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Abstract

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

While polyploidy, a state of having fully duplicated sets of chromosomes per cell, has been described in normally developing bone marrow megakaryocytes or as an adaptive response in other cell types, aneuploidy is never detected in normal cells. Tetraploidy or aneuploidy can be induced by several signals and it is highly prevalent in different forms of cancers, suggesting a role for this cell cycle state in promoting cellular transformation. Investigations suggested that loss of heterozygosity of cancer-related genes in stem cells might contribute to genetic instability in progeny cells and to subsequent cancer development. Deregulated expression of chromosome passenger proteins, such as Aurora kinases or Survivin, is a hallmark of various cancers, and experimentally induced changes in these regulators can promote tetraploidy or aneuploidy and loss of heterozygosity. Our studies described an induction of tetraploidy/aneuploidy by a stable form of Aurora-B, leading to acquisition of transformation properties. It is intriguing to speculate that in some cancers, tetraploidy/aneuploidy induced by deregulated expression of a mitotic regulator represents a primary event that leads to unbalanced expression of a cluster of crucial genes and to cellular transformation. J.Cell.Physiol. © 2005 Wiley-Liss, Inc.


OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

Polyploidy, the state of having greater than a diploid content of DNA (e.g., tetraploid, octaploid, etc.) has been recognized in a large variety of both, plant and animal cells during normal development or under stress, including aging (reviewed in Zimmet and Ravid (2000)). Polyploid cells are also found in malignant tissues in which they are believed to contribute to the development of cells with intermediate DNA content values (e.g., 3n, 4.5n, etc.) (reviewed in Zimmet and Ravid (2000); Ravid et al. (2002)). With the use of micro-array, researchers have demonstrated that genetically identical yeast strains (Saccharomycescerevisiae) with differences only in ploidy status (from haploid to tetraploid) display a substantial difference in gene expression, including of the G1 cyclins (Galitski et al., 1999). This finding has suggested that DNA content per se might affect cellular functions. Currently, the relationships between polyploidy and aneuploidy has not been studied extensively considering the prominent role of genetic instability in tumorigenesis (Storchova and Pellman, 2004). An understanding of the biochemical, gene expression, and signaling pathways that drive normal and abnormal polyploidization could lead to useful insights with respect to novel anti-cancer therapeutic approaches. The occurrence of polyploidy in normal and transformed cells poses a number of questions. Is polyploidy a protective mechanism upon stress, as suggested, or rather a maladaptive response? (Wagner et al., 2001; Ravid et al., 2002; Jones and Ravid, 2004) What mechanisms or signaling pathways are employed by normal developing polyploid cells (e.g., megakaryocytes or trophoblasts) to safeguard them from becoming aneuploid?

In megakaryocytes, polyploidization up to 128N can be attained, if the cells undergo repeated endomitotic cell cycles, characterized by a well coordinated entry of cells into a normal early mitotic phase, which includes prophase, metaphase and early anaphase (Roy et al., 2001). However, these cells skip late anaphase and cytokinesis (this truncated mitosis is referred to as polyploidy via endomitosis, reviewed in Ravid et al., 2002). In contrast, polyploidy may result from another type of truncated mitosis, referred to as polyploidy via abortive mitosis to describe the generally uncoordinated events that are driven by spindle checkpoint defects or by chemical treatments. These events are often associated with pathological conditions (reviewed in Zimmet and Ravid (2000); Ravid et al. (2002); Storchova and Pellman (2004)). It has been shown, in both tissue culture and in transgenic mice, that polyploidy via endomitosis in megakaryocytes is tightly regulated by a series of signaling pathways and gene expressions, including signaling through thrombopoietin, binding to its receptors c-Mpl (reviewed in Kaushansky, 2003), and is associated with elevated cyclin D3 expression and a rapid reentry into S-phase (Wang et al., 1995, 1999; Zimmet et al., 1997). There is also evidence that these cells possess a gene expression profile that is different from their diploid counterparts, including low expression of the tumor suppressor gene p53 (Malkin et al., 2000) in conjunction with high expression of the cell cycle inhibitor p21 to allow a short-lived progression through G1 phase (Mantel et al., 1999; Stewart et al., 1999; Baccini et al., 2001).

Numerous studies have shown that normal diploid cells of other lineages can be induced to undergo polyploidization via endomitosis as a consequence of stress (e.g., hypertension and senescence (reviewed in Ravid et al. (2002))). In addition, polyploid hepatocytes have been described to increase in number dramatically upon oxidative stress or after partial hepatoectomy (Dethloff and de la Iglesia, 1998; Gupta, 2000; Gandillet et al., 2003). Endothelial cells and fibroblasts have been shown in tissue biopsies and in cell culture to become polyploid upon aging and during tissue repair (Oberringer et al., 1999; Wagner et al., 2001). Hypertension can induce vascular smooth muscle cells and cardiac myocytes to become polyploid (Chobanian et al., 1984; Hixon et al., 2000). In these cases, polyploidy is believe to be a protective mechanism, which acts to prevent cellular proliferation in the vasculature or to increase DNA content in order to compensate for mutations introduced by genotoxic agents (Edgar and Orr-Weaver, 2001; Ravid et al., 2002). On the other hand, tetraploidy (cells with a double diploid DNA content) may reflect tissue damage as in Barret's esophagus (Galipeau et al., 1996), in which there is dysplasia of the esophageal epithelium following repeated exposure to acid reflux. The most pronounced dysplastic changes include the appearance of tetraploid cells and predict for esophageal cancer (Galipeau et al., 1996).

