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PubMed1995

Overexpression of cyclin D1 in the Dami megakaryocytic cell line causes growth arrest.

The maturation of megakaryocytes in vivo requires polyploidization or repeated duplication of DNA without cytokinesis. As DNA replication and cytokinesis are tightly regulated in somatic cells by cyclins and cyclin-dependent kinases, we sought to determine the pattern of cyclin gene expression in cells that undergo megakaryocytic differentiation and polyploidization. The Dami megakaryocytic cell line differentiates and increases ploidy in response to phorbol 12-myristate 13-acetate (PMA) stimulation in vitro. We used Northern blotting to analyze mRNA levels of cyclins A, B, C, D1, and E in PMA-induced Dami cells and found that cyclin D1 mRNA levels increased dramatically (18-fold). Similar increases in cyclin D1 mRNA were obtained for other cell lines (HEL and K562) with megakaryocytic properties, but not in HeLa cells. The increase in cyclin D1 was confirmed by Western immunoblotting of PMA-treated Dami cells. This finding suggested that cyclin D1 might participate in megakaryocyte differentiation by promoting endomitosis and/or inhibiting cell division. To address these possibilities, we constructed two stable Zn+2-inducible, cyclin D1-overexpressing Dami cell lines. Cyclin D1 expression alone was not sufficient to induce polyploidy, but in conjunction with PMA-induced differentiation, polyploidization was slightly enhanced. However, unlike other cell systems, cyclin D1 overexpression caused cessation of cell growth. Although the mechanism by which cyclin D1 may affect megakaryocyte differentiation is not clear, these data demonstrate that cyclin D1 is upregulated in differentiating megakaryocytic cells and may contribute to differentiation by arresting cell proliferation.

Cell Cycle↗
PubMedDate not supplied

[The cytogenetic characteristics of subjects with menstrual function disorders].

The frequency and the pattern of chromosomal aberrations as well as the frequency of metaphase plates with premature chromatid disjunction, polyploidy and endoreduplication were studied in lymphocyte cultures of women with disturbances of the menstrual function and in healthy women. The frequency of metaphase plates was significantly increased in persons with Turner's syndrome and reduced in the groups with amenorrhea 1 and 2 in comparison with the group of healthy women. There was no difference in chromosomal aberration pattern. Premature chromatid disjunction is characteristic of patients with disturbances of the menstrual function and healthy women. The frequency of metaphase plates with premature chromatid disjunction was elevated in groups with Turner's syndrome, amenorrhea 1 and premature sexual maturation in comparison with the control.

Adult↗
PubMedDate not supplied

[Can postradiation cell fusion be a factor in the protection of a cell population?].

From the analysis of the literature it is inferred that there is one more type of nonspecific protection which is based on the polyploidy process and functions at the cell population and tissue levels. With high radiation loads, this process maintains the functioning rate of the given tissue and the survival rate of the given cell type. A hypothesis is proposed that cell fusion and formation of somatic hybrids, that provide clone survival, are particularly effective in tumor tissues. This mechanism is activated at high radiation doses: fusion of injured cells and formation of polykaryons and then hybrids can give rise to cells capable of reproduction. The cellularity is restored.

Animals↗
PubMed1996

A brief staurosporine treatment of mitotic cells triggers premature exit from mitosis and polyploid cell formation.

At any point during the progression of many tumor types, cells can develop a hyperploid DNA content. Hyperploid tumors are significant more aggressive, with a higher growth rate and a poor patient prognosis. Yeast genetics have implicated three important genes involved in DNA ploidy changes: cdc2, cyclin b, and a specific inhibitor of the p34(cdc2)/cyclin B kinase, rum1. Mutations in these genes uncoupled the dependence mitosis on DNA replication in the fission yeast, Saccharomyces pombe. It was proposed that the inactivation of the mitotic kinase complex, p34(cdc2)/cyclin B, induces a G(1), state wherein the cells re-replicate their DNA without an intervening mitosis. We show in this report that treatment of only M phase-arrested mouse cells, with the protein kinase inhibitor staurosporine, induced polyploidy. Nocodazole-arrested metaphase FT210 cells were pulsed with 100 ng/ml of staurosporine for 1 h. This 1-h treatment results in the inhibition of the mitotic p34(cdc2) kinase. The inhibition of the mitotic kinases leads to a reduction in the histone H1 and H3 mitotic-associated phosphorylations, chromosome decondensation and nuclear membrane reformation. When released into normal growth medium, these cells are reset to a G(1)state, re-replicate their DNA without completing mitosis, and become octaploid.

