Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer

https://doi.org/10.1016/j.ceb.2010.06.003Get rights and content

When cells in our body change their genome and develop into cancer, we blame it on genome instability. When novel species conquer inhospitable environments, we credit it to genome evolution. From a cellular perspective, however, both processes are outcomes of the same fundamental biological properties  genome and pathway plasticity and the natural selection of cells that escape death and acquire growth advantages. Unraveling the consequences of genome plasticity at a cellular level is not only central to the understanding of species evolution but also crucial to deciphering important cell biological problems, such as how cancer cells emerge and how pathogens develop drug resistance. Aside from the well-known role of DNA sequence mutations, recent evidence suggests that changes in DNA copy numbers in the form of segmental or whole-chromosome aneuploidy can bring about large phenotypic variation. Although usually detrimental under conditions suitable for normal proliferation of euploid cells, aneuploidization may be a frequently occurring genetic change that enables pathogens or cancer cells to escape physiological or pharmacological roadblocks.

Introduction

Genomic instability has been a central issue in several basic fields of cell biology for the past decades, spanning from growth and cell cycle regulation, mitosis and meiosis, to cancer progression. Among the main products of genomic instability, and especially of chromosome instability, are DNA copy number changes that often involve relatively large chromosomal regions and in some cases span entire chromosomes. For the scope of this review, we will hereafter refer to segmental and whole-chromosome copy number changes collectively as ‘aneuploidy’. Tremendous efforts have been devoted to the elucidation of the mechanisms leading to aneuploidy (comprehensively reviewed in [1, 2]). We only emphasize here that there is a wide variety of roads that could lead to aneuploidy. Perturbations in components of the chromosome segregation machinery, in the spindle assembly checkpoint, in the S-phase checkpoint, as well as in homologous and non-homologous recombination pathways are some of the common causes leading to either segmental or whole-chromosome aneuploidy [1, 2]. With so many different doors open to aneuploidy, frequent observation of this mutation comes with no surprise. In fact, aneuploidy has long been observed in many different organisms and contexts (Table 1). This article focuses on the consequences of aneuploidy at the cellular level, which has been debated in at least two different but related contexts.

Section snippets

Debates on aneuploidy

Since most cancer cells are aneuploid, one debate has centered on whether aneuploidy is a cause or a consequence of cancer [3, 4]. As cancer cells are often defective in one or more cellular machineries that ensure genome integrity and stability, it is natural to think of aneuploidy as a, perhaps innocent, byproduct of the cellular transformation process itself [5]. The opposing argument is that, based on the view that cancer is a Darwinian process where cells are selected to overcome severe

Aneuploidy affects gene expression on multiple levels

An important question to answer in order to resolve the above debated issues is whether aneuploidy has phenotypic consequences, that is, whether it is ‘innocent’ or ‘guilty’ of causing phenotypic changes, and if the answer is yes, then what might the consequences be with respect to fitness or cancer progression. Evidence gathered in recent years across different organisms unequivocally suggests that changes in gene copy numbers caused by aneuploidy directly lead to changes in the level of mRNA

Aneuploidy profoundly affects the cellular phenotype

Despite a lack of conclusive demonstration on how aneuploidy may affect gene expression at the proteome level, evidence abounds that aneuploidy can bring about large changes in cellular phenotypes. Below we discuss several mechanisms by which aneuploidy affects phenotypic adaptation.

Conclusion and resolving the debates on aneuploidy

On the basis of the many ways by which aneuploidy can bring about phenotypic changes as discussed above, aneuploidy can be viewed as a large-effect mutation, through which large phenotypic leaps can be achieved in a single mutational step. In the classical theory of evolutionary adaptation, species are conceptualized as hikers on a fitness landscape that are trying to reach the nearest fitness peak through accumulation of a series of small-effect mutations [36] (Figure 2). In situations where

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work is supported by NIH grant RO1GM059964 to RL.

References (45)

  • P.C. Nowell

    The clonal evolution of tumor cell populations

    Science

    (1976)
  • L.M. Merlo et al.

    Cancer as an evolutionary and ecological process

    Nat Rev Cancer

    (2006)
  • P. Duesberg et al.

    Origin of multidrug resistance in cells with and without multidrug resistance genes: chromosome reassortments catalyzed by aneuploidy

    Proc Natl Acad Sci U S A

    (2001)
  • P. Duesberg et al.

    The chromosomal basis of cancer

    Cell Oncol

    (2005)
  • C. Gao et al.

    Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations

    Proc Natl Acad Sci U S A

    (2007)
  • C. Swanton et al.

    Chromosomal instability determines taxane response

    Proc Natl Acad Sci U S A

    (2009)
  • A. Selmecki et al.

    Aneuploidy and isochromosome formation in drug-resistant Candida albicans

    Science

    (2006)
  • S. Polakova et al.

    Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata

    Proc Natl Acad Sci U S A

    (2009)
  • M.J. Dunham et al.

    Characteristic genome rearrangements in experimental evolution of Saccharomyces cerevisiae

    Proc Natl Acad Sci U S A

    (2002)
  • D. Gresham et al.

    The repertoire and dynamics of evolutionary adaptations to controlled nutrient-limited environments in yeast

    PLoS Genet

    (2008)
  • T.R. Hughes et al.

    Widespread aneuploidy revealed by DNA microarray expression profiling

    Nat Genet

    (2000)
  • G. Rancati et al.

    Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor

    Cell

    (2008)
  • Cited by (92)

    View all citing articles on Scopus
    View full text