Chromosome instability and deregulated proliferation: an unavoidable duo.
ABSTRACT The concept that aneuploidy is a characteristic of malignant cells has long been known; however, the idea that aneuploidy is an active contributor to tumorigenesis, as opposed to being an associated phenotype, is more recent in its evolution. At the same time, we are seeing the emergence of novel roles for tumor suppressor genes and oncogenes in genome stability. These include the adenomatous polyposis coli gene (APC), p53, the retinoblastoma susceptibility gene (RB1), and Ras. Originally, many of these genes were thought to be tumor suppressive or oncogenic solely because of their role in proliferative control. Because of the frequency with which they are disrupted in cancer, chromosome instability caused by their dysfunction may be more central to tumorigenesis than previously thought. Therefore, this review will highlight how the proper function of cell cycle regulatory genes contributes to the maintenance of genome stability, and how their mutation in cancer obligatorily connects proliferation and chromosome instability.
SourceAvailable from: Anna V Roschke[Show abstract] [Hide abstract]
ABSTRACT: Whole-chromosomal instability (W-CIN) - unequal chromosome distribution during cell division - is a characteristic feature of a majority of cancer cells distinguishing them from their normal counterparts. The precise molecular mechanisms that may cause mis-segregation of chromosomes in tumor cells just recently became more evident. The consequences of W-CIN are numerous and play a critical role in carcinogenesis. W-CIN mediates evolution of cancer cell population under selective pressure and can facilitate the accumulation of genetic changes that promote malignancy. It has both tumor-promoting and tumor-suppressive effects, and their balance could be beneficial or detrimental for carcinogenesis. The characterization of W-CIN as a complex multi-layered adaptive phenotype highlights the intra- and extracellular adaptations to the consequences of genome reshuffling. It also provides a framework for targeting aggressive chromosomally unstable cancers.Frontiers in Oncology 12/2013; 3:302. DOI:10.3389/fonc.2013.00302
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ABSTRACT: Research of the past several decades suggests that bacterial infection can lead to genome instability of the host cell often resulting in cancer development. However, there is still a substantial lack of knowledge regarding possible mechanisms involved in the development of genomic instability. Several questions remain unanswered, namely: Why has the causative relationship between the bacterial infection and cancer been established only for a small number of cancers? What is the mechanism responsible for the induction of genome instability and cancer? Is the infection process required to cause genome instability and cancer? In this review, we present a hypothesis that the bacterial infection, exposure to heat-killed bacteria or even some bacterial determinants may trigger genome instability of exposed and distal cells, and thus may cause cancer. We will discuss the mechanisms of host responses to the bacterial infection and present the possible pathways leading to genome instability and cancer through exposure to bacteria.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 01/2014; 761. DOI:10.1016/j.mrfmmm.2014.01.004 · 4.44 Impact Factor
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ABSTRACT: Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context-dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesised that CIN permits accelerated genomic evolution through the generation of diverse DNA copy number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy number alterations which drive cancer proliferation.Cancer Research 06/2014; 74(17):4853–63. DOI:10.1158/0008-5472.CAN-13-2664 · 9.28 Impact Factor