，细胞变得衰老并发展基因组不稳定，导致CICs的发展。由此产生的CICs在CDKN2A (ARF)/p53模块的备选阅读框中包含突变，即在ARF或p53中。我们总结了最近建立的CIC发育和细胞不朽的知识，探索了ARF/p53模块在保护细胞免于转化中的作用，并描述了在正常细胞生长和分化过程中增加的基因组不稳定的危险因素，并与正常细胞中组蛋白H2AX下调到代表生长停滞的水平有关。
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.