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Age-association of cancer and aneuploidy syndromes. (A) Age is the most prevalent risk factor for cancer. Cancer incidence rates increase steadily with advancing age (source: SEER1992-2002). Most intriguingly, there is an exponential growth in incidence rates leading to an explosion in absolute numbers of newly diagnosed cancers beyond the age of 40 (in both sexes). (B) Incidence rates of trisomic pregnancies (aneuploidy syndromes, e.g. Morbus Down) increase exponentially starting at maternal age of 35 (data taken from Ref. [129]), known as the maternal-age effect. The similarity between both incidences is striking. By definition, aneuploidy syndromes are caused by chromosomal imbalance and it has been shown that the majority of oocytes in women aged 40 years or older are aneuploid [129– 131]. I propose a similar age-association of aneuploidy in tissue stem cells.  

Age-association of cancer and aneuploidy syndromes. (A) Age is the most prevalent risk factor for cancer. Cancer incidence rates increase steadily with advancing age (source: SEER1992-2002). Most intriguingly, there is an exponential growth in incidence rates leading to an explosion in absolute numbers of newly diagnosed cancers beyond the age of 40 (in both sexes). (B) Incidence rates of trisomic pregnancies (aneuploidy syndromes, e.g. Morbus Down) increase exponentially starting at maternal age of 35 (data taken from Ref. [129]), known as the maternal-age effect. The similarity between both incidences is striking. By definition, aneuploidy syndromes are caused by chromosomal imbalance and it has been shown that the majority of oocytes in women aged 40 years or older are aneuploid [129– 131]. I propose a similar age-association of aneuploidy in tissue stem cells.  

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Recently, an influential sequencing study found that more than 1700 genes had non-silent mutations in either a breast or colorectal cancer, out of just 11 breast and 11 colorectal tumor samples. This is not surprising given the fact that genomic instability is the hallmark of cancer cells. The plethora of genomic alterations found in every carcinom...

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... In humans, every second male and every third female develops cancer during their lifetime (Stindl 2008), but no naturally transmissible cancer cell line has been found, in more than 100 years of extensive medical research. Modern biological science must be based on logic, probability and reproducible experimental data, and must not be influenced by dominant global trends. ...
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The currently prevailing theory of a transmissible cancer cell lineage in Tasmanian devils was based on the discovery of apparently identical chromosomal aberrations in facial tumors of several animals. New findings of facial tumors that have no detectable cytogenetic similarities to previously published cancer karyotypes and the recent detection of varying portions of chromosome Y in all tumor cell lines of male devils (but none in tumors of females) cast doubt on the theory of a cancer transplant. Thus, I propose an alternative scenario in which similar chromosomal and genetic aberrations in individual cancers are a consequence of the low genetic diversity in populations of the Tasmanian devil resulting in a unique telomere length profile. Critically short telomeres on certain chromosome ends lead to chromosome-specific fusions and the activation of species-specific transposable elements that cause the observed karyotypic and molecular convergence. This new concept can explain the existence of genetic signs of tumor clonality within a population despite the independent origin of each facial cancer in these cancer-prone animals.
... It is a long-standing debate whether telomerase is reactivated during tumor progression or if tumors initiate from telomerase-positive stem cells [69][70][71][72][73][74][75][76][77][78]. The telomerase reactivation concept is based on two early observations: (i) Telomerase activity is detectable in human tumors and transformed cells but not in most primary human cells, e.g., normal human fibroblasts or embryonic kidney cells [19,79,80]; (ii) in the absence of telomerase, telomere shortening coincides with the induction of the 'cellular senescence' phenotype in cells with functional checkpoints [81,82]. ...
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High telomerase activity is detected in nearly all human cancers but most human cells are devoid of telomerase activity. There is well-documented evidence that reactivation of telomerase occurs during cellular transformation. In humans, tumors can rely in reactivation of telomerase or originate in a telomerase positive stem/progenitor cell, or rely in alternative lengthening of telomeres, a telomerase-independent telomere-length maintenance mechanism. In this review, we will focus on the telomerase positive tumors. In this context, the recent findings that telomerase reverse transcriptase (TERT) promoter mutations represent the most common non-coding mutations in human cancer have flared up the long-standing discussion whether cancer originates from telomerase positive stem cells or telomerase reactivation is a final step in cellular transformation. Here, we will discuss the pros and cons of both concepts in the context of telomere length-dependent and telomere length-independent functions of telomerase. Together, these observations may provoke a re-evaluation of telomere and telomerase based therapies, both in telomerase inhibition for cancer therapy and telomerase activation for tissue regeneration and anti-ageing strategies.
