Reappraisal of the Hansemann-Boveri hypothesis on the origin of tumors

Cancer is now known to be a genetic disease. In tumor development, cell nuclei undergo mutations, which can result in cytologically visible chromosome aberrations. The aneuploid errors may involve amplification or deletion of whole chromosomes or segments thereof. David Hansemann [1858-1920] and Theodor Boveri [1862-1915] were major contributors to early debates on the relationship between chromosomal defects, tumorigenesis and malignancies. In 1890, Hansemann observed asymmetrical nuclear divisions in human epithelial cancers. In these abnormal, but bipolar, divisions, a fraction of the chromosomes fails to segregate properly. Hansemann carefully documented the occurrence of asymmetric divisions in a wide variety of tumors. However, he remained a lifelong skeptic with regard to whether such events could be considered the underlying cause of tumors. Almost a quarter of a century after Hansemann's initial observations, Boveri considered the origin of tumors based on his earlier recognition of the functional specificity of each chromosome. He also explicitly drew on Hansemann's observations in proposing a model for tumorigenesis. Its central tenet was that a tumor typically originates from a single cell that has inherited a defined, but incorrectly combined, set of chromosomes. The rare occurrence of a pluripolar spindle represented Boveri's paradigm for a type of abnormal mitosis that can produce a host of random chromosomal combinations. He suggested that some of these combinations will induce tumorous transformation, and will inevitably arise occasionally. Since pluripolar and unbalanced bipolar divisions fail to distribute the hereditary chromatic material correctly, both of these mechanisms can give rise to tumor progenitors.     

Hansemann, Boveri, chromosomes and the gametogenesis-related theories of tumours

Theodor Boveri (1862-1915) is often credited with suggesting (in 1914) the first chromosomal theory of cancer, especially in terms of abnormal numbers of chromosomes arising in cells by multipolar mitoses in adult cells. However, multipolar mitoses in animal cells had been described as early as 1875, and Hansemann (1858-1920), in publications between 1890 and 1919, included this mechanism among various ways by which abnormal chromosome numbers might arise in cells and cause tumour formation. Both theories were conceived in a period when gametogenic ideas of tumour formation were current. Boveri based his theory on the observation that some cells in early sea urchin embryos having abnormal chromosome complements wander from their usual developmental paths. His observation may have been seen by other authors at the time as support for Cohnheim's "embryonic cell rest" theory of cancer. Hansemann's contribution is seen as both the original, and the more significant of the chromosomal theories of cancer.     

The spindle assembly checkpoint: perspectives in tumorigenesis and cancer therapy

Loss or gain of chromosomes, a condition known as aneuploidy, is a common feature of tumor cells and has therefore been proposed as the driving force for tumorigenesis. Such chromosomal instability can arise during mitosis as a result of mis-segregation of the duplicated sister chromatids to the two daughter cells. In normal cells, missegregation is usually prevented by the spindle assembly checkpoint (SAC), a sophisticated surveillance mechanism that inhibits mitotic exit until all chromosomes have successfully achieved bipolar attachment to spindle microtubules. Complete abrogation of SAC activity is lethal to normal as well as to tumor cells, as a consequence of massive chromosome mis-segregation. Importantly, many human aneuploid tumor cells exhibit a weakened SAC activity that allows them to tolerate gains or losses of a small number of chromosomes; and interfering with this SAC residual activity may constitute a suitable strategy to kill cancer cells. This review focuses on the potential link between SAC and tumorigenesis, and the therapeutic strategy to target the SAC for cancer treatment.     

Defining 'chromosomal instability'

Most scientists agree that the majority of human solid malignant tumors are characterized by chromosomal instability (CIN) involving gain or loss of whole chromosomes or fractions of chromosomes. CIN is thought to be an early event during tumorigenesis and might therefore be involved in tumor initiation. Despite its frequent occurrence in tumors and its potential importance in tumor evolution, CIN is poorly defined and is used inconsistently and imprecisely. Here, we provide criteria to define CIN and argue that few experimental approaches are capable of assessing the presence of CIN. Accurate assessment of CIN is crucial to elucidate whether CIN is a driving force for tumorigenesis and whether a chromosomally unstable genome is necessary for tumor progression.     