Tetraploidy can be induced in a variety of ways, including aberrant expression of proteins regulating the G2/M phase (Cyclin-B1, Aurora-A, Forkhead transcription factor M3) (Hauf et al., 2003; Shin et al., 2003), mitotic spindle checkpoint proteins (BUBR1, Mad2 Aurora-B, Survivin) (Barr et al., 2004; Meraldi et al., 2004) leading to abortive cytokinesis. Tetraploidy can also be induced by chemical agents and/or irradiation and be associated with tumorigenesis (Verdoodt et al., 1999; Kusuzaki et al., 2000; Ivanov et al., 2003). This latter type of polyploidy is thought to be a by-product of uncoordinated events during mitosis in which a defect in mitotic spindle checkpoint arrest allows for a “mitosis slippage,” resulting in cells with truncated mitosis, sometime at anaphase A, other times at anaphase B, or at cytokinesis (Dai et al., 2004). The resulting tetraploid cells can be cell cycle arrested, undergo apoptosis, or continue to the next division, to produce aneuploid daughter cells (Cahill et al., 1998; Meraldi et al., 2002; Margolis et al., 2003).

PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

Polyploidy often precedes aneuploidy during the events of tumorigenesis that are associated with high incidence of malignancy and poor prognosis (Duesberg et al., 2000; Nowak et al., 2002; Rajagopalan and Lengauer, 2004). It is generally accepted that aneuploidy in cancer cells is the rule and not the exception. Most heterogeneous tumor tissues (colorectal cancer, lung, breast, prostate, renal cell carcinoma, bladder cancer, thyroid cancer, some types of leukemia, glioblastoma, melanoma, and rare childhood tumors) contain large populations of aneuploid cells in conjunction with a relatively smaller percentage of polyploid cells (Park et al., 1995; Takanishi et al., 1996; Borre et al., 1998; Kaplan et al., 1998; Lemez et al., 1998; Parry et al., 1998; Gunawan et al., 1999; Lothschutz et al., 2002; Doherty et al., 2003; Roh et al., 2003). Among hematological malignancies, a shift in ploidy is often observed in acute lymphoblastic leukemia (ALL). In addition to a high frequency of translocations, deletions, and fusion of chromosomes (70% of adults and 80% of children), a common cytogenetic abnormality in childhood ALL is the occurrence of massive hyper-diploid (defined as having greater than 50–65 chromosomes, a condition observed in 20–30% of the cases). Polyploidy has also been described in choroid plexus carcinoma, a rare form of childhood brain tumor, in which freshly isolated tumor cells were found to have up to 200–400 chromosomes (Li et al., 1996). Moreover, there is a recent report that primary keratinocytes infected with human papillomavirus (HPV) type 16 E6, E7 become polyploid, possibly by abortive mitosis (Patel et al., 2004). In most solid cancers, the model chromosome number is near triploid, or near tetraploid. In some instances, the appearance of polyploid cells from a normal diploid cell background may be mediated by the tetraploidy/polyploidy checkpoints. This checkpoint ensures that cells with greater than 2N DNA contents do not progress past G1 after exiting from mitosis (Margolis et al., 2003). There are several mechanisms that can be envisioned as causes of a ploidy shift, including doubling of a hyper-haploid cell (defined as having a total of 30–40 chromosomes), a single event of aberrant mitosis, or normal polyploidization with subsequent loss and/or gain of chromosomes (Teixeira and Heim, 2005). Because of the high rate of chromosome loss in cycling polyploid cells (Brinkley, 2001; Nigg, 2002; Fabarius et al., 2003), it is very possible that aneuploidy develops from a tetraploid/polyploid population of cells during tumorigenesis.

CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

Cancer cells are characterized by a variety of genomic defects, such as inactivation of DNA repair genes, over-expression of growth promoting oncogenes, possession of extra or missing chromosomes, an abnormal number of centrosomes, and aberrant mitosis and cytokinesis (Meraldi et al., 2004). In a review by Hanahan, D. and Weinberg, R.A. (Hanahan and Weinberg, 2000), the authors describe hallmark definitions of malignant cancer cells, including: Inability to respond to signals of programmed cell death; Prevalence in a proliferative state in the absence of mitogenic signals; Unresponsiveness to anti-proliferative signals; loss of sensors to programmed senescence; Ability to metastasize and proliferate in different tissues and to induce new blood vessel formation; and ability to eventually kill the host organism. The transforming events that allow cancer cells to develop are not fully understood. A number of theories have been proposed, focusing on multi-step gene mutations (Fearon and Vogelstein, 1990), genomic instability (Lengauer et al., 1998), The Mutator Phenotype Hypothesis, and aneuploidy (Duesberg et al., 1998) (Fig. 1).

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Figure 1. Theories on involvement of aneuploidy in cancer promotion. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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The somatic gene mutation theory

The Somatic Gene Mutation theory includes several assumptions: (1) Cancer is caused by mutations in genes, such as p53, Rb, and Ras, which control cellular proliferation, and hence, it is a genetic disease. (2) Mutations of tumor suppressor genes and/or oncogenes release cells from inhibitory growth signals. (3) For a cell to become malignant, several damaging gene mutations are required, or both alleles of those genes must be mutated (two hits hypothesis) (Knudson, 2001; Hahn and Weinberg, 2002). First, this theory implies that cancers are derived from individual cell clones that have gradually accumulated mutations over time. Second, this theory suggests that normal cells destined to become cancerous must have faster than normal rates of mutation to acquire these genetic changes (i.e., a fast rate of 10−3 mutations as opposed to a normal rate of 10−7 to 10−8 mutation per nucleotide per cell division). Numerous tumor suppressor genes and oncogenes have been identified and mutations of these genes have been shown to lead to neoplastic transformation in transgenic mice (Hanahan and Weinberg, 2000). Yet, the somatic gene mutation theory fails to explain why cells within the same invasive tumor do not uniformly share the same mutations of relatively important genes, that is Ras and p53. Such cells also may share substantial differences in chromosome numbers, although they are thought to originate from clonal expansion (Soto and Sonnenschein, 2004). The heterogeneous nature of tumor cells (both in the rate and type of gene mutations and ploidy status) has prompted the search for additional or alternative unifying principles to explain tumorigenesis.