... The reversal of telomere dynamics in both sexes occurs in participants aged ࣙ80 years. Most interestingly, in cross-sectional cancer data sets from the U.S. National Cancer Institute, after a sharp rise starting at middle age, cancer incidence patterns also reverse in participants aged ࣙ80 years (Stindl, 2008). (Replicative telomere erosion in somatic tissues during aging is causally involved in the genesis of carcinoma (Stindl, 2008) and other age-associated diseases.) ...
... Most interestingly, in cross-sectional cancer data sets from the U.S. National Cancer Institute, after a sharp rise starting at middle age, cancer incidence patterns also reverse in participants aged ࣙ80 years (Stindl, 2008). (Replicative telomere erosion in somatic tissues during aging is causally involved in the genesis of carcinoma (Stindl, 2008) and other age-associated diseases.) ...
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Correspondence re: Lapham K, Kvale MN, Lin J, et al. 2015. Automated assay of telomere length measurement and informatics for 100,000 subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics 200: 1061–1072.
... The aneuploidy theory -the oldest theory of cancer, fi rst hypothesized by Theodor Boveri more than 100 years ago - posits that any spontaneous or exogenously induced occur- rence of an unbalanced number of chromosomes (i.e., aneu- ploidy) precipitates an autocatalytic cascade that increases the extent of aneuploidy in each aff ected cell progressively, leading inevitably to eventual genomic instability and onco- genic transformation (see, e.g., Duesberg et al. 1998, Stindl 2008. Aneuploidy arises when chromosomes missegregate (i.e., fail to segregate in a numerically balanced way), either during germ-cell division (i.e., via chromosome nondisjunc- tion during the anaphase of meiosis) or during somatic-cell division (i.e., via chromosome nondisjunction or loss during mitosis). ...
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A 1999 California state agency cancer potency (CP) evaluation of methyl tert-butyl ether (MTBE) assumed linear risk extrapolations from tumor data were plausible because of limited evidence that MTBE or its metabolites could damage DNA, and based such extrapolations on data from rat gavage and rat and mouse inhalation studies indicating elevated tumor rates in male rat kidney, male rat Leydig interstitial cells, and female rat leukemia/lymphomas. More recent data bearing on MTBE cancer potency include a rodent cancer bioassay of MTBE in drinking water; several new studies of MTBE genotoxicity; several similar evaluations of MTBE metabolites, formaldehyde, and tert-butyl alcohol or TBA; and updated evaluations of carcinogenic mode(s) of action (MOAs) of MTBE and MTBE metabolite's. The lymphoma/leukemia data used in the California assessment were recently declared unreliable by the U.S. Environmental Protection Agency (EPA). Updated characterizations of MTBE CP, and its uncertainty, are currently needed to address a variety of decision goals concerning historical and current MTBE contamination. To this end, an extensive review of data sets bearing on MTBE and metabolite genotoxicity, cytotoxicity, and tumorigenicity was applied to reassess MTBE CP and related uncertainty in view of MOA considerations. Adopting the traditional approach that cytotoxicity-driven cancer MOAs are inoperative at very low, non-cytotoxic dose levels, it was determined that MTBE most likely does not increase cancer risk unless chronic exposures induce target-tissue toxicity, including in sensitive individuals. However, the corresponding expected (or plausible upper bound) CP for MTBE conditional on a hypothetical linear (e.g., genotoxic) MOA was estimated to be ∼2 × 10-5 (or 0.003) per mg MTBE per kg body weight per day for adults exposed chronically over a lifetime. Based on this conservative estimate of CP, if MTBE is carcinogenic to humans, it is among the weakest 10% of chemical carcinogens evaluated by EPA.