Alkaloids↗
PubMed1996

Persistent gestational trophoblastic disease: DNA image cytometry and interphase cytogenetics have limited predictive value.

DNA flow cytometry has shown a wider spectrum of DNA content in the complete hydatidiform mole (CM) than the originally reported diploidy. Conflicting results have been published about the relationship of DNA content and the occurrence of persistent gestational trophoblastic disease (PGTD). In the present study, 71 cases of CM and 4 cases of partial mole accompanied by PGTD and 100 cases of CM without PGTD were evaluated with DNA image cytometry for differences in DNA-ploidy pattern, expressed as the 2.5c and 5c exceeding rates. A pilot study of 20 cases of each group was performed using interphase cytogenetics to detect differences in the frequency of numerical chromosomal aberrations and in sex chromosome composition. For this purpose, DNA probes specific for the pericentromeric regions of chromosomes 1 and X and for the long arm of chromosome Y were incubated on 6-micron paraffin tissue sections. The results showed no differences between CMs with or without PGTD; DNA polyploidy occurred in 99% and 98% of cases, respectively; the 2.5c exceeding rate and 5c exceeding rate were 62.6 and 62.4, and 6.5 and 6.0, respectively. The frequency of numerical chromosomal aberrations as detected by interphase cytogenetics was 23.4 and 22.8%. An XY pattern was found in 3 of 20 cases of CM with PGTD and in 4 of 20 cases of CM without PGTD. The four cases of partial mole showed a DNA-ploidy pattern identical to that of a CM. For this reason, they would be better reclassified as CMs, despite the presence of nucleated red blood cells or amnion. Although nuclear atypia and corresponding increased DNA content is pronounced but variable in CMs, the occurrence of PGTD is not related to variations in quantitative DNA content nor to gross heterology or homology in sex chromosomes.

Adult↗
PubMed1996

[Induction of hyperdiploidy and chromosome breaks in LIM1215 cells expressing the exogenous mutant p53].

The effect of modifications of p53 expression on the incidence of numerical and structural chromosome aberrations was studied. Infection of LIM1215 cells containing two alleles of the wild-type p53 gene (P53wt) with the recombinant viruses that expressed mutant cDNAs coding for human p53 (His273, Trp248, and His175) resulted in appearance of hyperdiploid cells in populations and an increased proportion of metaphases with chromosome breakage. Expression of the exogenous p53wt or vectors HSG/neo and pPS/neo, which did not contain the p53 cDNA, did not induce numerical or structural chromosome aberrations. Treatment of cells with caffeine decreased the p53wt content and increased the proportion of metaphases with chromosome breaks; however, it did not induce hyperdiploidy in the majority of cell lines. Only in the subline that expressed the exogenous p53Trp248 did caffeine treatment increase the proportion of hyperdiploid variants, which was correlated with the hyperexpression of the product of the mutant allele. The increase in the frequency of chromosome breaks probably resulted from p53wt inactivation, whereas changes in chromosome number might be induced by some additional activities of p53 determined by mutations. Possible mechanisms for inducing heteroploidy by mutant p53 variants, including the role of endoreduplication in inducing hyper- and polyploidy, are discussed.

Cell Line↗
PubMed1977

[Pulse cytophotometric investigations concerning the biological behaviour of laryngeal carcinomas (author's transl)].