The mutator phenotype hypothesis

Loeb and colleagues proposed the Mutator Phenotype Hypothesis to explain why cancer cells have a much faster rate of random mutations and how this phenotype may account for the genetic changes observed in cancer (Loeb, 1991, 2001). This theory postulates that once normal cells acquire mutations of genes that control the fidelity of DNA replication and repair, they are prone to develop random mutations (Mutator Phenotype). Some of these mutations may permit cells to have selective advantages to expand and achieve clonal dominance (Loeb et al., 2003; Bielas and Loeb, 2005).

The genomic instability theory

Lengauer and Vogelstein observed that a very high degree of genomic instability, characterized by the gain or loss of portions of chromosomes or entire chromosomes is present in the early stages (pre-neoplastic) of colon cancer development. Based on this finding, they proposed the Genomic Instability Theory of cancer in 1997. This theory argued that, at least in colon cancer, chromosomal losses or gains are the early events that lead to the loss of tumor suppressor genes and/or gain of oncogenes, which are widely believed to drive malignant transformation (Lengauer et al., 1997, 1998; Cahill et al., 1999; Rajagopalan and Lengauer, 2004; Lengauer, 2005). One of the main assertions of this theory is that as cells acquire mutations in master genes, such as genes required for cell division and segregation of chromosomes. Subsequent divisions are prone to result in more mistakes, leading to instability in chromosome number, a critical early event in tumorigenesis. While emphasizing the importance of genetic instability as early events, this theory still holds that mutations in cancer related genes are a prerequisite for transformation. This theory explains a number of characteristics of tumor cells, including aneuploidy and fast rates of mutation. Compelling evidence in support of this theory was recently reported by Hanks et al. (2004) in relation to individuals with a rare genetic disorder, mosaic variegated aneuploidy, in which more than 25% of the cells in the body are aneuploid. This phenotype is characterized by mutation in both alleles of the chromosome segregation gene, BUB1B. Affected individuals frequently develop childhood cancers, such as rhabdomyosarcoma and leukemia. This report is the first to suggest that aneuploidy may have a direct causal role in the development of cancer in human.

The aneuploidy theory of cancer

The Mutator Phenotype and Early Genetic Instability Theories cannot explain malignancies caused by non-genotoxic carcinogens, which are not mutagens but can act as aneugens (chemical agents that disrupt the mitotic spindle and cause chromosome mis-segregation) and are associated with tumorigenesis. For instance, asbestos, a non-mutagenic carcinogen, has been shown to bind to the mitotic spindle, causing chromosome mis-segregation and genetic instability (Fabarius et al., 2003). Asbestos has not been reported in the literature to cause specific cancer related gene mutations. In light of this, Duesberg and colleagues proposed the Aneuploidy Theory in 1998 (Duesberg et al., 1998; Duesberg and Li, 2003). The first assumption of this theory is that cancer is not a disease of gene mutations per se but a disease of gene dosage (i.e., having 3, 5, or 0 copy/copies of a normal set of genes via random aneuploidization). The second assumption is that carcinogens or spontaneous cell-cycle accidents are more effective inducers of aneuploidy than specific mutations. Hence, according to this theory cancer development does not necessarily require mutations in cancer related genes at the DNA level but an imbalance in the dosage of thousands of normal genes caused by chromosomal gains or losses. Therefore, cells may become transformed before mutations of tumor suppressor genes and/or oncogenes occur. Two very recent studies support the notion that a duplicate set of chromosomes increases the chances of chromosome mis-segregation, aneuploidy and cellular transformation (Fujiwara et al., 2005; Shi and King, 2005).

Regardless of which theory of cancer evolution best explains individual types of cancer, they each identify aneuploidy and genetic instability as having a causal role in tumorigenesis.

REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

There are a variety of ways in which cells may become aneuploid (Rajagopalan and Lengauer, 2004), including: (1) Telomere dysfunction, which has been linked to aneuploidy in cancer. Studies have shown that telomere shortening in telomerase knockout mice after succeeding generations is associated with tumorigenesis. Cells with truncated telomeres are more prone to chromosome translocation and fusion (reviewed in Sharpless and DePinho (2004)). (2) Defective mitotic spindle checkpoint. During the transition from metaphase into anaphase, cells evolve surveillance mechanisms to ensure proper attachment of mitotic spindles to kinetochore/centromere before the segregation of chromosomes begins. Important protein components of this spindle checkpoint include: BUB1, 2, 3, Mad-1,2,3, and the chromosome passenger protein Aurora-B. Seminal studies in diverse species, ranging from yeasts to humans, have concluded that defects in this checkpoint allow the cell to progress through metaphase/anaphase with unequal attachment of the spindle/kinetochore, giving rise to aneuploid daughter cells (reviewed in Nigg (2001); Nasmyth (2002)). (3) Defective Mitotic spindle assembly. The aberrant duplication of centrosomes at early mitosis (this is often due to mutation of genes involved in centrosome maturation and duplication, including Aurora-A or via chemical agents) has been demonstrated to cause polyploid or aneuploid daughter cells. The resulting functional defects of mitotic spindle assembly lead to lagging chromosomes as they segregate during a precise time frame at the transition into anaphase (Brinkley, 2001). (4) Abnormal chromosomal rearrangement, breakage, and fusion, has been demonstrated to be a source of aneuploidy (Gisselsson et al., 2000). (5) Abortive cytokinesis, which can lead to the formation of polyploid cells and has been suggested to cause aneuploidy via tetraploid intermediates (Fishman, 1998).

STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

With the findings of stem cells in breast cancers, Wilm's tumors, hematological malignancy, and neuroblastomas (Al-Hajj et al., 2003; Sell, 2004) (referred as tumor stem cell, TSC), there has been increased interest in understanding the role of tumor stem cells in tumorigenesis. Given the scarcity of stem cells in tumors, their existence in the heterogeneous tumor tissue has been demonstrated experimentally only recently, although hypothesized decades ago (Sell, 2004). Tumor stem cells are phenotypically similar to normal stem cells in their abilities to self-renew, and to differentiate into multiple tissues or cell lineages within the same tissue. However, they differ from normal stem cells with respect to the balance of self-renewal and differentiation. Normal stem cells generally give rise to progenitors cells, which commit into a specific cell type with a limited life span. Under normal physiological conditions, the self-renewal capability of normal stem cells is inhibited by cell cycle inhibitors, such as p21 and p18 and is tightly and reversibly regulated by the need for differentiation or tissue regeneration (reviewed in Sell (2004)). In p21 −/− mice, hematopoeitic stem cells (HSC) tend to cycle faster than wild-type cells, while the proliferation of marrow progenitor cells is repressed, resulting in a larger pool of HSC and a smaller pool of lineage committed progenitors (Mantel et al., 1999). Hence, as observed in other systems, the proliferation of normal stem cells requires a balance between differentiation and self-renewal, depending on their stage of development (Sell, 2004). In contrast, tumor stem cells are believed to have irreversible defects in cyclin inhibitors, coupled with disruptions in feedback mechanisms to control differentiation or apoptosis (Sharpless and DePinho, 2004; Bissell and Labarge, 2005). Tumor stem cells in leukemia are thought to originate directly from hematopoeitic stem cells or marrow progenitors, depending on the developmental stage at which genetic changes occur (Lemez et al., 1998). It is reasonable to hypothesize that some cancers may evolve from tissue specific progenitor stem cells because of their self-renewal, tissue evasion and ineffective senescent properties. The likelihood of environmental agents, reactive oxygen species, and hormones to cause genetic and epigenetic changes in stem cell is greater than that in their short-lived, differentiated counterparts. Studies (Deng et al., 1996; Smith and Boulanger, 2002; Al-Hajj et al., 2003) have suggested that loss of heterozygosity of cancer related genes in mammary stem cells might contribute to genetic instability in progeny cells and subsequent breast cancer development. With the exception of polyploidy resulting from stem cell fusion (Wang et al., 2003), a role of polyploidy and aneuploidy in the development of tumor stem cells has not been reported. However, given the important role of polyploidy and aneuploidy in tumorigenesis, an analysis of the degree of changes in ploidy in tumor stem cells would be worthwhile.

CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

Accurate segregation of chromosomes following each cell division requires a perfect synchrony of regulated protein proteolysis, phosphorylation and dephosphorylation, the localization and recruitment of a chromosome passenger complex, and the physical interaction between the centromere and the mitotic spindles at the metaphase to anaphase transition. At the same time, the surveillance mechanism orchestrated by Mad1 and BubR1 ensures that the separation of chromosomes does not progress if these processes become asynchronous. In mammalian cells, the protein complex consisting of Aurora B kinase, Survivin, INCENP, and Borealin, (also referred as the chromosome passenger complex (CPC)) displays a distinct localization pattern throughout mitosis, suggesting that it has an important function in regulating mitosis. During prophase, this complex associates with condensed chromosomes and then concentrates at the inner centromere during prometaphase. At the onset of anaphase, the complex relocates to the central spindle. As the central spindle elongates at cytokinesis, the chromosome passenger proteins coalesce at the midbody, the site of the cleavage furrow. The CPC must be degraded at telophase for cells to exit mitosis normally. Various studies have demonstrated that altered subcellular localization patterns of the CPC are associated with mitotic arrest, mis-segregation of chromosomes, abortive cytokinesis, and polyploidy (reviewed in Vagnarelli and Earnshaw (2004)). Moreover, the progeny of cells with such defects have been shown to be tumorigenic in xenograft mouse models (Ota et al., 2002; Katayama et al., 2003).

INCENP (properties and effects of its deregulated expression on the cell cycle)

