• Gravina S, Dong X, Yu B, Vijg J. Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 2016 Jul 5;17(1):150. PubMed: 27380908. Categories: OncoSENS

    Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome.

    Genome Biol. 2016 Jul 5;17(1):150.

    Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome.

    Gravina S, Dong X, Yu B, Vijg J.

    Abstract

    Abstract:

    BACKGROUND:

    Transmission fidelity of CpG DNA methylation patterns is not foolproof, with error rates from less than 1 to well over 10 % per CpG site, dependent on preservation of the methylated or unmethylated state and the type of sequence. This suggests a fairly high chance of errors. However, the consequences of such errors in terms of cell-to-cell variation have never been demonstrated by experimentally measuring intra-tissue heterogeneity in an adult organism.

    RESULTS:

    We employ single-cell DNA methylomics to analyze heterogeneity of genome-wide 5-methylcytosine (5mC) patterns within mouse liver. Our results indicate a surprisingly high level of heterogeneity, corresponding to an average epivariation frequency of approximately 3.3 %, with regions containing H3K4me1 being the most variable and promoters and CpG islands the most stable. Our data also indicate that the level of 5mC heterogeneity is dependent on genomic features. We find that non-functional sites such as repeat elements and introns are mostly unstable and potentially functional sites such as gene promoters are mostly stable.

    CONCLUSIONS:

    By employing a protocol for whole-genome bisulfite sequencing of single cells, we show that the liver epigenome is highly unstable with an epivariation frequency in DNA methylation patterns of at least two orders of magnitude higher than somatic mutation frequencies.

     

  • Gravina S, Ganapathi S, Vijg J. Single-cell, locus-specific bisulfite sequencing (SLBS) for direct detection of epimutations in DNA methylation patterns. Nucleic Acids Res. 2015 Apr 19. pii: gkv366. PubMed: 25897117. Categories: OncoSENS

    Single-cell, locus-specific bisulfite sequencing (SLBS) for direct detection of epimutations in DNA methylation patterns.

    Nucleic Acids Res. 2015 Apr 19. pii: gkv366.

    Single-cell, locus-specific bisulfite sequencing (SLBS) for direct detection of epimutations in DNA methylation patterns.

    Gravina S, Ganapathi S, Vijg J.

    Abstract

    Abstract:

    Stochastic epigenetic changes drive biological processes, such as development, aging and disease. Yet, epigenetic information is typically collected from millions of cells, thereby precluding a more precise understanding of cell-to-cell variability and the pathogenic history of epimutations. Here we present a novel procedure for directly detecting epimutations in DNA methylation patterns using single-cell, locus-specific bisulfite sequencing (SLBS). We show that within gene promoter regions of mouse hepatocytes the epimutation rate is two orders of magnitude higher than the mutation rate.

  • Silva H, Halvorsen D, Henson JD. Control ALT, Delete Cancer The Scientist (magazine). Read on external site. Categories: OncoSENS

    Control ALT, Delete Cancer

    The Scientist (magazine).

    Control ALT, Delete Cancer

    Silva H, Halvorsen D, Henson JD.

    Abstract

    Abstract:

    Because age is the largest risk factor for cancer, as the life expectancy of the world’s population continues to increase, cancer incidence is projected to rise dramatically. A 2011 report on Global Health and Aging released by the National Institutes of Health and World Health Organization predicts a tripling of the number of people aged 65 or older to 1.5 billion by 2050, and the annual number of new cancer cases is projected to reach 27 million by 2030. Undoubtedly, alleviating the diseases and disabilities associated with an aging global population will require the development of new anticancer approaches to avoid economic and humanitarian calamities.

    Cellular immortality is a hallmark of cancers that distinguishes them from normal tissue. Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called the telomeres, gets shorter. When the telomeres shorten too much, an alarm signal is generated, and the cell permanently stops dividing and enters senescence or undergoes apoptosis. Telomere shortening thus acts as a biological mechanism for limiting cellular life span.  Cancer cells, on the other hand, can become immortalized by activating a telomere maintenance mechanism (TMM) that counteracts telomere shortening by synthesizing new telomeric DNA from either an RNA template using the enzyme telomerase or a DNA template using a mechanism called alternative lengthening of telomeres (ALT).

  • Boura JS, Vance M, Yin W, Madeira C, Lobato da Silva C, Porada CD, Almeida-Porada G. Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells. Mol Ther Methods Clin Dev. 2014 Sep;2014(1). pii: 14041. PubMed: 25279386. Categories: OncoSENS, RepleniSENS

    Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells.

    Mol Ther Methods Clin Dev. 2014 Sep;2014(1). pii: 14041.

    Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells.

    Boura JS, Vance M, Yin W, Madeira C, Lobato da Silva C, Porada CD, Almeida-Porada G.

