Mini-reviewCentrosome amplification, chromosome instability and cancer development
Introduction
For a normal cell to transform to a fully malignant cell, a number of specific genes need to be mutated. Each mutation alone or in combination with other mutations render one or more malignant phenotypes, including immortalization, mitogen-independent growth, anchorage-independent growth, loss of tissue specificity, to name a few. Acquisition of these malignant characteristics occurs in a step-wise fashion (tumor progression), originally described by Foulds [1]. In 1976, because of frequent karyotypic alterations in cancer cells compared with normal cells, Nowell [2] hypothesized that genomic instability is the driving force behind tumor progression. Through the accumulation of knowledge on tumor progression at a molecular level, this concept was extended by Loeb to propose that cells acquire mutation(s) that increase the mutation rate (mutator phenotype) during tumor progression, enabling cells to rapidly accumulate many specific mutations required for malignant transformation [3].
Various types of genetic lesions can be found in cancer cells, including DNA sequence mutations (i.e. point mutation, insertion and deletion, recombination, etc.) and chromosome mutations [i.e. translocation, double-minute chromosomes, aneuploidy (chromosome loss and gain), etc.]. Although it is apparently meaningless to label which type of mutation is most important for carcinogenesis, it is clear that aneuploidy influences the rate of tumor progression to a great extent, since loss or gain of even a single chromosome can introduce multiple mutations required for acquisition of malignant phenotypes. Chromosome loss and gain can be in most cases equated to chromosome segregation errors due to mitotic and cytokinetic defects. In this respect, there are a number of potential mechanisms that could consequentially destabilize chromosomes, including loss of mitotic checkpoint function, defective kinetochore function, and abnormal amplification of centrosomes. Among these, much attention has recently been given to centrosome amplification, because of its prevalent occurrence in human cancer [4], [5]. In this review, I will discuss a recent progress in the study of centrosomes in the context of chromosome instability and cancer development and mechanistic aspects of centrosome amplification in association with mutations of tumor suppressor proteins.
Section snippets
Biology of centrosomes
The centrosome is a small non-membranous organelle (1–2 μm in diameter) normally localized at the periphery of nucleus. Its primary function is to nucleate (anchor) microtubules, hence often denoted as a major microtubule organizing center (MTOC). The centrosome in animal cells consists of a pair of centrioles, which are joined by fibers connecting their proximal ends, and a number of different proteins surrounding the centriole pair, which are referred to as pericentriolar material (PCM) as a
Centrosome amplification and chromosome instability
The presence of two centrosomes at mitosis is critical for the formation of bipolar mitotic spindles (Fig. 1C). Since chromosomes are pulled toward each spindle pole, the bipolarity of mitotic spindles is essential for the accurate chromosome segregation into daughter cells during cytokinesis. Thus, numeral homeostasis of centrosomes is highly controlled. Abrogation of this control results in abnormal amplification of centrosomes (presence of more than two centrosomes), which in turn increases
Loss or mutation of p53 and centrosome amplification in culture cells and in tumor tissues
Numerous studies have shown that centrosome amplification is a frequent event in almost all types of solid tumors, including those of breast [27], [28], [29], [30], bladder [31], [32], [33], brain [27], [34], bone [35], [36], liver [37], lung [27], colon [27], prostate [38], pancreas [39], ovary [40], testicle [41], cervix [42], gallbladder and bile duct [43], adrenal cortex [44], and head and neck squamous cell [28], [45]. Centrosome amplification has also been detected in certain cases of
Synergistic induction of centrosome amplification in human cells by p53 inactivation and cyclin E overexpression
In mouse cells, loss of p53 alone is sufficient to induce centrosome amplification [49], [55]. However, it is not the case for human cells. Human primary fibroblasts transfected with dominant negative mutant p53 or silenced for p53 expression by short interference RNA do not show a readily detectable degree of centrosome amplification (nor chromosome instability), even when exposed to DNA synthesis inhibitors [33], [56], [57]. One critical difference between mouse and human cells is the
DNA damage, cell cycle arrest and centrosome amplification
Another well-studied tumor suppressor protein that has been shown to result in centrosome amplification when mutated is BRCA1. BRCA1 is a product of a familial breast and ovarian cancer susceptibility gene [64]. Involvement of BRCA1 in numeral homeostasis of centrosomes was initially shown by the finding that embryonic fibroblasts derived from mice deficient for a full length wild-type BRCA1 contain amplified centrosomes [65]. In a similar manner, loss of BRCA2, another familial breast cancer
Centrosome amplification vs. genomic convergence in cancer
There has been a sudden increase in the number of publications on the studies examining the clinical specimens and established cancer cell lines for potential associations of mutations of genes (i.e. p53, BRCA1, etc.) vs. centrosome amplification, mutations of genes vs. chromosome instability, and centrosome amplification vs. chromosome instability. Although every finding is informative, it has come to my attention to clarify one basic caution to be taken for conducting such studies. There is a
Centrosome amplification and cancer chemotherapy
As described earlier, exposure to DNA synthesis inhibitors promotes centrosome amplification and chromosome instability in cells lacking functional p53. Considering the high frequency of p53 mutation in human cancer, it is important to address the effect of commonly used anti-cancer drugs targeting S-phase (DNA duplication) on centrosomes [88]. When p53−/− mouse cells were exposed to sub-toxic concentrations of the S-phase targeting chemotherapeutic agents (i.e. 5′-fluoruracil, arabinoside-C),
Acknowledgements
I first would like to make an apology for not being able to cite many important studies, especially of the studies of clinical specimen, due to a large number of publications related to the subjects. The preparation of this manuscript is in part supported by National Institute of Health (CA90522 and CA95925).
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