Deregulation of the centrosome cycle and the origin of chromosomal instability in cancer

Wilma L Lingle, Kara Lukasiewicz, Jeffrey L Salisbury
Advances in Experimental Medicine and Biology 2005, 570: 393-421
Although we have begun to tap into the mechanisms behind Boveri's initial observation that supernumerary centrosomes cause chromosome missegregation in sea urchin eggs, there is still much left to discover with regard to chromosomal instability in cancer. Many of the molecular players involved in regulation of the centrosome and cell cycles, and the coupling of the two cycles to produce a bipolar mitotic spindle have been identified. One theme that has become apparent is that cross talk and interrelatedness of the pathways serve to provide redundant mechanisms to maintain genomic integrity. In spite of this, cells occasionally fall prey to insults that initiate and maintain the chromosomal instability that results in viable malignant tumours. Deregulation of centrosome structure is an integral aspect of the origin of chromosomal instability in many cancers. There are numerous routes to centrosome amplification including: environmental insults such as ionising radiation and exposure to estrogen (Li et al., 2005); failure of cytokinesis; and activating mutations in key regulators of centrosome structure and function. There are two models for initiation of centrosome amplification (Figure 2). In the first, centrosome duplication and chromosome replication remain coupled and cells enter G2 with 4N chromosomes and duplicated centrosomes. However, these cells may fail to complete mitosis, and thus reenter G1 as tetraploid cells with amplified centrosomes. In the second, the centrosome cycle is uncoupled from chromosome replication and cells go through one or more rounds of centriole/centrosome duplication in the absence of chromosome replication. If these cells then go through chromosome replication accompanied by another round of centrosome duplication, cells complete G2 with 4N chromosomes and more than 2 centrosomes, and therefore are predisposed to generate multipolar mitotic spindles. Fragmentation of centrosomes due to ionising radiation is a variation of the second model. Once centrosome amplification is present, even in a diploid cell, that cell has the potential to yield viable aneuploid progeny. The telophase cell in Figure 3C illustrates this scenario. In a normal telophase configuration, the total number of chromosomes is 92 (resulting from the segregation of 46 pairs of chromatids), with each daughter nucleus containing 46 individual chromosomes. Based on the number of kinetochore signals present, the lower nucleus in Figure 3C has approximately 28 chromosomes, and the elongate upper nucleus has approximately 60, for a total of 88. Due to superimposition of kinetochores in this maximum projection image, 88 is an underestimate of the actual number of kinetochores and is not significantly different from the expected total of 92. A cell resulting from the lower nucleus with only around 28 chromosomes would probably not be viable, much as Boveri's experiments indicated. However, the upper nucleus with at least 60 chromosomes could be viable. This cell would enter G1 as hypotriploid (69 chromosomes = triploid) with 2 centrosomes. During S and G2, the centrosomes and chromosomes would double, and the following mitosis could be tetrapolar with a 6N chromosome content. When centrosome amplification is accompanied by permissive lapses in cell cycle checkpoints, the potential for malignant growth is present. These lapses could result from specific genetic mutations and amplifications, epigenetic gene silencing, or from massive chromosomal instability caused by the centrosome amplification. Centrosome amplification, therefore, can serve to exacerbate and/or generate genetic instabilities associated with cancers.

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