    Abstract

    Abstract:

    Mesenchymal stromal cells (MSC) constitutively express low levels of human leukocyte antigen-G (HLA-G), which has been shown to contribute to their immunomodulatory and anti-inflammatory properties. Here, we hypothesized that overexpression of HLA-G on bone marrow-derived MSC would improve their immunomodulatory function, thus increasing their therapeutic potential. Therefore, we investigated which gene transfer system is best suited for delivering this molecule while maintaining its immuno-modulatory effects. We performed a side-by-side comparison between three nonviral plasmid-based platforms (pmax-HLA-G1; MC-HLA-G1; pEP-HLA-G1) and a viral system (Lv-HLA-G1) using gene transfer parameters that yielded similar levels of HLA-G1-expressing MSC. Natural killer (NK) cell-mediated lysis assays and T cell proliferation assays showed that MSC modified with the HLA-G1 expressing viral vector had significantly lower susceptibility to NK-lysis and significantly reduced T cell proliferation when compared to nonmodified cells or MSC modified with plasmid. We also show that, in plasmid-modified MSC, an increase in Toll-like receptor (TLR)9 expression is the mechanism responsible for the abrogation of HLA-G1's immunomodulatory effect. Although MSC can be efficiently modified to overexpress HLA-G1 using viral and nonviral strategies, only viral-based delivery of HLA-G1 is suitable for improvement of MSC's immunomodulatory properties.

  • Akman K, Haaf T, Gravina S, Vijg J, Tresch A. Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data. Bioinformatics. 2014 Jul 1;30(13):1933-4. doi: 10.1093/bioinformatics/btu142. Epub 2014 Mar 10. PubMed: 24618468. Categories: OncoSENS

    Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

    Bioinformatics. 2014 Jul 1;30(13):1933-4. doi: 10.1093/bioinformatics/btu142. Epub 2014 Mar 10.

    Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

    Akman K, Haaf T, Gravina S, Vijg J, Tresch A.

    Abstract

    Abstract:

    SUMMARY:

    Here we present the open-source R/Bioconductor software package BEAT (BS-Seq Epimutation Analysis Toolkit). It implements all bioinformatics steps required for the quantitative high-resolution analysis of DNA methylation patterns from bisulfite sequencing data, including the detection of regional epimutation events, i.e. loss or gain of DNA methylation at CG positions relative to a reference. Using a binomial mixture model, the BEAT package aggregates methylation counts per genomic position, thereby compensating for low coverage, incomplete conversion and sequencing errors.

    AVAILABILITY AND IMPLEMENTATION:

    BEAT is freely available as part of Bioconductor at www.bioconductor.org/packages/devel/bioc/html/BEAT.html. The package is distributed under the GNU Lesser General Public License 3.0.

  • Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhães JP. The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation Res 2012;15(5):483-94. PubMed: 23098078. Categories: OncoSENS

    The role of DNA methylation in aging, rejuvenation, and age-related disease.

    Rejuvenation Res 2012;15(5):483-94.

    The role of DNA methylation in aging, rejuvenation, and age-related disease.

    Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhães JP.

    Abstract

    Abstract:

    DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

  • Wood JA, Colletti E, Mead LE, Ingram D, Porada CD, Zanjani ED, Yoder MC, Almeida-Porada G Distinct contribution of human cord blood-derived endothelial colony forming cells to liver and gut in a fetal sheep model Hepatology. 2012 Sep;56(3):1086-96. doi: 10.1002/hep.25753. PubMed: 22488442. Categories: OncoSENS, RepleniSENS

    Distinct contribution of human cord blood-derived endothelial colony forming cells to liver and gut in a fetal sheep model

    Hepatology. 2012 Sep;56(3):1086-96. doi: 10.1002/hep.25753.

    Distinct contribution of human cord blood-derived endothelial colony forming cells to liver and gut in a fetal sheep model

    Wood JA, Colletti E, Mead LE, Ingram D, Porada CD, Zanjani ED, Yoder MC, Almeida-Porada G

    Abstract

    Abstract:

    Although the vasculogenic potential of circulating and cord blood (CB)-derived endothelial colony-forming cells (ECFC) has been demonstrated in vitro and in vivo, little is known about the inherent biologic ability of these cells to home to different organs and contribute to tissue-specific cell populations. Here we used a fetal sheep model of in utero transplantation to investigate and compare the intrinsic ability of human CB-derived ECFC to migrate to the liver and to the intestine, and to define ECFC's intrinsic ability to integrate and contribute to the cytoarchitecture of these same organs. ECFCs were transplanted by an intraperitoneal or intrahepatic route (IH) into fetal sheep at concentrations ranging from 1.1-2.6 × 10(6) cells/fetus. Recipients were evaluated at 85 days posttransplant for donor (human) cells using flow cytometry and confocal microscopy. We found that, regardless of the route of injection, and despite the IH delivery of ECFC, the overall liver engraftment was low, but a significant percentage of cells were located in the perivascular regions and retained the expression of hallmark endothelial makers. By contrast, ECFC migrated preferentially to the intestinal crypt region and contributed significantly to the myofibroblast population. Furthermore, ECFC expressing CD133 and CD117 lodged in areas where endogenous cells expressed those same phenotypes. CONCLUSION: ECFC inherently constitute a potential source of cells for the treatment of intestinal diseases, but strategies to increase the numbers of ECFC persisting within the hepatic parenchyma are needed in order to enhance ECFC therapeutic potential for this organ.

  • Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011 Feb 21;192(4):547-56. PubMed: 21321098. Categories: ApoptoSENS, OncoSENS, RepleniSENS

    Four faces of cellular senescence.

    J Cell Biol. 2011 Feb 21;192(4):547-56.

    Four faces of cellular senescence.

    Rodier F, Campisi J.

    Abstract

    Abstract:

    Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

  • Peto MV. Aluminium and iron in humans: bioaccumulation, pathology, and removal. Rejuvenation Res 2010 Oct;13(5):589-98. PubMed: 21142669. Categories: AmyloSENS, LysoSENS, OncoSENS

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Rejuvenation Res 2010 Oct;13(5):589-98.

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Peto MV.

    Abstract

    Abstract:

    It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.

  • de Grey, ADNJ. WILT: necessity, feasibility, affordability In: The Future of Aging: Pathways to Human Life Extension (G. Fahy et al., eds.), Springer, 2010, pp. 667-685. Categories: OncoSENS

    WILT: necessity, feasibility, affordability

    In: The Future of Aging: Pathways to Human Life Extension (G. Fahy et al., eds.), Springer, 2010, pp. 667-685.

    WILT: necessity, feasibility, affordability

    de Grey, ADNJ.

    Abstract

    Abstract:

    Despite immense investment of resources, biomedical progress in postponing death from most cancers has fallen far short of prior expert prediction. Having intercellular natural selection at its disposal, cancer is arguably the hardest part of aging to combat biomedically. WILT (Whole-body Interdiction of Lengthening of Telomeres), first suggested in 2004, is a radical proposal that seeks to address this feature of cancer head-on, by pre-emptively altering as many as possible of our mitotically competent cells in such a way that the capacity for indefinite cell division could not be achieved even by the high degree of mutagenesis and selection that a tumour harbours. WILT also incorporates proposals for addressing the severe side-effects that these alterations would certainly have. In this chapter, following an introduction to the motivation for WILT, I first evaluate the likelihood that alternative, less daunting but comparably effective approaches to controlling cancer will emerge in a similar timeframe, thereby making WILT mercifully unnecessary. Then I provide an update on the various technologies that comprise WILT, with emphasis on progress showing that WILT is likely both to be implementable within a few decades and to achieve the anti-cancer efficacy that I have previously claimed for it. Finally I address a different type of concern: that, even if technologically achievable, WILT is so complex that it may never be economically practicable.

  • Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):929-35. PubMed: 19265030. Categories: MitoSENS, OncoSENS

    Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage.

    Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):929-35.

    Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage.

    Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S.

    Abstract

    Abstract:

    OBJECTIVE: The enzyme telomerase and its catalytic subunit the telomerase reverse transcriptase (TERT) are important for maintenance of telomere length in the nucleus. Recent studies provided evidence for a mitochondrial localization of TERT. Therefore, we investigated the exact localization of TERT within the mitochondria and its function. METHODS AND RESULTS: Here, we demonstrate that TERT is localized in the matrix of the mitochondria. TERT binds to mitochondrial DNA at the coding regions for ND1 and ND2. Binding of TERT to mitochondrial DNA protects against ethidium bromide-induced damage. TERT increases overall respiratory chain activity, which is most pronounced at complex I and dependent on the reverse transcriptase activity of the enzyme. Moreover, mitochondrial reactive oxygen species are increased after genetic ablation of TERT by shRNA. Mitochondrially targeted TERT and not wild-type TERT revealed the most prominent protective effect on H(2)O(2)-induced apoptosis. Lung fibroblasts from 6-month-old TERT(-/-) mice (F2 generation) showed increased sensitivity toward UVB radiation and heart mitochondria exhibited significantly reduced respiratory chain activity already under basal conditions, demonstrating the protective function of TERT in vivo. CONCLUSIONS: Mitochondrial TERT exerts a novel protective function by binding to mitochondrial DNA, increasing respiratory chain activity and protecting against oxidative stress-induced damage.

  • Bollmann FM. The many faces of telomerase: emerging extratelomeric effects. Bioessays. 2008 Aug;30(8):728-32. PubMed: 18623070. Categories: OncoSENS

    The many faces of telomerase: emerging extratelomeric effects.

    Bioessays. 2008 Aug;30(8):728-32.

    The many faces of telomerase: emerging extratelomeric effects.

    Bollmann FM.

    Abstract

    Abstract:

    Telomeres, the ends of chromosomes, shorten with each cell division. To expand their replicative potential, various cell types use the ribonucleoprotein telomerase, which lengthens telomeres by its reverse transcriptase activity. Because of its ability to immortalize cancer cells, telomerase also plays a significant role in tumor growth. However, in recent years, a wide variety of non-canonical effects of telomerase that are independent of telomere lengthening have been discovered, and even the notion that telomerase is restricted to very few cell types has been questioned. These effects also seem to be important in carcinogenesis and might explain the tumor-promoting effects of telomerase independently of telomere elongation. Here, the current understanding of the extratelomeric roles of telomerase and their physiological and pathological significance is reviewed.