25 laryngeal carcinomas were investigated by pules cytophotometry, stained with ethidium bromide after pepsination. The karyograms were interpreted as DNA-distribution curves. In diploid populations the height of the 4c-peak was taken as a measure of proliferation rate. Aneuploidy and polyploidy were estimated by camparison with human diploid material . In our material we found 13 polyploid tumors (under them 6 aneuploid populations from 7 at all). After dividing the cases into two groups (1: with slow, 2: with rapid progression) the moiety of polyploid and aneuploid tumors and the height of the 4c-peak was significantly higher in group 2. The pulse cytophotometry gives reliable additional informations showing the great variability of biological characteristics of laryngeal carcinomas. Possibly this is a basis of a more differentiated therapy.

Aneuploidy↗
PubMed1997

[Genome multiplication mechanisms in the development of albumen gland polyploid cells of Succinea lauta (Gastropoda:Pulmonata). VI. Ultrastructural research of endomitotic structure].

This ultrastructural study of endomitosis in polyploid albumen gland cells of succineid snail. S. lauta was made to extend the previous research (Anisimov, 1997). The investigation was prosecuted on ultrathin sections by means of transmission electron microscopy. The insertion of 3H-thymidine and 3H-uridine into the nuclei and the light microscopy control of nuclear ploidy allowed to identify glands on early and intensive polyploidization stages and to ignore pseudoendomitotic terminally differentiated cells. Considering ultrastructural qualities and information about the cell population kinetics enabled us to discriminate between predifferentiation (2-4c), protodifferentiation (4-8c) and promoted differentiation (8-16c) cell stages. The endomitotic cycle was observed synchronously with the development of cytoplasmatic structures and secretion production in differentiating cells of ploidy levels 4-8-16c. According to morphological condition of the chromatin and chromosomes, G1-, S- and G2-interphase periods can be determined, such as successive stages of endomitosis (endopro-, meta-, ana-, and telophase). The following main features of endomitosis are accentuated: the normal (mitotic) chromosome cycle with total compaction in endometaphase and differential decompaction in interphase; the absence of the mitotic spindle; integrity of the nuclear envelope, nucleolus and contacts between them and chromosomes; part of chromosomes split nonsimultaneously and incompletely in the endoanaphase, or endomitosis with diplochromosomes rarely occurs. Chromosome nondisjunction is a temporary process that does not lead to a permanent chromosome endoreduplication (polyteny). It is emphasized that the normal chromosome cycle is combined with a complete block of cytoplasmic structures. Possible reasons of mitotic cycle reduction during the transition of differentiating cells to endomitotic polyploidy are discussed.

Animals↗
PubMed1997

[Comparative study of the level of cardiomyocyte hypertrophy in patients suffering from ischemic heart disease with normal arterial pressure and in hypertension].

A study was performed on the human atrial myocytes, isolated by means of alkaline dissociation of bioptates, obtained in clinics during open heart surgery, from two groups of patients. The first group consisted of 8 men aged from 40 to 62 years, with ischemic heart disease and normal arterial blood pressure. The second group involved 10 men, aged from 43 to 67 years, with ischemic heart disease and arterial hypertension. The nuclear DNA and the total protein in the cytoplasm of isolated cardiomyocytes were revealed by means of the two consecutive tests: the Feulgen and Naphthol yellow S staining. DNA and protein contents were determined by two wave-length scanning cytophotometry. It is ascertained that the temperate arterial hypertension exerted no appreciable influence on the polyploidy level of atrial myocytes, which correlated with the age of patient; in both groups (coefficients 0.7 and 0.4 for the first and second groups, resp.). The myocyte areas correlate with their ploidy (coefficients--0.7 and 0.7, accordingly). The protein contents in myocytes also correlate with their ploidy (0.5 and 0.7). The average protein content in myocytes of patients in the second group is higher than in the first group, the difference is most distinct when calculating the protein quantity per 2c-genome (717 +/- 34 a. u. and 517 +/- 51 a. u., resp.). A comparison of cytochemical and morphometric indices with some clinical findings obtained by means of echocardiography allowed to reveal the presence of correlative connections among them. The protein contents in myocytes correlate with the left ventricle mass (coefficients 0.6 and 0.5 for the first and second groups, resp.). The correlation between the rate of transmitral blood flow and myocyte ploidy (0.8 and 0.9), and the correlation between the myocyte area and the rate of transmitral blood flow (0.8 and 0.8) look convincing.