Inner Centromeric Protein (INCENP) was the first protein identified in the chromosome passenger protein complex. The C-terminus (IN-Box) of this protein is conserved from yeast to humans. INCENP binds to Aurora-B through the IN-Box sequences and stimulates its kinase activity during mitosis (Adams et al., 2001a). Deletion analysis of this protein has revealed that an N-terminal region (amino acid 1–68) is important for targeting INCENP to the centromere/kinetochore and midzone at anaphase (Ainsztein et al., 1998). INCENP is an essential gene, given that its targeted deletion in mice leads to polyploidization of embryonic cells and induces early embryonic lethality (32–64 cell stage) (Cutts et al., 1999). RNAi-mediated downregulation of endogenous INCENP has been shown to produce severe mitotic mis-segregation of chromosomes in C. elegans and Drosophila (Adams et al., 2001b; Bishop and Schumacher, 2002). Overexpression of the dominant negative form of INCENP in mammalian cells showed similar defects, in addition to the appearance of abnormal number of centrosomes. Thus, tight regulation of INCENP is clearly essential for cell division (Greaves, 2001). In vitro studies have shown that aberrant levels of INCENP disrupt the chromosome passenger complex and cause Aurora-B and Survivin to mislocalize in prometaphase (Cooke et al., 1987; Wheatley et al., 2001; Bishop and Schumacher, 2002). Aberrant expression of INCENP also induces chromosome mis-segregation and abortive cytokinesis in yeast, fruit flies, and mammalian cells (Vagnarelli and Earnshaw, 2001; Wheatley et al., 2001). It has been shown in yeast that dephosphorylation of INCENP by Cdc14 is required for the transfer of the chromosome passenger complex to the central spindle at anaphase. Point mutations that generate a non-phosphorylated INCENP resulted in daughter cells with chromosomal loss, likely due to lagging chromosomes (Pereira and Schiebel, 2003). Interestingly, chromosomal alignment remained intact while the non-phosphorylated INCENP localized prematurely at the centromere prior to anaphase onset (Adam et al., 2000). This study implies that the function of Aurora-B as a guardian of spindle attachment and alignment does not depend solely on the localization of INCENP. Hence, the protein level, kinase activities, and sub-cellular localization of the chromosome passenger complex proteins appear to be equally important in preventing polyploid and aneuploid phenotypes.

Borealin (properties and effects of its deregulated expression on the cell cycle)

Borealin (alternatively called Dasra) was recently cloned and characterized as a new member of the chromosome passenger complex in vertebrate (Gassmann et al., 2004; Sampath et al., 2004). Borealin displays a typical pattern of subcellular localization to the centromere, central spindle, and midbody during mitosis. Depletion of Survivin or INCENP by RNAi has been shown to disrupt this specific localization of Borealin. Similar to other chromosome passenger proteins, RNAi-mediated knock down of endogenous Borealin also causes spindle defects, chromosome mis-segregation, and pronounced disruption of spindle assembly (Sampath et al., 2004). Interestingly, Borealin appears to act prior to the onset of anaphase. Borealin is a direct substrate of Aurora-B and is required to target the CPPs to the centromere but not to the midzone during anaphase (Gassmann et al., 2004). Given the similarity in the expression pattern and functions of Borealin to those of other CPPs, it will be important to elucidate the functional links between Borealin, Survivin, INCENP, and Aurora-B in normal and cancerous cells.

Survivin (properties and effects of its deregulated expression on the cell cycle)

Survivin, a 16 KDa protein as a monomer and 32 KDa as a dimer, is the smallest member in the Inhibitor of Apoptosis Protein (IAP) family, and contains a BIR domain, which is characteristic of this family of proteins. Unlike other members of the IAP family, Survivin does not have ubiquitin ligase activity (E3) and is the only member protein that forms a homodimer in solution (Chantalat et al., 2000; Muchmore et al., 2000; Verdecia et al., 2000). Interestingly, it is also a component of the chromosome passenger complex that associates with Aurora-B, and it follows a similar pattern of expression and localization during mitosis. Its expression has been found to peak at G2/M and its degradation occurs in a cell-cycle dependent manner (Zhao et al., 2000). In differentiated tissue, Survivin expression is virtually absent, in contrast to its high expression in actively proliferating lineages, including CD34+ hematopoietic stem and progenitor cells (when stimulated by the combination of thrombopoietin (TPO), stem cell factor (SCF), and Flt3 ligand (FL)) (Fukuda and Pelus, 2002), vascular endothelial cells (Tran et al., 1999), vascular smooth muscle cells (Blanc-Brude et al., 2002), thymus T- and B-cells (Kobayashi et al., 1999), and particularly in tumor cells (reviewed in Li (2005)). Survivin can be found in three splice variants that differ in size (Survivin 2B, Delta Ex3, and 3B) as a result from translation of an alternate exon 2B, skipping of exon 3 and/or a frameshift with premature stop codon (Conway et al., 2000). However, these splice variants still retain two features in common: the dimer interphase and the BIR domain at the N-terminus (Li, 2005). Published studies have suggested that survivin can form homodimers or heterodimers with its splice variants (Song et al., 2004; Li, 2005). These homodimers/heterodimers are hypothesized to have distinct functions in regulating apoptosis or cellular proliferation, depending on the type of dimer and its subcellular localization (Song et al., 2004). The Survivin 2B variant is cytosolic, while the Delta Ex3 variant is localized mainly in the nucleus. The Delta Ex3 variant contains a nuclear localization sequence (NLS, R/K-rich region 81RRKNLRKLRRK91) (Li, 2005). Survivin 2B expression is lost at later stages of malignancy, while normal Survivin and its Delta Ex3 variant maintain a high expression profile, suggesting a differential role in tumor development (Fortugno et al., 2002; Krieg et al., 2002). In vitro studies have demonstrated that Survivin's localization to the central spindle and midbody at telophase is dependent on phosphorylation at Thr117 by Aurora-B, and mutation of this site leads to disruption of its association with INCENP (Wheatley et al., 2004), suggesting that phosphorylation of Thr 117 is important for Survivin's role as a chromosome passenger protein. Homozygous deletion of Survivin in mice results in embryonic lethality at day 4.5, characterized by the presence of catastrophic mitosis (cell death during mitosis), giant multinucleate cells, in addition to a large population of polyploid cells (Uren et al., 2000). Forced overexpression of Survivin has been shown to inhibit IL-3-induced apoptosis in B-lymphocytes (Ambrosini et al., 1997) and in UV-induced apoptosis in primary keratinocytes (Grossman et al., 2001). In addition, published studies have suggested that overexpression of Survivin shortens G1 phase arrest and accelerates S phase, potentially through activation of Cdk2/Cyclin-E complex (Suzuki et al., 2000a,b). The important role of Survivin in regulating endomitosis in polyploidizing megakaryocytes and vascular smooth muscle cells has also been described (Zhang et al., 2004; Gurbuxani et al., 2005; Nagata et al., 2005). It has been shown that during these endomitotic cell cycles, Survivin does not colocalize with Aurora-B or INCENP, as typically observed at the centromere and at the central spindle/midbody during cytokinesis of normally dividing cells. Overexpression of Survivin was shown to reduce polyploidization in cultured primary vascular smooth cells (Nagata et al., 2005) as well as in megakaryocytes (Gurbuxani et al., 2005).