Genome reversion process of endopolyploidy confers chromosome instability on the descendent diploid cells

Endotetraploidy with 4-chromatid chromosomes divides by a bipolar, 2-step meiotic-like division back to diploidy (subcells), which is chiefly achieved by co-segregation of whole genomes uncoupled from spindle participation. This study shows diploid subcell inheritance of endopolyploid-division traits: perpendicular division relative to the cytoskeleton axis, dysfunctional centromere/kinetochore regions and whole genomic separations from co-segregation. The assimilation of these traits into the innate mitotic machinery of the subcells resulted in diploid mitotic divisions that tolerated mild disturbances in cycling progression and in chromosomal distributions. The data were interpreted as demonstrating a blending together of endopolyploid and mitotic division traits with result of an endo-modified mitosis in subcell propagation. Additionally, chromosomal stickiness caused breakage in anaphase/telophase. The observations are discussed in regard to a potential for slowly developing aneuploidy with increasing genomic complexity, which is widely accepted to be the basic route in tumorigenesis.     

Aurea Mediocritas: The Importance of a Balanced Genome

Aneuploidy, defined as an abnormal number of chromosomes, is a hallmark of cancer. Paradoxically, aneuploidy generally has a negative impact on cell growth and fitness in nontransformed cells. In this work, we review recent progress in identifying how aneuploidy leads to genomic and chromosomal instability, how cells can adapt to the deleterious effects of aneuploidy, and how aneuploidy contributes to tumorigenesis in different genetic contexts. Finally, we also discuss how aneuploidy might be a target for anticancer therapies.As Horace famously wrote in his Odes, the “golden mean” is the secret to a happy, balanced life. Recent work, reviewed here, emphasizes the importance of this kind of balance for the genetics of human cells.Maintaining a stable genome is critical for the preservation of genetic information during the life span of an organism. Despite mechanisms designed to ensure a diploid karyotype, errors can and do occur during chromosome segregation that result in the gain and loss of whole chromosomes. In vitro estimates suggest that normal, diploid cells missegregate a chromosome once every 100 cell divisions (Thompson and Compton 2008). The in vivo rate of chromosome missegregation is unknown, but could vary between different cell types. Even if the rate is low, an abnormal number of chromosomes, or aneuploidy, could have a significant impact on normal cell physiology, as well as tumorigenesis.Aneuploidy, at the level of the organism, is detrimental and generally incompatible with life. In humans, only three aneuploidies—trisomy 13, 18, and 21—are viable, and only trisomy 21 is compatible with a life span beyond infancy (Hassold et al. 2007). Despite the deleterious consequences of aneuploidy in normal physiological contexts, an abnormal number of chromosomes is one of the hallmarks of cancer cells. Aneuploidy is found in ∼90% of solid tumors and >50% of blood cancers (Beroukhim et al. 2010; Mitelman et al. 2013). Whether aneuploidy is a cause or consequence of cell transformation is a frequent topic of debate. The challenge for establishing a causal relationship stems from the complexity of cancer cells, in which numerical chromosome abnormalities are rarely found in isolation but are usually accompanied by other genomic alterations, such as point mutations, translocations, and microsatellite instability. This complexity makes it difficult to define the initiating event(s) in tumorigenesis.This review focuses on whole-chromosome aneuploidy, although it has been shown that the gain and loss of chromosome arms is also a common occurrence in cancer cells (Beroukhim et al. 2010; Mitelman et al. 2013). We review the molecular pathways leading to aneuploidy, the effects of aneuploidy on cellular physiology, and the links between aneuploidy and tumorigenesis. Finally, we also explore the exciting concept of targeting aneuploidy as a novel therapeutic approach in treating cancer.     

Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells

Telomeres are essential for protecting the ends of chromosomes and preventing chromosome fusion. Telomere loss has been proposed to play an important role in the chromosomal rearrangements associated with tumorigenesis. To determine the relationship between telomere loss and chromosome instability in mammalian cells, we investigated the events resulting from the introduction of a double-strand break near a telomere with I-SceI endonuclease in mouse embryonic stem cells. The inactivation of a selectable marker gene adjacent to a telomere as a result of the I-SceI-induced double-strand break involved either the addition of a telomere at the site of the break or the formation of inverted repeats and large tandem duplications on the end of the chromosome. Nucleotide sequence analysis demonstrated large deletions and little or no complementarity at the recombination sites involved in the formation of the inverted repeats. The formation of inverted repeats was followed by a period of chromosome instability, characterized by amplification of the subtelomeric region, translocation of chromosomal fragments onto the end of the chromosome, and the formation of dicentric chromosomes. Despite this heterogeneity, the rearranged chromosomes eventually acquired telomeres and were stable in most of the cells in the population at the time of analysis. Our observations are consistent with a model in which broken chromosomes that do not regain a telomere undergo sister chromatid fusion involving nonhomologous end joining. Sister chromatid fusion is followed by chromosome instability resulting from breakage-fusion-bridge cycles involving the sister chromatids and rearrangements with other chromosomes. This process results in highly rearranged chromosomes that eventually become stable through the addition of a telomere onto the broken end. We have observed similar events after spontaneous telomere loss in a human tumor cell line, suggesting that chromosome instability resulting from telomere loss plays a role in chromosomal rearrangements associated with tumor cell progression.     

The Sex Chromosomes in Evolution and in Medicine

The recent emergence of human cytogenetics has a firm foundation in studies on other forms of life. Historical highlights are Mendel''s studies on the garden pea (published in 1865 but lost in an obscure journal until 1900); formulation of cytogenic postulates by Sutton and Boveri (1902-1903); Bridges'' discovery of chromosome abnormalities in Drosophila (1916), followed by numerous similar studies in plants; and demonstration of the chromosomal basis of the syndromes of Down, Klinefelter and Turner in man (1959).The sex chromosomes (XX and XY) evolved from a pair of undifferentiated autosomes of a premammalian ancestor, the X chromosome changing less than the Y as they evolved. Eleven numerical abnormalities of the sex chromosomes are known in man, and knowledge of their effects on development is accumulating. The abnormal complexes range in size from the XO error of Turner''s syndrome to the XXXXY error of a variant of Klinefelter''s syndrome.     

Preventing aneuploidy: the contribution of mitotic checkpoint proteins

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.     

Cytology of aberrations induced by X-rays in oocytes of Drosophila melanogaster.

200 first-division configurations were analyzed for cytological aberrations induced by X-rays in late meiotic prophase in oocytes of Drosophila melanogaster. For the 3000 and 6000 r doses, 38 and 66%, respectively, were classified as abnormal. The aberrant divisions included displacement of the chromosomes suggesting their non-disjunction, loss of a whole chromosome, fragments and heterologous exchanges and unidentifiable aberrations. Non-disjunctional chromosomes were free of heterologous exchanges. The concept that a majority of X-ray-induced dominant lethals is due to chromosomal breakage is supported by the findings of the present study.     

Human 14-3-3 gamma protein results in abnormal cell proliferation in the developing eye of Drosophila melanogaster

During mitosis, correct bipolar chromosome attachment to the mitotic spindle is an essential prerequisite for the equal segregation of chromosomes. The spindle assembly checkpoint can prevent chromosome segregation as long as not all chromosome pairs have obtained bipolar attachment to the spindle. The chromosomal passenger complex plays a crucial role during chromosome alignment by correcting faulty chromosome-spindle interactions (e.g. attachments that do not generate tension). In the process of doing so, the chromosomal passenger complex generates unattached chromosomes, a specific situation that is known to promote checkpoint activity. However, several studies have implicated an additional, more direct role for the chromosomal passenger complex in enforcing the mitotic arrest imposed by the spindle assembly checkpoint. In this review, we discuss the different roles played by the chromosomal passenger complex in ensuring proper mitotic checkpoint function. Additionally, we discuss the possibility that besides monitoring the presence of unattached kinetochores, the spindle assembly checkpoint may also be capable of responding to chromosome-microtubule interactions that do not generate tension and we propose experimental set-ups to study this.     