Adult↗
PubMed1996

Flow cytometric DNA analysis of cirrhotic liver cells in patients with hepatocellular carcinoma can provide a new prognostic factor.

BACKGROUND: DNA flow cytometry of hepatocellular carcinoma (HCC) cells has been investigated in many studies, but, to the best of our knowledge, there are no data on DNA analysis of cirrhotic parenchyma around the HCC. In this study, cell kinetics and ploidy of parenchymal cells around HCC were performed to ascertain if this would predict the possibility of recurrence in the cirrhotic areas. METHODS: The DNA content of 93 cases of HCC and of cirrhotic liver around the tumor nodules was analyzed by flow cytometry. Ploidy and proliferative index of HCC and cirrhotic liver were compared with macroscopic, histologic, and clinical features of each case and linked with the behavior of these tumors. Survival curves were assessed according to the Kaplan-Meier method. A multivariate analysis based on Cox proportional hazards regression model was performed on cases of diploid cirrhosis cells in which the S-phase fraction was evaluable. RESULTS: The univariate analysis of survival suggested significant roles for age, number of intrahepatic nodules, Edmondson-Steiner's classification, portal invasion, vascular invasion, presence of necrosis, hepatitis B surface antigen, alpha-feto-protein, Child's score, ploidy, and S-phase fraction of HCC cells. The DNA analysis of the cirrhotic cells showed that polyploidy was dramatically reduced in patients with HCC, compared with normal hepatocytes, and aneuploid clones were present among diploid cells. High S-phase fraction of cirrhotic cells and Child-Pugh classification were the strongest independent parameters affecting the tumor behavior in this study. CONCLUSIONS: The results of this study suggest that S-phase fraction of cirrhotic liver parenchyma may be employed as a new parameter in the prognostic evaluation of HCC patients.

Adult↗
PubMed1998

Prognostic significance of DNA cytometry of postirradiation cervicovaginal smears.

BACKGROUND: Cytologic sampling is performed routinely after radiotherapy for cervical carcinoma. The prognostic significance of postirradiation dysplastic and atypical cells is uncertain because of difficulties in distinguishing preneoplastic and cancerous changes from benign radiation changes. DNA cytometry studies may provide a more objective method of identifying significant lesions. METHODS: Postirradiation cervical carcinoma patients with cervical/vaginal smears containing atypical or dysplastic cells were identified prospectively. Papanicolaou smears were destained, restained with a Feulgen stain, and evaluated for DNA content using image cytometry. Pathologic and clinical records were monitored on each patient for evidence of recurrence or biopsy-proven dysplasia. RESULTS: Of 46 patients, 14 had been diagnosed on cytology as having atypical squamous cells, 4 as having atypical/suspicious cells, 12 with low grade squamous intraepithelial lesions (SIL), 3 with high grade SIL, and 13 with ungraded SIL. DNA histograms were classified as follows: 14 diploid, 19 polyploid, and 13 aneuploid. Cytologic diagnosis and histogram type were correlated significantly and both correlated with clinical outcome. The probability of either postirradiation dysplasia or recurrence was as follows: SIL, 82%; suspicious, 100%; polyploid, 79%; and aneuploid, 92%. Patients with atypical squamous cells of undetermined significance or diploidy most frequently had negative follow-up (57% each). All patients with both SIL and aneuploidy developed either dysplasia or recurrence. The stage of disease did not correlate with outcome or histogram pattern. CONCLUSIONS: DNA analysis of postirradiation cytologic smears demonstrating atypia or dysplasia may provide useful ancillary information. The presence of aneuploidy usually signifies either recurrence or dysplasia. Polyploidy most frequently occurs in dysplastic processes, whereas diploid histograms usually denote a benign disease course.

Adult↗
PubMed1996

Down-regulation of tumour gelatinase/inhibitor balance and preservation of tumour endothelium by an anti-metastatic ruthenium complex.