With regard to its antiapoptotic properties, Survivin has been shown to bind to Smac/Diablo, a caspase activator and/or to procaspase 9 via the hepatitis B X-interacting protein complex to mediate this effect (Marusawa et al., 2003; Song et al., 2003). A study by Song et al. (2004) demonstrated that a single amino acid change (Asp53_Ala53) converts Survivin from an antiapoptotic to proapoptotic regulator, suggesting that it has a dual role in controlling cell death at mitosis. Studies of Survivin function as both a chromosome passenger protein and as an anti/pro apoptotic factor has been a subject of much interest. Recent work has described a new type of cell death, termed “mitosis catastrophe,” often observed in cells with defective mitosis spindle assembly checkpoint, chromosome mis-segregation and abortive cytokinesis (reviewed in Castedo et al. (2004)). Although “mitosis catastrophe” is believed to be triggered by aberrant events during mitosis and not signals originating in G1 or S-phase, this type of programmed cell death still converges on the action of caspases, as suggested by several studies (Li et al., 1999; Grossman et al., 2001; Carter et al., 2003). Survivin may ensure the survival of cells with correct chromosome segregation by directly inhibiting caspases through its anti-apoptosis and/or chromosome checkpoint properties. On the other hand, Survivin, through its pro-apoptotic properties, may also ensure that cells undergo apoptosis if mitotic events are defective.

Aurora-B (properties and effects of its deregulated expression on the cell cycle)

The Aurora/Ipl1 (increase-in-Ploidy protein-1) protein kinases have been shown to orchestrate vital mitotic events, including G2/M transition, centrosome duplication, chromosome condensation, bi-polar spindle-kinetochore attachment, chromosome segregation, and cytokinesis. Their roles are evolutionarily conserved in yeast, nematodes, and mammalian cells (reviewed in Adams et al. (2001c); Katayama et al. (2003)). While lower organisms have only one form of Aurora kinase (Ipl-1), mammalian cells have three types, Aurora-A, Aurora-B, and Aurora-C, whose function and localization are distinct in space and time during cell division. The function of Aurora-C in mammalian cells has not been studied extensively. Aurora-A localizes to the centrosomes during early anaphase and is required for mitotic entry (Castro et al., 2002). Aurora-B, (also called AIM-1, Stk-5) regulates the formation of a stable bi-polar spindle-kinetochore attachment in mitosis. It is part of the CPP, needed for chromosome segregation and cytokinesis (Hauf et al., 2003; Gassmann et al., 2004; Sampath et al., 2004). Aurora-B is regulated at the mRNA level, at the protein level, and at the level of its kinase activity (reviewed in Adams et al. (2001c); Andrews et al. (2003); Katayama et al. (2003); Ducat and Zheng (2004)). INCENP has been shown to stimulate the kinase activity of Aurora-B (Kang et al., 2001; Bishop and Schumacher, 2002; Honda et al., 2003), and there are conflicting reports on the regulation of Aurora-B by Survivin (Honda et al., 2003). In a cell-free system, Survivin seems to enhance the kinase activity of Aurora-B (via Histone-H3-Ser10 phosphorylation) (Chen et al., 2003), provided that its kinase activity is first reduced in cells with siRNA-mediated Survivin knock down. How Aurora-B activity/function is terminated at the end of mitosis is an additional intriguing question (Meraldi et al., 2004). A recent study demonstrated that Aurora-B is regulated by protein degradation through the A-box and KEN box sequences (Nguyen et al., 2005). Most importantly, overexpression of a non-degradable A-Box mutant leads to aneuploid/polyploidy, suggesting that Aurora-B's proteolysis plays an important role in the regulation of Aurora-B level and chromosome segregation (and potentially stability) at each cell division (Nguyen et al., 2005). Another study (Scrittori et al., 2005) identified a very short sequence in the C-terminus of Aurora-B (326–331) as responsible for its function and subcellular localization. Taken together, these investigations demonstrate that Aurora-B's stability is regulated through its N-terminus, whereas the C-terminus contains the sequences required for its function and subcellular localization.