  • de Grey AD. Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging. Mech Ageing Dev 2007;128(7-8):456-9. PubMed: 17588643. Categories: OncoSENS

    Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging.

    Mech Ageing Dev 2007;128(7-8):456-9.

    Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging.

    de Grey AD.

    Abstract

    Abstract:

    Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage -- whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones -- has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer. However, its role in contributing to the rates of other aspects of aging is less clear. Here I argue that, in animals prone to cancer, evolutionary pressure to postpone cancer will drive the fidelity of nDNA maintenance and repair to a level greatly exceeding that needed to prevent nDNA damage from reaching levels during a normal lifetime that are pathogenic other than via cancer or, possibly, apoptosis resistance. I term this the "protagonistic pleiotropy of chromosomal damage" (PPCD) hypothesis, because this interaction of cancer-related and -unrelated damage is the converse of the well-known "antagonistic pleiotropy" phenomenon. I then consider a selection of recent data on the rate of accumulation of nDNA damage in the context of this hypothesis, and conclude that all presently available evidence is consistent with it. If this conclusion is correct, the implications for the feasibility of greatly postponing mammalian (and eventually human) aging and age-related pathology are far-reaching.

  • Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dolle ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 2006;441(7096):1011-1014. PubMed: 16791200. Categories: OncoSENS

    Increased cell-to-cell variation in gene expression in ageing mouse heart.

    Nature 2006;441(7096):1011-1014.

    Increased cell-to-cell variation in gene expression in ageing mouse heart.

    Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dolle ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J.

    Abstract

    Abstract:

    The accumulation of somatic DNA damage has been implicated as a cause of ageing in metazoa. One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice. To confirm that increased stochasticity of gene expression could be a result of increased genome damage, we treated mouse embryonic fibroblasts in culture with hydrogen peroxide. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at a lacZ reporter locus. These results underscore the stochastic nature of the ageing process, and could provide a mechanism for age-related cellular degeneration and death in tissues of multicellular organisms.

  • Somel M, Khaitovich P, Bahn S, Paabo S, Lachmann M. Gene expression becomes heterogeneous with age. Curr Biol 2006;16(10):R359-R360. PubMed: 16713941. Categories: OncoSENS

    Gene expression becomes heterogeneous with age.

    Curr Biol 2006;16(10):R359-R360.

    Gene expression becomes heterogeneous with age.

    Somel M, Khaitovich P, Bahn S, Paabo S, Lachmann M.

    Abstract

    Abstract:

    No abstract available.

  • Rubin H. What keeps cells in tissues behaving normally in the face of myriad mutations? BioEssays 2006;28(5):515-524. PubMed: 16615084. Categories: OncoSENS

    What keeps cells in tissues behaving normally in the face of myriad mutations?

    BioEssays 2006;28(5):515-524.

    What keeps cells in tissues behaving normally in the face of myriad mutations?

    Rubin H.

    Abstract

    Abstract:

    The use of a reporter gene in transgenic mice indicates that there are many local mutations and large genomic rearrangements per somatic cell that accumulate with age at different rates per organ and without visible effects. Dissociation of the cells for monolayer culture brings out great heterogeneity of size and loss of function among cells that presumably reflect genetic and epigenetic differences among the cells, but are masked in organized tissue. The regulatory power of a mass of contiguous normal cells is expressed in its capacity to normalize the appearance and growth behavior of solitary homophilic neoplastic cells, and to redirect differentiation of solitary heterophilic stem-like cells. Intimate contact between the interacting cells is required to induce these changes. The normalization of the neoplastic phenotype does not require gap junctional communication between cells, though transdifferentiation might. These varied relationships are manifestations of the unifying biological principle of "order in the large over heterogeneity in the small".

  • Dollé ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J. Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res 2006;596(1-2):22-35. PubMed: 16472827. Categories: OncoSENS

    Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice.

    Mutat Res 2006;596(1-2):22-35.

    Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice.

    Dollé ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J.

    Abstract

    Abstract:

    Genetic defects in nucleotide excision repair (NER) are associated with premature aging, including cancer, in both humans and mice. To investigate the possible role of increased somatic mutation accumulation in the accelerated appearance of symptoms of aging as a consequence of NER deficiency, we crossed four different mouse mutants, Xpa-/-, Ercc6(Csb)-/-, Ercc2(Xpd)m/m and Ercc1-/m, with mice harboring lacZ-reporter genes to assess mutant frequencies and spectra in different organs during aging. The results indicate an accelerated accumulation of mutations in both liver and kidney of Xpa defective mice, which correlated with a trend towards a decreased lifespan. Until 52 weeks, Xpa deficiency resulted mainly in 1-bp deletions. At old age (104 weeks), the spectrum had undergone a shift, in both organs, to G:C-->T:A transversions, a signature mutation of oxidative DNA damage. Ercc1-/m mice, with their short lifespan of 6 months and severe symptoms of premature aging, especially in liver and kidney, displayed an even faster lacZ-mutant accumulation in liver. In this case, the excess mutations were mostly genome rearrangements. Csb-/- mice, with mild premature aging features and no reduction in lifespan, and Xpdm/m mice, exhibiting prominent premature aging features and about 20% reduction in lifespan, did not have elevated lacZ-mutant frequencies. It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation.