... Confusing cause with effect: the correlation of chromosome Y loss in older men with elevated cancer and mortality risk I therefore suggest that the authors rethink their hypotheses and include telomere erosion as the underlying cause of both phenomena. Accordingly, the observed chromosome Y loss would simply be a biological marker for relatively short telomeres in the somatic tissues of a male individual, which in turn increases the risk for chromosomal instability and subsequently cancer (Stindl 2008). Hence, a reinvestigation of the blood samples with a focus on mean telomere length, using the southern blot technique (Elbers et al. 2014), is highly recommended. ...
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Correspondence re: Forsberg, L. A., et al. 2014. "Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer." Nat Genet 46 (6):624-8. doi: 10.1038/ng.2966.
... (a) According to the recent literature, the enzyme telomerase seems incapable of elongating telomeres to the extent required for the new model. The main function of telomerase has been shown to be one of a stabilizer of telomere length in germ, embryonic and cancer cells (Stindl 2008). In my view, the most promising candidate is a mechanism called alternative lengthening of telomeres (ALT), which has been found in a subset of tumors and tumor-derived cell lines to significantly extend telomeres by >50 kb. ...
... These immune cells show complex patterns of migration and replenishment, which are influenced by various factors (e.g., stress) and might, therefore, not provide a reliable picture of the telomere reserve of an individual. The other shortcoming is the widespread ignorance of the mechanisms of somatic tissue regeneration by adult stem cells (Stindl 2008). Consequently, I suggest that telomere length and the available number of adult tissue stem cells in a given species might be the determining factors of lifespan, regeneration capacity of tissues and aging. ...
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Charles Darwin knew that the fossil record is not overwhelmingly supportive of genetic and phenotypic gradualism; therefore, he developed the core of his theory on the basis of breeding experiments. Here, I present evidence for the existence of a cell biological mechanism that strongly points to the almost forgotten European concept of saltatory evolution of nonadaptive characters, which is in perfect agreement with the gaps in the fossil record. The standard model of chromosomal evolution has always been handicapped by a paradox, namely, how speciation can occur by spontaneous chromosomal rearrangements that are known to decrease the fertility of heterozygotes in a population. However, the hallmark of almost all closely related species is a differing chromosome complement and therefore chromosomal rearrangements seem to be crucial for speciation. Telomeres, the caps of eukaryotic chromosomes, erode in somatic tissues during life, but have been thought to remain stable in the germline of a species. Recently, a large human study spanning three healthy generations clearly found a cumulative telomere effect, which is indicative of transgenerational telomere erosion in the human species. The telomeric sync model of speciation presented here is based on telomere erosion between generations, which leads to identical fusions of chromosomes and triggers a transposon-mediated genomic repatterning in the germline of many individuals of a species. The phenotypic outcome of the telomere-triggered transposon activity is the saltatory appearance of nonadaptive characters simultaneously in many individuals. Transgenerational telomere erosion is therefore the material basis of aging at the species level.
... The AGI theory explains that all these phenomena arise by exceeding an as-yet-poorly-defined threshold of preneoplastic aneuploidy, which can be induced either by environmental exposure(s) to clastogenic agents, or by replicative telomere erosion leading to stem-cell exhaustion and telomere crisis, or both. Exceeding this aneuploidy threshold is posited to induce an autocatalytic ''Viennese Cascade'' process of karyotype evolution observed as ''genetic instability'', lasting years to decades [94,97,103] . This process is posited ultimately to yield the malignant/cancer phenotype by stochastic, Darwinian accumulation of activated sets of otherwise inactive or recessive genes, which normally control phenotypic repertoires reserved for embryonic morphogenesis and wound healing, but become activated or dominant via chromosome imbalance and associated aberrant DNA methylation [92,103]. ...
... Exceeding this aneuploidy threshold is posited to induce an autocatalytic ''Viennese Cascade'' process of karyotype evolution observed as ''genetic instability'', lasting years to decades [94,97,103] . This process is posited ultimately to yield the malignant/cancer phenotype by stochastic, Darwinian accumulation of activated sets of otherwise inactive or recessive genes, which normally control phenotypic repertoires reserved for embryonic morphogenesis and wound healing, but become activated or dominant via chromosome imbalance and associated aberrant DNA methylation [92,103]. The AGI theory is supported indirectly by the strong correlation between aneuploidy and subsequent genomic instability, and by the plausibility of a relatively simple underlying mechanism [90,99,104]. ...