The anti-metastatic ruthenium complex Na[trans-RuCl4(DMSO)Im] was given i.p. at 22 and 44 mg/kg/day, on days 8-13 after tumour implantation, to mice carrying s.c. implants of MCa mammary carcinoma. The aim of the study was to compare the effects on lung metastasis formation with those on primary tumour cells. This investigation was based on flow cytometry analysis after propidium iodide and acridine orange staining, histology of tumour parenchyma and RT-PCR analysis for the type-IV collagenases MMP-9 and MMP-2 and their respective inhibitors TIMP-1 and TIMP-2 mRNAs. Na[trans-RuCl4(DMSO)Im] is not cytotoxic for tumour cells but has the capacity of interacting with nucleic acids, giving a general reduction of nucleic acid content as shown by a marked reduction of acridine orange staining and a tendency to a reduction of DNA polyploidy with marked reduction of 8n and 4n cell populations. Na[trans-RuCl4(DMSO)Im] also influences a proteolytic system which has the potential of degrading the basement membrane and has been related to metastatic aggressiveness: it markedly reduces, in a dose-dependent manner, MMP-2/TIMP-2 balance, but not that of MMP-9/TIMP-1. The different enzyme/inhibitor mRNA levels between untreated and treated tumours seem to be unaffected by tumour-infiltrating lymphocytes and are paralleled by the maintenance of connective tissue around blood vessels in the tumour mass. Correspondingly, lung metastasis formation is markedly reduced, to less than 10% of that seen in controls.

Acridine Orange↗
PubMed1997

Nuclear lamina assembly in the first cell cycle of rat liver regeneration.

The nuclear lamina is a fibrous structure at the nucleoplasmic surface of the inner nuclear membrane. Its assembly state is regulated by phosphorylation of its protein components, the lamins A, B, and C. The isoprenylation of the lamins is essential for their proper membrane anchoring and functionality. The content and the membrane association of nuclear lamins and the subcellular localization at light and electron microscopical levels were studied at different times of rat liver regeneration. This model for the good synchrony of the first cell cycle is particularly suited for the study of cell-cycle-dependent modifications and is particularly interesting for the increased protein prenylation found in S phase. The biochemical results show an increased lamin content in nuclear proteins in G1 phase and a decreased content in M phase, along with an enhanced cytosolic localization of A and C lamins at later stages. The morphological results show in M phase, also in nondividing cells, a decreased lamin-like immunoreactivity around the nucleus with an apparent nuclear lamina disassembly. These data emphasize the dynamic organization of nuclear lamina not only in mitosis but also in interphase. The reduction and partial solubilization of nuclear lamina in M phase suggest a reorganization of the nuclear envelope also in those cells that do not appear in mitosis but have replicated their DNA content that will result in a higher degree of polyploidy.

Animals↗
PubMed2000

The 'SUN' family: yeast SUN4/SCW3 is involved in cell septation.

SUN4 is the fourth member of the SUN gene family from S. cerevisiae, whose products display high homology in their 258 amino acid C-terminal domain. SIM1, UTH1, NCA3 (the founding members) are involved in different cellular processes (DNA replication, ageing, mitochondrial biogenesis) and it is shown herein that SUN4 plays a role in the cell septation process. sun4 delta cells are larger than wild-type and begin a new cell cycle before they have separated from their mother cell. This phenotype is more pronounced in sun4Delta cells also deleted for UTH1. FACS analysis shows apparent polyploidy which disappears when the cell cycle is arrested by mating factor or nocodazole, indicating that cell septation is delayed without modification of the doubling time. Elutriated sun4 delta uth1 delta daughter cells are born larger, and therefore enter S phase sooner than their wild-type counterpart. S phase duration, as well as timing of Clb2 degradation, is normal, but cell septation is delayed. Sun4p/Scw3p was recently described as a cell wall protein (Cappellaro et al., 1998) and, consistent with this notion, electron micrographs of sun4 delta cells show defects in the final steps of cell wall septation. Our data suggest that Sun4p and Uth1p might contribute to the regulated process of cell wall morphogenesis and septation.