  • Vulliamy TJ, Marrone A, Knight SW, Walne A, Mason PJ, Dokal I. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 2006;107(7):2680-2685. PubMed: 16332973. Categories: OncoSENS

    Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation.

    Blood 2006;107(7):2680-2685.

    Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation.

    Vulliamy TJ, Marrone A, Knight SW, Walne A, Mason PJ, Dokal I.

    Abstract

    Abstract:

    The two genes mutated in the bone marrow failure syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC.

  • Bielas JH, Loeb LA. Mutator phenotype in cancer: timing and perspectives. Environ Mol Mutagen 2005;45(2-3):206-213. PubMed: 15672382. Categories: OncoSENS

    Mutator phenotype in cancer: timing and perspectives.

    Environ Mol Mutagen 2005;45(2-3):206-213.

    Mutator phenotype in cancer: timing and perspectives.

    Bielas JH, Loeb LA.

    Abstract

    Abstract:

    Normal human cells replicate their DNA with exceptional accuracy. During every division cycle, each daughter cell receives a full and accurate complement of genetic information. It has been estimated that approximately one error occurs during DNA replication for each 10(9) to 10(10) nucleotides polymerized. Stem cells, the cells that are progenitors of cancer, may replicate their genes even more accurately. In contrast, the malignant cells that constitute a tumor are markedly heterogeneous and exhibit multiple chromosomal abnormalities and alterations in the nucleotide sequence of DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we initially hypothesized that during tumor progression, cancer cells must exhibit a mutator phenotype. In this perspective, we summarize the evidence supporting a mutator phenotype in human cancer, analyze recent measurements of mutations in human cancer, consider the timing for the expression of a mutator phenotype, and focus on the important consequences of large numbers of random mutations in human tumors.

  • de Grey ADNJ. Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention. Front Biosci 2005;10:2420-2429. PubMed: 15970505. Categories: OncoSENS

    Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention.

    Front Biosci 2005;10:2420-2429.

    Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention.

    de Grey ADNJ.

    Abstract

    Abstract:

    The intrinsic genetic instability of cancer cells makes age-related cancers more difficult to postpone or treat than any other age-related diseases. Any treatment that a cancer can resist by activating or inactivating specific genes is unlikely to succeed over the long term, because pre-existing cancer cells with the necessary gene expression pattern will withstand the therapy and proliferate. "Whole-body Interdiction of Lengthening of Telomeres" (WILT) is a proposal to pre-empt this problem by deleting from as many of our cells as possible the genes needed for telomere elongation. Cancers lacking these genes can never reach a life-threatening stage by altering gene expression, only by acquiring new genes, which is far more unlikely. Continuously-renewing tissues can be maintained by periodic reseeding with telomere elongation-incompetent stem cells that have had their telomeres lengthened in vitro with exogenous telomerase. Here, I describe why WILT might prove to be an exceptionally powerful anti-cancer modality.

  • Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005;102(30):10604-10609. PubMed: 16009939. Categories: OncoSENS

    Epigenetic differences arise during the lifetime of monozygotic twins.

    Proc Natl Acad Sci USA 2005;102(30):10604-10609.

    Epigenetic differences arise during the lifetime of monozygotic twins.

    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M.

    Abstract

    Abstract:

    Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype.

  • de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers. Ann N Y Acad Sci. 2004 Jun;1019:147-70. PubMed: 15247008. Categories: OncoSENS

    Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.

    Ann N Y Acad Sci. 2004 Jun;1019:147-70.

    Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.

    de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG.

    Abstract

    Abstract:

    Despite enormous effort, progress in reducing mortality from cancer remains modest. Can a true cancer "cure" ever be developed, given the vast versatility that tumors derive from their genomic instability? Here we consider the efficacy, feasibility, and safety of a therapy that, unlike any available or in development, could never be escaped by spontaneous changes of gene expression: the total elimination from the body of all genetic potential for telomere elongation, combined with stem cell therapies administered about once a decade to maintain proliferative tissues despite this handicap. We term this therapy WILT, for whole-body interdiction of lengthening of telomeres. We first argue that a whole-body gene-deletion approach, however bizarre it initially seems, is truly the only way to overcome the hypermutation that makes tumors so insidious. We then identify the key obstacles to developing such a therapy and conclude that, while some will probably be insurmountable for at least a decade, none is a clear-cut showstopper. Hence, given the absence of alternatives with comparable anticancer promise, we advocate working toward such a therapy.

  • Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004;36(5):447-449. PubMed: 15098033. Categories: OncoSENS

    Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.

    Nat Genet 2004;36(5):447-449.

    Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.

    Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I.

    Abstract

    Abstract:

    Telomerase is a ribonucleoprotein complex that is required to synthesize DNA repeats at the ends of each chromosome. The RNA component of this reverse transcriptase is mutated in the bone marrow failure syndrome autosomal dominant dyskeratosis congenita. Here we show that disease anticipation is observed in families with this disease and that this is associated with progressive telomere shortening.

  • Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429(6994):883-891. PubMed: 15190254. Categories: OncoSENS

    Gene regulation and DNA damage in the ageing human brain.

    Nature 2004;429(6994):883-891.

    Gene regulation and DNA damage in the ageing human brain.

    Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA.

    Abstract

    Abstract:

    The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.

  • Stelzner M, Hoagland VD, Woolman JD. Identification of optimal harvest sites of ileal stem cells for treatment of bile acid malabsorption in a dog model. J Gastrointest Surg 2003;7(4):516-522. PubMed: 12763409. Categories: OncoSENS

    Identification of optimal harvest sites of ileal stem cells for treatment of bile acid malabsorption in a dog model.

    J Gastrointest Surg 2003;7(4):516-522.

    Identification of optimal harvest sites of ileal stem cells for treatment of bile acid malabsorption in a dog model.

    Stelzner M, Hoagland VD, Woolman JD.

    Abstract

    Abstract:

    Ileal mucosal stem cells expressing the sodium-dependent ileal bile acid transporter (IBAT) have been successfully transplanted into the jejunum of rodents in projects aimed at creating a "neoileum" to treat bile acid malabsorption. To find optimal harvest sites for a dog model of stem cell transplantation, the exact location of peak IBAT expression in the donor ileum needs to be known. We therefore mapped IBAT function, IBAT mRNA, and IBAT protein in the ileum of Beagle dogs (N=3). Mucosal samples were taken every 5 cm in the ileum and every 20 cm in the jejunum of each dog. Sodium-dependent (active) and sodium-independent (passive) taurocholate uptake rates were measured using a standardized everted sleeve technique. IBAT mRNA concentrations were determined by semiquantitative reverse transcriptase-polymerase chain reaction and IBAT protein concentrations by fluorometric immunohistochemical analysis. The small bowel measured 208+/-17 cm (mean+/-standard error of the mean). Active and passive uptake rates were found to follow distinct distribution curves. Significant active uptake was seen only at the terminal 50 cm and peaked at 479+/-176 pM/mm(2). Depending on location, active uptake accounted for approximately half of the total uptake. IBAT mRNA and protein distributions corroborated uptake curves. The terminal 10 to 50 cm of ileum has the highest bile acid uptake capacity. This short segment appears to be the most promising donor site for ileal stem cell transplants to create a "neoileum" in dogs.

  • Bennett-Baker PE, Wilkowski J, Burke DT. Age-associated activation of epigenetically repressed genes in the mouse. Genetics 2003;165(4):2055-2062. PubMed: 14704185. Categories: OncoSENS

    Age-associated activation of epigenetically repressed genes in the mouse.

    Genetics 2003;165(4):2055-2062.

    Age-associated activation of epigenetically repressed genes in the mouse.

    Bennett-Baker PE, Wilkowski J, Burke DT.

    Abstract

    Abstract:

    Epigenetic control of gene expression is a consistent feature of differentiated mammalian cell types. Epigenetic expression patterns are mitotically heritable and are stably maintained in adult cells. However, unlike somatic DNA mutation, little is known about the occurrence of epigenetic change, or epimutation, during normal adult life. We have monitored the age-associated maintenance of two epigenetic systems--X inactivation and genomic imprinting--using the genes Atp7a and Igf2, respectively. Quantitative measurements of RNA transcripts from the inactive and active alleles were performed in mice from 2 to 24 months of age. For both genes, older animal cohorts showed reproducible increases in transcripts expressed from the silenced alleles. Loss of X chromosome silencing showed cohort mean increases of up to 2.2%, while imprinted-gene activation increased up to 6.7%. The results support the hypothesis that epigenetic loss of gene repression occurs in normal tissues and may be a contributing factor in progressive physiological dysfunction seen during mammalian aging. Quantitatively, the loss of epigenetic control may be one to two orders of magnitude greater than previously determined somatic DNA mutation.

  • Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM, Sakano Y, Paupard MC, Hall DH, Driscoll M. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 2002;419(6909):808-814. PubMed: 12397350. Categories: OncoSENS

    Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans.

    Nature 2002;419(6909):808-814.

    Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans.

    Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM, Sakano Y, Paupard MC, Hall DH, Driscoll M.

    Abstract

    Abstract:

    The nematode Caenorhabditis elegans is an important model for studying the genetics of ageing, with over 50 life-extension mutations known so far. However, little is known about the pathobiology of ageing in this species, limiting attempts to connect genotype with senescent phenotype. Using ultrastructural analysis and visualization of specific cell types with green fluorescent protein, we examined cell integrity in different tissues as the animal ages. We report remarkable preservation of the nervous system, even in advanced old age, in contrast to a gradual, progressive deterioration of muscle, resembling human sarcopenia. The age-1(hx546) mutation, which extends lifespan by 60-100%, delayed some, but not all, cellular biomarkers of ageing. Strikingly, we found strong evidence that stochastic as well as genetic factors are significant in C. elegans ageing, with extensive variability both among same-age animals and between cells of the same type within individuals.