Illicit survival of cancer cells during polyploidization and depolyploidization

Tetraploidy and the depolyploidization of tetraploid cells may contribute to oncogenesis. Several mechanisms have evolved to avoid the generation, survival, proliferation and depolyploidization of tetraploids. Cells that illicitly survive these checkpoints are prone to chromosomal instability and aneuploidization. Along with their replication, tetraploids constantly undergo chromosomal rearrangements that eventually lead to pseudodiploidy by two non-exclusive mechanisms: (i) multipolar divisions and (ii) illicit bipolar divisions in the presence of improper microtubule-kinetochore attachments. Here, we describe the regulation and the molecular mechanisms that underlie such a 'polyploidization-depolyploidization' cascade, while focusing on the role of oncogenes and tumor suppressor genes in tetraploidy-driven tumorigenesis. We speculate that the identification of signaling/metabolic cascades that are required for the survival of tetraploid or aneuploid (but not diploid) cancer cells may pave the way for the development of novel broad-spectrum anticancer agents.     

Chromosomes in solid tumors.

Systematic chromosomal studies in solid tumors have been scanty (excepting meningiomas), because of the fact that it is difficult to obtain tumor material at desired times and only in about 10--15% of the cases adequate chromosome preparations are suitable with a direct technique or short term culture. A few facts that emerge from the study of various solid tumors are as follows: 1. modal number of chromosomes in parimary tumors tends to be lower that of metastatic; 2. certain chromosomes and chromosome regions are more susceptible for breakage to oncogenic conditions, hence, there is non-random involvement of certain chromosomes in human neoplasia and 3. certain chromosome changes are more often associated with metastatic spread than others.     

Telomere functions: lessons from yeast

Telomeres are specialized DNA protein structures that form the ends of eukaryotic chromosomes. In yeast, loss of even a single telomere causes a prolonged, but transitory, cell-cycle arrest. During this arrest, many broken chromosomes acquire a new telomere by one of three pathways, although at the cost of a partial loss of heterozygosity. In addition, a substantial fraction of the chromosomes lacking a telomere is lost, which generates an aneuploid cell. In these cases, the broken chromosome is usually replicated and segregated for ten or more cell divisions in unstable form. Extrapolation from yeast suggests that the gradual loss of telomeric DNA that accompanies ageing in humans may initiate the kinds of chromosomal rearrangements and genetic changes that are associated with tumorigenesis.     

Numerical chromosomal changes in DNA hypodiploid solid tumors: restricted loss and gain of certain chromosomes.

BACKGROUND: DNA hypodiploidy is a unique and rare finding associated with aggressive behavior in solid tumors. Identifying the chromosomal changes underlying this feature may provide important information on the development and progression of these neoplasms. METHODS: Fluorescence in situ hybridization analysis using alpha-satellite probes for nine autosomes and the two sex chromosomes was performed on interphase cells from 27 solid tumors which had been shown to be DNA hypodiploid by flow cytometry. The chromosomal abnormalities were correlated with the DNA index and tumor subtypes. RESULTS: The data show mutually exclusive loss of certain chromosomes and compensatory gain of other chromosomes in different tumors. The net loss was slightly more than the net gain for the chromosomes tested. Polysomy of chromosome 7 and monosomy of chromosomes 17, X and loss Y were found in most tumors. Significant differential loss of chromosomes 6,10, and 12 among DNA hypodiploid breast, kidney and lung carcinomas was noted. CONCLUSIONS: Our study shows (i) gain of chromosome 7 and loss chromosome 17 in most DNA hypodiploid tumors, (ii) specific chromosomal loss was noted in breast and renal cell carcinomas, and (iii) that different mechanisms for DNA hypodiploid and hyperdiploid development may exist.     