Basic Helix-Loop-Helix Proteins↗
PubMed1984

Genital warts and cervical cancer. III. Subclinical papillomaviral infection and cervical neoplasia are linked by a spectrum of continuous morphologic and biologic change.

Human papillomaviral (HPV) infection is now widely advanced as an important etiologic factor in cervical cancer. This study was undertaken to clarify morphologic relationships within the biologic spectrum linking subclinical papillomaviral infection (SPI) to cervical intraepithelial (CIN). Two pathologists analyzed 72 colposcopic biopsies, using a semi-objective rating scheme that scored 24 different histologic criteria. Each individual criterion was checked for reproducibility, and validated against an objective measure of papillomaviral infection (immunoperoxidase staining) or premalignant change (microspectrophotometry). The individual criteria were then combined into histologic indices of benign warty change, presumed viral atypia, abnormal cell phenotype, and disturbed tissue maturation. Histologic expression of papillomaviral infection decreased with increasing degrees of premalignant change. Plotting the index of abnormal cell phenotype against that of disturbed tissue maturation produced a linear plot in which cases clustered into four diagnostic groups. The histologic indices of papillomaviral infection displayed significant curvilinear correlations with genotypic distortion, benign warty change being maximal in the CIN 1 range and presumed viral atypia in the CIN 2 range. Disturbance of nuclear DNA content also increased with worsening diagnosis; diploidy being most common in SPI (67%), polyploidy in CIN 1 (59%), and aneuploidy in CIN 2 (65%) and CIN 3 (82%). Conversely, capsid antigen production decreased from 36% in SPI to 9% in CIN 3. Three aneuploid epithelia were immunoperoxidase positive. These inverse relationships between late viral expression and nuclear distortion fit experimental models of viral oncogenesis. The gradual transition and morphologic overlap between diagnostic groups support the postulate that SPI and CIN are a single disease spectrum, in which differences are those of degree rather than of kind.

Adolescent↗
PubMed1995

Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study.

BACKGROUND: Olfactory neuroblastoma is an uncommon neuroectodermal tumor of the upper nasal cavity, microscopic features of which are not always homogeneous. No morphologic features have been found to correlate reliably with prognosis. METHODS: Twenty-six olfactory neuroblastomas occurring in 14 females and 12 males, ages 18-78 years, were studied by immunohistochemistry, electron microscopy, and DNA flow cytometry. Survival rates were statistically analyzed relative to several variables. RESULTS: Microscopically, 22 tumors formed a morphologic spectrum intermediate between paraganglioma (PG) and neuroblastoma (NB). Others included two ganglioneuroblastomas (GNB), one lesion exhibited biphasic (neuronal and epithelial) differentiation, and one tumor showed predominantly epithelial features. Immunoreactivity for neuronal and neuroendocrine markers included synaptophysin in 77%, neurofilament protein in 38%, class III beta-tubulin in 81%, and chromogranin A in 77%. In 88% of cases, elongated S-100 protein-positive cells surrounded tumor lobules. Cytokeratin and epithelial membrane antigen immunoreactivity were noted in six (23%) and two (8%) tumors, respectively. Aberrant p53 expression was detected in 16 tumors (62%). The Ki-67 labeling index (LI) varied from 0%-43.8% (mean, 7.4%). Ultrastructurally, 80-230 nm dense core granules were noted within perikarya and as in microtubule-containing processes in all of the 11 tumors studied by electromicroscopy. Lobules of seven tumors were surrounded by electron-dense sustentacular cells. Epithelial tumors exhibited obviously epithelial features in addition to neuronal differentiation. DNA flow cytometry demonstrated a high incidence of polyploidy and aneuploidy (78%) and a wide range of percent S phase fractions (1.5%-21.8%; mean, 9.0%). The study showed that longer survival rates are related significantly to (1) the occurrence of metastases which was linked to tumor subtype, (2) to a higher incidence of S-100 protein-positive cells, and (3) to a low (< 10%) Ki-67 labeling index. CONCLUSIONS: The present study indicates that (1) although typical olfactory neuroblastomas exhibit PG/NB differentiation, they more closely resemble PG, (2) occasional tumors show GNB and/or epithelial differentiation, and (3) survival rates may correlate with S-100 protein immunoreactivity and Ki-67 LI. Cancer 1995; 76:4-19.