... Even if it is assumed that aneuploidy, which has the strongest correlation to malignant tumorigenesis (Duesberg et al. 2006), is the necessary condition for cancer development, there still is no consensus over how the process of progressing aneuploidy is started. One idea is that an unspecific aneuploidy is introduced 'either by carcinogens or spontaneously' ( Duesberg et al. 2006), whereas there are others suggesting that somatic mutation (Pihan and Doxsey 2003; Schneider and Kulesz-Martin 2004; Michor et al. 2005; Li and Zhang 2009), telomere dysfunction (Chadeneau et al. 1995; Artandi et al. 2000; Stewénius et al. 2005; Stindl 2008), or centrosome amplification (Fukasawa et al. 1996; Lingle et al. 1998; Mayer et al. 2003; Basto et al. 2008; Castellanos et al. 2008) starts aneuploidy. Regardless of which mechanism exactly is regarded to lead to aneuploidy, many authors agree that there is some sort of malfunction in chromosomal distribution during mitosis, as described by Hansemann and Boveri already about a 100 years ago. ...
... The ''phenotype instability,'' where cancer cells can switch their phenotypes in response to microenvironmental cues, has been described in detail for melanoma by Hoek and Goding in 2010 (85). Both genetic and epigenetic (86) alterations can be responsible for the different phenotypes of otherwise histologically identical cancer types (87). Lambert et al. reported a continuous change of the hematopoietic stem cell phenotype over time, while progressing through the cell cycle (88). ...
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In recent years, a special type of cancer cell--the cancer stem cell (CSC)--has been identified and characterized for different tumors. CSCs may be responsible for the recurrence of a tumor following a primarily successful therapy and are thought to bear a high metastatic potential. For the development of efficient treatment strategies, the establishment of reliable methods for the identification and effective isolation of CSCs is imperative. Similar to their stem cell counterparts in bone marrow or small intestine, different cluster of differentiation surface antigens have been characterized, thus enabling researchers to identify them within the tumor bulk and to determine their degree of differentiation. In addition, functional properties characteristic of stem cells can be measured. Side population analysis is based on the stem cell-specific activity of certain ATP-binding cassette transporter proteins, which are able to transport fluorescent dyes out of the cells. Furthermore, the stem cell-specific presence of aldehyde dehydrogenase isoform 1 can be used for CSC labeling. However, the flow cytometric analysis of these CSC functional features requires specific technical adjustments. This review focuses on the principles and strategies of the flow cytometric analysis of CSCs and provides an overview of current protocols as well as technical requirements and pitfalls. A special focus is set on side population analysis and analysis of ALDH activity. Flow cytometry-based sorting principles and future flow cytometric applications for CSC analysis are also discussed.
... Major advances in the development of in vitro and in vivo assays have enabled identification and characterization of many types of adult stem cells as well as functional evaluation of the tumorigenic effects of cancer-related genetic alterations in these populations of stem cells (Stindl, 2008). In addition, the discovery of the Philadelphia chromosome by Newell and Hungerford has had far-reaching implications in our understanding of the genetic basis and the stem cell origin of some types of cancer (Nowell and Hungerford, 1960). ...
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The tumor predisposition disorder neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system. It is caused by mutations in the Nf1 tumor-suppressor gene, which encodes a GTPase-activating protein (GAP) that negatively regulates p21-RAS. Development of malignant nerve tumors and neurofibromas occurs frequently in NF1. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, or the identity of the specific cell type that gives rise to dermal or cutaneous neurofibromas. In this study, we identify a population of stem/progenitor cells residing in the dermis termed skin-derived precursors (SKPs) that, through loss of Nf1, form neurofibromas. We propose that SKPs, or their derivatives, are the cell of origin of dermal neurofibroma. We also provide evidence that additional signals from nonneoplastic cells in the tumor microenvironment play essential roles in neurofibromagenesis.