  • Vijg J, Dollé ME. Large genome rearrangements as a primary cause of aging. Mech Ageing Dev 2002;123(8):907-915. PubMed: 12044939. Categories: OncoSENS

    Large genome rearrangements as a primary cause of aging.

    Mech Ageing Dev 2002;123(8):907-915.

    Large genome rearrangements as a primary cause of aging.

    Vijg J, Dollé ME.

    Abstract

    Abstract:

    In his introductory chapter of the Mutation Research special issue on 'Genetic Instability and Aging', the late Bernard Strehler provided some historical perspectives on the long-standing hypothesis that aging is primarily caused by changes in the genome of somatic cells (Strehler, 1995, Mutat. Res. 338 (1995) 3). Based on his own findings of a loss of ribosomal RNA gene copies in postmitotic tissues of dogs as well as humans during aging, his main conclusion was that deletional mutations are more likely than point mutations to be a main causal factor in aging. To directly assess the levels of different types of spontaneous mutations in organs and tissues during aging, we have used a mouse model harboring a chromosomally integrated cluster of lacZ-containing plasmids that can be recovered and analyzed in Escherichia coli. Our results indicate the accumulation of mutations in some but not all organs of the mouse with significant differences in mutational spectra. In addition to point mutations, genome rearrangements involving up to 66 Mb of genomic DNA appeared to be a major component of the mutational spectra. Physical characterization of the breakpoints of such rearrangements indicated their possible origin by erroneous, non-homologous DNA double-strand break repair. Based on their increased occurrence during aging in some tissues and their often very large size, we have designed a model for an aging tissue in terms of a cellular mosaic with a gradual increase in genome rearrangements that leads to functional senescence, neoplastic transformation or death of individual cells by disrupting nuclear architecture and patterns of gene regulation.

  • Dollé ME, Vijg J. Genome dynamics in aging mice. Genome Res 2002;12(11):1732-1738. PubMed: 12421760. Categories: OncoSENS

    Genome dynamics in aging mice.

    Genome Res 2002;12(11):1732-1738.

    Genome dynamics in aging mice.

    Dollé ME, Vijg J.

    Abstract

    Abstract:

    Random spontaneous genome rearrangements are difficult to detect in vivo, especially in postmitotic tissues. Using a lacZ-plasmid reporter mouse model, we have previously presented evidence for the accumulation of large genome rearrangements in various tissues, including postmitotic tissues, during aging. These rearrangements, which were found to be organ-specific and to increase with age, have one breakpoint in the lacZ-reporter locus and the second elsewhere in the mouse genome. In this present work, we have used a mouse genome sequence database to physically characterize a total of 49 genome rearrangements in the brain, heart, and liver from young and old mice at two lacZ-plasmid reporter loci. Half of all breakpoints in the mouse genome occurred in chromosomes 3 and 4, each carrying a lacZ-reporter cluster, at distances varying from <100 kb to 66 Mb, indicating intrachromosomal deletions or inversions. The other half of the breakpoints in the mouse genome was found randomly on any of the other chromosomes, indicating translocations. Alternatively, part of the intra- and extrachromosomal events could involve transpositions. Regions of extended homology were not found at the breakpoints. These results lead us to postulate potential mechanisms for the origin of large genome rearrangements in mouse tissues and to predict their possible impact as a potential cause of aging.

  • Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 2001;28(2):155-159. PubMed: 11381263. Categories: OncoSENS

    Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.

    Nat Genet 2001;28(2):155-159.

    Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.

    Rudolph KL, Millard M, Bosenberg MW, DePinho RA.

    Abstract

    Abstract:

    Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. We therefore sought to determine whether telomere dysfunction exerts differential effects on cancer initiation versus progression of mouse and human intestinal neoplasia. In successive generations of ApcMin Terc-/- mice, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas. That telomere dysfunction also contributes to human colorectal carcinogenesis is supported by the appearance of anaphase bridges (a correlate of telomere dysfunction) at the adenoma-early carcinoma transition, a transition recognized for marked chromosomal instability. Together, these data are consistent with a model in which telomere dysfunction promotes the chromosomal instability that drives early carcinogenesis, while telomerase activation restores genomic stability to a level permissive for tumor progression. We propose that early and transient telomere dysfunction is a major mechanism underlying chromosomal instability of human cancer.

  • Gonzalez-Suarez E, Samper E, Flores JM, Blasco MA. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet 2000;26(1):114-117. PubMed: 10973262. Categories: OncoSENS

    Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis.

    Nat Genet 2000;26(1):114-117.

    Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis.

    Gonzalez-Suarez E, Samper E, Flores JM, Blasco MA.