A model for genetic complementation controlling the chromosomal abnormalities and loss of heterozygosity formation in cancer

The relationship between the apparently random chromosomal changes found in aneuploidy and the genetic instability driving the progression of cancer is not clear. We report a test of the hypothesis that aneuploid chromosomal abnormalities might be selected to preserve cell-survival genes during loss of heterozygosity (LOH) formations which eliminate tumor suppressor genes. The LOHs and structurally abnormal chromosomes present in the aneuploid LoVo (colon), A549 (lung), SUIT-2 (pancreas), and LN-18 (glioma) cancer cell lines were identified by single nucleotide polymorphisms (SNPs) and Spectral Karyotyping (SKY). The Mann-Whitney U and chi square tests were used to evaluate possible differences in chromosome numbers and abnormalities between the cell lines, with two-tailed P values of <0.01 being considered significant. The cell lines differed significantly in chromosome numbers and frequency of structurally abnormal chromosomes. The SNP analysis revealed that each cell line contained at least a haploid set of somatic chromosomes, consistent with our hypothesis that cell-survival genes are widely scattered throughout the genome. Further, over 90% of the chromosomal abnormalities seemed to be selected, often after LOH formation, for gene-dosage compensation or to provide heterozygosity for specific chromosomal regions. These results suggest that the chromosomal changes of aneuploidy are not random, but may be selected to provide gene-dosage compensation and/or retain functional alleles of cell-survival genes during LOH formation.     

Theodor Boveri and the origin of malignant tumours

As long ago as 1914, Theodor Boveri suggested that there is an inhibitory mechanism in every normal cell that prevents the process of cell division until the inhibition has been overcome by a special stimulus. From his work on abnormal mitoses in the eggs of echinoderms, Boveri also suggested that the inhibitor resided in the chromosomes. The relevance of Boveri's ideas to modern cancer research is discussed in this Retrospective article.     

Meiotic Chromosome Behavior in a Human Male t（8;15） Carrier

Reciprocal translocation is one of the most common structural chromosomal rearrangements in human beings; it is widely recognized to be associated with male infertility. This association is mainly based on the abnormal chromosome behavior of the translocated chromosomes and sex chromosomes during meiosis prophase I in reciprocal translocation carriers. However, the underlying mechanisms are not completely known. Here we report a reciprocal translocation carrier of t（8;15）, who is oligozoospermic due to apoptosis of primary spermatocytes and to premature germ cell desquamation from seminiferous tubules. Further analysis showed abnormal synapsis and recombination frequency in this patient, indicating a connection between chromosome behavior and apoptosis of primary spermatocytes. We also compared these observations with recently reported findings on spermatogenesis defects in reciprocal translocation carriers, and discuss the possible mechanisms underlying both common and unique phenotypes of reciprocal translocations involving different chromosomes with the aim of further understanding the regulation of human spermatogenesis.     

Array CGH analysis reveals chromosomal aberrations in mouse lung adenocarcinomas induced by the human lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

Exposure to genotoxic carcinogens in tobacco smoke is a major cause of lung cancer. However, the effect this has on DNA copy number and genomic stability during lung carcinogenesis is unclear. Here we used bacterial artificial chromosome array-based comparative genomic hybridization to examine the effect of NNK, a potent human lung carcinogen present in tobacco smoke, on the major genomic changes occurring during mouse lung adenocarcinogenesis. Observed were significantly more gross chromosomal changes in NNK-induced tumors compared with the spontaneous tumors. An average of 5.6 chromosomes were affected by large-scale changes in DNA copy number per NNK-induced tumor compared with only 2.0 in spontaneous lung tumors (p = 0.017). Further analysis showed that gains on chromosomes 6 and 8, and losses on chromosomes 11 and 14 were more common in NNK-induced tumors (p 相似文献   

Nondisjunction reduplication of chromosome 3 is not a common mechanism in the development of human renal cell tumors

Because of the recurrent loss of regions of the chromosome 3 short arm in renal cell carcinomas, a chromosomal mechanism for the expression of recessive cancer genes has been implicated in the development of this type of tumor. Nondisjunction and subsequent reduplication of a mutant chromosome is one of the presumed mitotic mechanisms leading to the expression of recessive cancer genes. Using variant fluorescence at the centromeric region of chromosome 3 and a restriction fragment length polymorphism on chromosome 3p, we found chromosome 3 heteromorphism in the constitutional cells of 14 of 15 patients with renal tumors showing two normal chromosomes 3. This heteromorphism was maintained in each tumor. Therefore, the mechanism of nondisjunction and reduplication in the development of homozygosity for a mutant chromosome 3 in renal tumors remains questionable.