BBA - Reviews on Cancer (v.1786, #1)

The chromosome shuffle by René H. Medema (1-3).

Aneuploid cells are frequently observed in human tumors, suggesting that aneuploidy may play an important role in the development of cancer. In this review, I discuss the processes that may give rise to aneuploid cells in normal tissue and in tumors. Aneuploid cells may arise directly from diploid cells through errors in chromosome segregation, as a consequence of incorrect microtubule-kinetochore attachments, or through failure of the spindle checkpoint. A second route to formation of aneuploid cells is through a tetraploid intermediate, where division of tetraploid cells can yield very high rates of chromosome missegregation as a consequence of multipolar spindle formation. Diploid cells may become tetraploid through a variety of mechanisms, including endoreduplication, cell fusion, and cytokinesis failure. Although aneuploid cells may arise from either diploid or tetraploid cells, the fate of the resulting aneuploid cells may be distinct. It is therefore important to understand the different pathways that can give rise to aneuploid cells, and how the varied origins of these cells affect their subsequent ability to survive or proliferate.
Keywords: Aneuploidy; Tetraploidy; Chromosome nondisjunction; Spindle checkpoint; Cytokinesis;

Centrosomes play a critical role in formation of bipolar mitotic spindles, an essential event for accurate chromosome segregation into daughter cells. Numeral abnormalities of centrosomes (centrosome amplification) occur frequently in cancers, and are considered to be the major cause of chromosome instability, which accelerates acquisition of malignant phenotypes during tumor progression. Loss or mutational inactivation of p53 tumor suppressor protein, one of the most common mutations found in cancers, results in a high frequency of centrosome amplification in part via allowing the activation of the cyclin-dependent kinase (CDK) 2–cyclin E (as well as CDK2–cyclin A) which is a key factor for the initiation of centrosome duplication. In this review, the role of centrosome amplification in tumor progression, and mechanistic view of how centrosomes are amplified in cells through focusing on loss of p53 and aberrant activities of CDK2–cyclins will be discussed.
Keywords: Centrosome; Chromosome instability; p53; CDK2; Cyclin E; Cyclin A;

Preventing aneuploidy: The contribution of mitotic checkpoint proteins by Saskia J.E. Suijkerbuijk; Geert J.P.L. Kops (24-31).
Aneuploidy, an abnormal number of chromosomes, is a trait shared by most solid tumors. Chromosomal instability (CIN) manifested as aneuploidy might promote tumorigenesis and cause increased resistance to anti-cancer therapies. The mitotic checkpoint or spindle assembly checkpoint is a major signaling pathway involved in the prevention of CIN. We review current knowledge on the contribution of misregulation of mitotic checkpoint proteins to tumor formation and will address to what extent this contribution is due to chromosome segregation errors directly. We propose that both checkpoint and non-checkpoint functions of these proteins contribute to the wide array of oncogenic phenotypes seen upon their misregulation.
Keywords: Mitosis; Mitotic checkpoint; Aneuploidy; Tumorigenesis; Chromosomal; Instability;

Accurate chromosome segregation in mitosis is crucial to maintain a diploid chromosome number. A majority of cancer cells are aneuploid and chromosomally unstable, i.e. they tend to gain and lose chromosomes at each mitotic division. Chromosome mis-segregation can arise when cells progress through mitosis with mis-attached kinetochores. Merotelic kinetochore orientation, a type of mis-attachment in which a single kinetochore binds microtubules from two spindle poles rather than just one, can represent a particular threat for dividing cells, as: (i) it occurs frequently in early mitosis; (ii) it is not detected by the spindle assembly checkpoint (unlike other types of mis-attachments); (iii) it can lead to chromosome mis-segregation, and, hence, aneuploidy. A number of studies have recently started to unveil the cellular and molecular mechanisms involved in merotelic kinetochore formation and correction. Here, I review these studies and discuss the relevance of merotelic kinetochore orientation in cancer cell biology.
Keywords: Aneuploidy; Merotelic; Kinetochore; Chromosome segregation; Cancer;