Adult↗
PubMed2000

Aneuploidy, the somatic mutation that makes cancer a species of its own.

The many complex phenotypes of cancer have all been attributed to "somatic mutation." These phenotypes include anaplasia, autonomous growth, metastasis, abnormal cell morphology, DNA indices ranging from 0.5 to over 2, clonal origin but unstable and non-clonal karyotypes and phenotypes, abnormal centrosome numbers, immortality in vitro and in transplantation, spontaneous progression of malignancy, as well as the exceedingly slow kinetics from carcinogen to carcinogenesis of many months to decades. However, it has yet to be determined whether this mutation is aneuploidy, an abnormal number of chromosomes, or gene mutation. A century ago, Boveri proposed cancer is caused by aneuploidy, because it correlates with cancer and because it generates "pathological" phenotypes in sea urchins. But half a century later, when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer although, (1) many carcinogens do not mutate genes, (2) there is no functional proof that mutant genes cause cancer, and (3) mutation is fast but carcinogenesis is exceedingly slow. Intrigued by the enormous mutagenic potential of aneuploidy, we undertook biochemical and biological analyses of aneuploidy and gene mutation, which show that aneuploidy is probably the only mutation that can explain all aspects of carcinogenesis. On this basis we can now offer a coherent two-stage mechanism of carcinogenesis. In stage one, carcinogens cause aneuploidy, either by fragmenting chromosomes or by damaging the spindle apparatus. In stage two, ever new and eventually tumorigenic karyotypes evolve autocatalytically because aneuploidy destabilizes the karyotype, ie. causes genetic instability. Thus, cancer cells derive their unique and complex phenotypes from random chromosome number mutation, a process that is similar to regrouping assembly lines of a car factory and is analogous to speciation. The slow kinetics of carcinogenesis reflects the low probability of generating by random chromosome reassortments a karyotype that surpasses the viability of a normal cell, similar again to natural speciation. There is correlative and functional proof of principle: (1) solid cancers are aneuploid; (2) genotoxic and non-genotoxic carcinogens cause aneuploidy; (3) the biochemical phenotypes of cells are severely altered by aneuploidy affecting the dosage of thousands of genes, but are virtually un-altered by mutations of known hypothetical oncogenes and tumor suppressor genes; (4) aneuploidy immortalizes cells; (5) non-cancerous aneuploidy generates abnormal phenotypes in all species tested, e.g., Down syndrome; (6) the degrees of aneuploidies are proportional to the degrees of abnormalities in non-cancerous and cancerous cells; (7) polyploidy also varies biological phenotypes; (8) variation of the numbers of chromosomes is the basis of speciation. Thus, aneuploidy falls within the definition of speciation, and cancer is a species of its own. The aneuploidy hypothesis offers new prospects of cancer prevention and therapy.

Aneuploidy↗
PubMed2000

Analysis of chromosome abnormalities in sperm and embryos from two 45,XY,t(13;14)(q10;q10) carriers.

Robertsonian translocation t(13q14q) is studied in sperm and embryos of two couples undergoing preimplantation genetic diagnosis (PGD) in which both males are carriers of the translocation. It is already known that the chances of achieving pregnancy for a translocation carrier are directly linked to the number of normal or balanced embryos available for replacement. In our work it was found that the frequency of balanced spermatozoa was almost identical in both patients (74 and 77%), and after PGD, the frequencies of abnormal embryos caused by the translocation were also similar. Sperm chromosome analysis in translocation carriers can provide a reasonable basis for estimating a baseline of chromosome abnormalities to be found in embryos during an assisted reproductive cycle. However, individual factors not linked to the translocation can also produce other chromosome abnormalities (mosaicism, haploidy, polyploidy) and may compromise the chances of achieving a viable pregnancy.

Adult↗