The most extensively studied function of Aurora-B is its involvement in mitotic spindle attachment. In order for chromosomes to separate equally, a synchronized alignment of sister chromatids at metaphase coupled with stable bi-polar attachments between the mitotic spindle and the kinetochore must take place. During this dynamic process, there are various ways in which the kinetochore-microtubule can form unstable attachments. This includes the case of kinetochore attaching to the spindle from both poles (merotellic) or when both sister kinetochores are attached to the same spindle pole (syntellic). If these unstable attachments are not corrected in time as the cell enters anaphase, lagging chromosomes and unequal separation of chromosomes occur in the daughter cells. Reduction of endogenous Aurora-B by genetic (iRNA) or pharmacological agents (ZM447439, and Hesperadin) results in merotellic and/or syntellic attachment and subsequent disruption of chromosome segregation (Hauf et al., 2003). Experiments using microinjection of anti-Aurora-B antibodies reveals that inhibition of Aurora-B in mitotic Xenopus tissue culture cells abrogates the spindle checkpoint and causes an early exit from mitosis with no evidence of anaphase or cytokinesis, concomitantly with the appearance of chromosome misalignment and polyploid cells (Kallio et al., 2002). How Aurora-B promotes stable bi-polar attachment and prevents unstable merotellic and/or syntellic attachment continues to be under investigation. The current model, derived from various studies with both yeast and mammalian cells, proposes that Aurora-B, through its kinase activity and interaction with various proteins (such as the mitotic centromere associated kinesin, MCAK), actively facilitates the depolymerization of microtubules associated with unstable attachments. Evidence for this model in mammalian cells includes the finding that Aurora-B directly interacts with MCAK to promote microtubule depolymerization (Andrews et al., 2004; Lan et al., 2004). In addition, its interaction with protein phosphatase I keeps depolymerization in check, once stable attachments are achieved (Murnion et al., 2001; Sugiyama et al., 2002). In budding yeast, Aurora-B is believed to function as a sensor for the pulling force and tension generated by the spindle-kinetochore complex (Biggins et al., 1999; Tanaka et al., 2002; Pinsky et al., 2003; Dewar et al., 2004). Recently, the yeast Aurora-B homolog, Ipl1 has been shown to interact with the Damp1 complexes, which interact directly with the kinetochore and microtubule to regulate bipolar attachment of mitotic spindles (Cheeseman et al., 2002). Specific mutation (S to A) of all four Ipl1 phosphorylation sites in the Dam1p protein causes cell death, suggesting an essential role for Ipl1/Dam1p phosphorylation (Cheeseman et al., 2002). Because of its vital role in correcting chromosome-spindle attachment, deregulated expression of Aurora-B/Ipl1 can be expected to impair chromosome segregation and mitotic progression, leading to aneuploidy.

Another function of Aurora-B, that has been described, concerns its role in the spindle assembly checkpoint during the transition into anaphase. Defective mitotic spindle assembly or detachment of the kinetochore directly triggers Bub1, Mad1, and other spindle checkpoint proteins to bind and inhibit the activity of the Cdc20-APC/c E3 ligase (a component of proteasome-mediated degradation and also regarded as the effector of the spindle checkpoint), leading to a transient arrest of the cells at metaphase. Several studies have demonstrated that Aurora-B participates in the recruitment/association of Mps1, Bub1, CENP-E, Bub3, Mad1, and Mad2 to kinetochores (Carvalho et al., 2003; Ditchfield et al., 2003). A recent investigation indicated that Aurora-B directly associates with the Cdc20–APC/c complex (Nguyen et al., 2005). Moreover, other studies showed that depletion of endogenous Aurora-B impairs the cells' ability to localize Cdc20, Cdc27, and Cdc23 (subcomponents of the APC/c) to unattached kinetochores such that cells fail to activate the spindle checkpoint in response to microtubule destabilization (Murata-Hori and Wang, 2002; Ditchfield et al., 2003; Dewar et al., 2004; Lampson et al., 2004). These functional studies have demonstrated that Aurora-B is an indispensable member of the spindle assembly checkpoint, acting upstream of Bub1 and Mad1 and indicate that deregulation of Aurora-B disrupts this protein composition to prevent the spindle checkpoint (Vigneron et al., 2004).

During telophase, Aurora-B also has a role in ensuring the completion of cytokinesis (Kimura et al., 1997; Terada et al., 1998a; Terada, 2001; Goto et al., 2003). Drosophila cells lacking Aurora-B protein do not proceed to cytokinesis and as a result undergo polyploidization (Giet and Glover, 2001). Drug-mediated inhibition of this kinase in proliferating mammalian cells can also induce polyploidy (Hauf et al., 2003) and/or cell death by “catastrophic mitosis” (Keen and Taylor, 2004). In bone marrow megakaryocytes which undergo endomitotic cell cycles and polyploidization during normal development, Aurora-B has been shown to be normally expressed at early anaphase, but scarce in the midzone at late mitosis in many of the megakaryocytes tested (Zhang et al., 2004). Another study reported proper Aurora-B expression/localization during early mitosis (Geddis and Kaushansky, 2004).