Sister chromatid cohesion is a major feature of the eukaryotic chromosome. It entails the formation of a physical linkage between the two copies of a chromosome that result from the duplication process. This linkage must be maintained until chromosome segregation takes place in order to ensure the accurate distribution of the genomic information. Cohesin, a multiprotein complex conserved from yeast to humans, is largely responsible for sister chromatid cohesion. Other cohesion factors regulate the interaction of cohesin with chromatin as well as the establishment and dissolution of cohesion. In addition, the presence of cohesin throughout the genome appears to influence processes other than chromosome segregation, such as transcription and DNA repair. In this review I summarize recent advances in our understanding of cohesin function and regulation in mitosis, and discuss the consequences of impairing the cohesion process at the level of the whole organism.
Keywords: Cohesin; Chromosome segregation; Topoisomerase II; Mouse models;

To cell cycle, swing the APC/C by Renske van Leuken; Linda Clijsters; Rob Wolthuis (49-59).
For successful mitosis, Cyclin B1 and Securin must be degraded efficiently before anaphase. Destruction of these mitotic regulators by the 26S proteasome is the result of their poly-ubiquitination by a multi-subunit E3 ligase: the Anaphase-Promoting Complex or Cyclosome (APC/C). Clearly, the APC/C is not just important for mitosis. Destruction of APC/C substrates such as Cdc20, Plk1, Aurora A and Skp2 directs events in G1. Strikingly, the APC/C needs to stay active even in quiescent cells to keep them out of the cell cycle and forms an intriguing link with pRb. An inactive APC/C stabilizes Geminin, Cyclin A and Cyclin B1, thereby securing completion of DNA synthesis and progression through G2-phase. In prometaphase the APC/C becomes active again, but is controlled by the spindle assembly checkpoint. Here we discuss how the APC/C is either held in check or released. We argue that shedding more light on the APC/C is also important to understand cancer and could help the design of treatment.
Keywords: Cyclin A; Cyclin B1; Securin; Cdc20; Cdh1; pRb; Geminin; APC/C; Cyclosome; Mitosis; Cell cycle;

The Aurora kinase family in cell division and cancer by Gerben Vader; Susanne M.A. Lens (60-72).
The Aurora protein kinase family (consisting of Aurora-A, -B and -C) is an important group of enzymes that controls several aspects of cell division in mammalian cells. Dysfunction of these kinases has been associated with a failure to maintain a stable chromosome content, a state that can contribute to tumourigenesis. Additionally, Aurora-A is frequently found amplified in a variety of tumour types and displays oncogenic activity. On the other hand, therapeutic inhibition of these kinases has shown great promise as potential anti-cancer treatment, most likely because of their essential roles during cell division. This review will focus on our present understanding of the different roles played by these kinases, their regulation throughout cell division, their deregulation in human cancers and on the progress that is made in targeting these important regulators in the treatment of cancer.
Keywords: Mitosis; Cell division; Checkpoint; Cancer; Aurora;

Studying chromosome instability in the mouse by Floris Foijer; Viji M. Draviam; Peter K. Sorger (73-82).
Aneuploidy has long been recognized as one of the hallmarks of cancer. It nonetheless remains uncertain whether aneuploidy occurring early in the development of a cancer is a primary cause of oncogenic transformation, or whether it is an epiphenomenon that arises from a general breakdown in cell cycle control late in tumorigenesis. The accuracy of chromosome segregation is ensured both by the intrinsic mechanics of mitosis and by an error-checking spindle assembly checkpoint. Many cancers show altered expression of proteins involved in the spindle checkpoint or in proteins implicated in other mitotic processes. To understand the role of aneuploidy in the initiation and progression of cancer, a number of spindle checkpoint genes have been disrupted in mice, most through conventional gene targeting (to create germ-line knockouts). We describe the consequence of these mutations with respect to embryonic development, tumor progression and an unexpected link to premature aging; readers are referred elsewhere for a discussion of other cell cycle regulators.
Keywords: Spindle checkpoint; Mouse models; Aneuploidy; Chromosome instability;