    Abstract

    Abstract:

    Inhibition of telomerase is proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumour growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumour therapy, as its inhibition is unlikely to have toxic effects. Mice deficient for Terc RNA (encoding telomerase) lack telomerase activity, and constitute a model for evaluating the role of telomerase and telomeres in tumourigenesis. Late-generation Terc-/- mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas). The appearance of these tumours is thought to be a consequence of chromosomal instability in these mice. These observations have challenged the expected effectiveness of anti-telomerase-based cancer therapies. Different cell types may nonetheless vary in their sensitivity to the chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms. Here we show that late-generation Terc-/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumour development in multi-stage skin carcinogenesis. Our results predict that an anti-telomerase-based tumour therapy may be effective in epithelial tumours.

  • Trosko JE, Ruch RJ. Cell-cell communication in carcinogenesis. Front Biosci 1998;3:d208-d236. PubMed: 9458335. Categories: OncoSENS

    Cell-cell communication in carcinogenesis.

    Front Biosci 1998;3:d208-d236.

    Cell-cell communication in carcinogenesis.

    Trosko JE, Ruch RJ.

    Abstract

    Abstract:

    To explain the complex carcinogenic process by which a single normal cell in human beings can be converted to an invasive and metastatic cancer cell, a number of experimental findings, epidemiological observations and their associated hypothesis/theories have been integrated in this review. All cancers have been generally viewed as the result of a disruption of the homeostatic regulation of a cell's ability to respond appropriately to extra-cellular signals of the body which trigger intra-cellular signal transducting mechanisms which modulate gap junctional intercellular communication between the cells within a tissue. Normal homeostatic control of these three forms of cell communication determines whether: (a) the cell remains quiescent (Go); (b) enters into the cell proliferation phase; (c) is induced to differentiate; (d) is committed to apoptose; or (e) if it is already differentiated, it can adaptively respond. During the evolution from single cell organisms to multicellular organisms, new cellular/biological functions appeared, namely, the control of cell proliferation ("contact inhibition"), the appearance of the process of differentiation from committed stem cells of the various tissues and the need for programmed cell death or apoptosis. Interestingly, cancer cells have been characterized as cells: (a) having been derived from a stem-like cell; (b) without their ability to control cell growth or without the ability to contact inhibit; (c) which can not terminally differentiate under normal conditions; and (d) having altered ability to apoptosis under normal conditions. During that evolutionary transition from the single cell organism to the multicellular organism, many new genes appeared to accompany these new cellular functions. One of these new genes was the gene coding for a membrane associated protein channel (the gap junction) which between coupled cells, allowed the passive transfer on ions and small molecular weight molecules. A family of over a dozen of these highly evolutionarily-conserved genes (the connexin genes) coded for the connexin proteins. A hexameric unit of these connexins in one cell (a connexon) couples with a corresponding connexon in a contiguous cell to join the cytoplasms. This serves to synchronize either the metabolic or electrotonic functions of cells within a tissue. Most normal cells within solid tissues have functional gap junctional intercellular communication (GJIC) (exceptions are free-standing cells such as red blood cells, neutrophils, and several, if not all, the stem cells). On the other hand, the cancer cells of solid tissues appear to have either dysfunctional homologous or heterologous GJIC. Therefore, among the many differences between a cancer cell and its normal parental cell, the carcinogenic process involves the transition from a normal, GJIC-competent cell to one that is defective in GJIC. The review examines how GJIC can be either transiently or stably modulated by endogenous or exogenesis chemicals or by oncogenes and tumor suppressor genes at the transcriptional, translational, or posttranslational levels. It also uses the gap junction as the biological structure to facilitate cellular/tissue homeostasis to be the integrator for the "stem cell" theory, "disease of differentiation theory", "initiation/promotion/progression" concepts, nature and nurture concept of carcinogenesis, the mutation/ epigenetic theories of carcinogenesis, and the oncogene/ tumor suppressor gene theories of carcinogenesis. From this background, implications to cancer prevention and cancer therapy are generated.

  • Dollé ME, Giese H, Hopkins CL, Martus HJ, Hausdorff JM, Vijg J. Rapid accumulation of genome rearrangements in liver but not in brain of old mice. Nat Genet 1997;17(4):431-434. PubMed: 9398844. Categories: OncoSENS

    Rapid accumulation of genome rearrangements in liver but not in brain of old mice.

    Nat Genet 1997;17(4):431-434.

    Rapid accumulation of genome rearrangements in liver but not in brain of old mice.

    Dollé ME, Giese H, Hopkins CL, Martus HJ, Hausdorff JM, Vijg J.

    Abstract

    Abstract:

    Somatic mutations have long been considered a possible cause of ageing. To directly study mutational events in organs and tissues of ageing mammals, a transgenic mouse model has been generated that harbours lacZ reporter genes as part of chromosomally integrated plasmids. Using this model, we determined spontaneous mutant frequencies and spectra in mouse liver and brain as a function of age. In the liver, mutant frequencies increased with age from birth to 34 months; in the brain, an increase was observed only between birth and 4-6 months. Molecular characterization of the mutations showed that a substantial portion involved genome rearrangement events, with one breakpoint in a reporter gene and the other in the mouse flanking sequence. In the liver, these genome rearrangements did not increase with age until after 27 months, when they increased rapidly. In brain, the frequency of genome rearrangements was lower than in liver and did not increase with age.