CHROMOSOME PASSENGER PROTEINS AND CANCER

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

Aurora kinases have been found to be overexpressed in a variety of malignant cancers (as listed in: http://cgap.nci.nih.gov), and this overexpression is suspected to contribute to chromosome instability (Terada et al., 1998). The link between overexpression of the Aurora kinases in mammalian cells and carcinogenesis is believed to be causal and to be dependent on perhaps, the disruption of normal centrosome or centromere function, spindle checkpoint regulation, and cytokinesis (Terada et al., 1998; Goepfert and Brinkley, 2000; Meraldi et al., 2002; Ota et al., 2002; Carmena and Earnshaw, 2003). Overexpression of the chromosome passenger proteins (CPP), including Aurora-A, Aurora-B, Survivin, and INCENP has been observed in ovarian, breast, and prostate cancers, and shown to correlate with aneuploidy (Bischoff et al., 1998; Tatsuka et al., 1998; Giet and Prigent, 1999; Adams et al., 2001a; Altieri, 2003; Katayama et al., 2003). In addition, chromosomes containing the CPP are often affected in aneuploid cells (Sen et al., 2002; Fujita et al., 2004). The mechanisms that explain how overexpression of CPP proteins, individually or together, promotes aneuploidy remain an important, unanswered question. Only recently, have studies been carried out to determine whether ectopic expression of the CPP drives cellular transformation by means of increasing proliferation, by centrosome amplification, or by inducing chromosome instability. Overexpression of Aurora-A has been shown to potentiate HRAS (Harvey sarcoma virus oncogenes)-induced transformation in vitro, whereas reduced endogenous Aurora-A expression by short hair-pin RNA (shRNA) decreased transformation (Tatsuka et al., 2005). It has been suggested that overexpression of Aurora-A results in cells with increased number of centrosomes (3–4) and consequently impairs their ability to segregate chromosomes equally (Nigg, 2002). Similarly, correlative data showing overexpression of Aurora-B kinase in solid tumors and tumor cell lines has been reported (Tatsuka et al., 1998; Ota et al., 2002; Sen et al., 2002; Mayer et al., 2003; Araki et al., 2004; Sorrentino et al., 2005). However, given the tight regulation of Aurora-B at the protein level (Zhang et al., 2004), only a handful of studies have been able to demonstrate the overexpression of Aurora-B induces oncogenic transformation. These studies include those using xenograft models of localized tumor formation in mice injected with cells overexpressing Aurora-B (Ota et al., 2002; Nguyen et al., 2005). In these studies, oncogenic transformation appears to be mediated by aneuploidy, and to be a consequence of Aurora-B overexpression. Inhibition of the Aurora kinases, in general, blocks progression of the cell cycle and induces cell death by “catastrophic mitosis.” Several studies have exploited this type of cell death using Aurora kinase inhibitors (VX-680 for Aurora-A, Hesperadin, and ZM447439 for Aurora-B (Hauf et al., 2003; Doggrell, 2004; Harrington et al., 2004; Gadea and Ruderman, 2005) and reviewed in Keen and Taylor (2004)) to suppress tumor growth in vivo. Reduction of endogenous Aurora-B expression by such means has been shown to diminish the growth of thyroid anaplastic carcinoma tumor cells (Sorrentino et al., 2005). However, it is possible that inhibition of Aurora kinases is unable to completely prevent tumor growth, since reduced expression of these kinases also leads to aneuploidy (as reviewed in Bischoff and Plowman (1999); Giet and Prigent (1999); Adams et al. (2001c); Descamps and Prigent (2001); Wheatley et al. (2001); Andrews et al. (2003); Carmena and Earnshaw (2003); Castedo et al. (2004); Ducat and Zheng (2004)), and such inhibition would be expected to prevent the activation of the spindle checkpoint, causing cells to exit mitosis prematurely.

Overexpression of Survivin in a wide range of tumor tissues, including leukemia (ALL, AML), colo-rectal cancers, astrocytic tumors, and breast cancer has been consistently reported in the literature (Altieri, 2003; Cong and Han, 2004; Li, 2005). Moreover, overexpression of Survivin in cancer tissues is closely correlated with poor prognosis (Choi et al., 2001; Nakayama and Kamihira, 2002; Sasaki et al., 2002; Sui et al., 2002; Kajiwara et al., 2003). The role of Survivin in cancer promotion has been studied using a transgenic mouse model (Grossman et al., 2001). Grossman et al. (2001) have shown that exogenous expression of Survivin (driven by the keratinocyte specific promoter (K14)) inhibits UVB-induced apoptosis, and this inhibition is more pronounced when the expression of p53 is reduced. Hence, this study suggests that Survivin functions as an inhibitor of apoptosis, and thereby contributes to transformation. However, given Survivin's role as a chromosome passenger protein, the consequences of its overexpression on chromosome stability have not been fully explored.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED

Aneuploidy and tetraploidy are prevalent in cancers of different origin. Inducers of this state of high DNA content per cell and of abnormal numbers of chromosomes are typically highly expressed in a variety of cancers. These include the components of the chromosome passenger protein (CPP) complex. Polyploidy/aneuploidy are associated with an altered gene expression profile as well as with chromosome instability. Studies point to the intriguing possibility that deregulated expression of CPPs could lead to tetraploidy/aneuploidy, orchestrated changes in gene expression and to cellular transformation (Fig. 2). Future investigations should focus on the direct ability of tetraploid/aneuploid cells to induce cancer in vivo, as well as on the identification of the genetic signature of these cells. Finally, the possibility that loss of heterozygosity of cancer related genes in mammary stem cells may contribute to genetic instability in progeny cells and to subsequent breast cancer development is intriguing and analysis of the degree of changes in ploidy in various tumor stem cells would be worthwhile pursuing.

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Figure 2. Generation of tetraploid cells and their potential fate. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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LITERATURE CITED

  1. Top of page
  2. Abstract
  3. OVERVIEW: CHARACTERISTICS OF TETRAPLOIDY AND ANEUPLOIDY AND THEIR INDUCTION UNDER DIFFERENT CONDITIONS
  4. PREVALENCE OF POLYPLOIDY/ANEUPLOIDY IN DIFFERENT CANCERS
  5. CANCER THEORIES: POTENTIAL INVOLVEMENT OF TETRAPLOIDY OR ANEUPLOIDY IN CANCER PROMOTION
  6. REGULATORS OF MITOSIS AND MECHANISMS LEADING TO TETRAPLOIDY OR ANEUPLOIDY
  7. STEM CELLS, ANEUPLOIDY, AND CANCER DEVELOPMENT
  8. CHROMOSOME PASSENGER PROTEINS AND THEIR ROLE IN PLOIDY PROMOTION
  9. CHROMOSOME PASSENGER PROTEINS AND CANCER
  10. CONCLUSIONS
  11. Acknowledgements
  12. LITERATURE CITED