Review articles

By Dr. Alketa Bakiri , Dr. Ervin Mingomataj
Corresponding Author Dr. Ervin Mingomataj
Dept. of Allergology & Clinical Immunology, Mother Theresa School of Medicine, Rruga M. Shyri, P. 47,Apt. 15, Tirana - Albania
Submitting Author Dr. Ervin Mingomataj
Other Authors Dr. Alketa Bakiri
Hygeia Hospital Tirana, - Albania


Endogenous retroviruses, Epigenetic mechanisms, Maternal immunosupression, Spontaneous neoplasia, Telomerase dysfunction, Trophoblast implantation

Bakiri A, Mingomataj E. Spontaneous Neoplasia: A Destiny of Viviparous Mammal. WebmedCentral CANCER 2013;4(2):WMC004073
doi: 10.9754/journal.wmc.2013.004073

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Click here
Submitted on: 25 Feb 2013 10:34:34 PM GMT
Published on: 27 Feb 2013 01:34:19 PM GMT


True cancers are more frequent among vertebrates, including viviparous mammals. The most evidenced risk factor for these pathologies among vertebrates seems to be retroviral infections. A part of their genome is incorporated mainly in mammalians as endogenous retroviruses (ERVs). This parasitic genome is vital for viviparous mammals, because functional ERVs are essential host system for transient immune suppression and tolerance of “foreign” embryo at the stage of trophoblast implantation. After that, the ERVs genome gets imprinted due to epigenetic mechanisms. In aging mammals, the ERVs genome could be epigenetically reactivated as an attempt to bypass the replicative cell senescence, leading also to the potential development of neoplasia. These facts may lead to the suggestion that ERVs genome is an evident risk factor per se in the development of spontaneous cancers among mammals. Generally, the development of cancer-like disorders among other phyla needs the stimulant effect of strong pollutants and the development of true cancer among other vertebrata needs the retroviral infections. In contrast to them, viviparous mammals contain the ERVs in their genome and therefore may develop the neoplasia even in absence of environmental oncogenic agents. This suggests that artificial exclusion of carcinogenic genome could be fatal for the viviparous mammalian self or at least for its natural reproduction, as long as ERVs genome is essential for transient immune suppression and tolerance of “foreign” mammalian embryo.

Neoplasia in Animal Kingdom

“To be or not to be (... active): This is the question!” Shakespeare

Neoplasia disorders result from abnormal, uncontrolled proliferation of genetically altered cells that invade and destroy adjacent tissues [1]. The genetic abnormalities (e.g., mutation, translocation, etc) of transformed or tumor cells could be caused by physical (e.g., radiation), chemical (e.g., carcinogens) or infectious (e.g., oncoviral) agents. Different studies have demonstrated that neoplasia is widespread in the whole animal kingdom from sponges to human, but only in the vertebrate subphylum there is abundant evidence of a large variety of malignancies associated with metastasis [1]. The causes for many of tumors in vertebrates are often unclear, but oncoviral infections appear to be involved in several cases. This involvement is reported in various jawed vertebrates such as bony fishes [2-12], different amphibians [13-22], reptiles [23-26], as well as endothermic vertebrates (birds and mammals) [27-30]. In mammals these pathologies are more abundant and better characterized, and in some of them are developed various models of aggressive multi-organ spontaneous metastasis [1,31,32].

Meanwhile, evidence suggests that both the frequency and the diversity of types of neoplasia in invertebrates are less than in vertebrates [1]. In both marine and fresh water invertebrates, the major factors for neoplastic disease appear to be environmental stressors (e.g., pollutants), whereas there is little to no evidence of virally-induced tumors. This includes different phyla such as freshwater and marine sponges [1], chordates [33,34], nematodes [35,36], mollusks [37-41], various classes of arthropods (insects and crustaceans) [42-47], or deuterostomes [48-51]. However, similar tumor-like mass of cells frequently occur within echinoderm tissues and can also correspond to unwanted material, mostly degenerating ceolomocytes [49]. This indicates that multiple examples of neoplastic diseases in diverse invertebrates exist, but definitive evidence in this group of spontaneous metastasis such as a clear invasion of multiple tissues by tumor cells is rare [1].

Oncogenic Retroviruses and the Mammalian Reproduction

As already mentioned, neoplasia has been reported far more frequently in vertebrates, while a potentially more fundamentally important difference in neoplastic diseases between invertebrates and vertebrates is metastasis or real malignancy [1]. In general, the malignancies in vertebrates are caused by oncoviruses, especially retroviruses. Retroviruses are viruses that have RNA as their genome but make DNA copies of it in the infected cell [52]. Some retroviruses are known to transduce tumor genes into the new host, which, while promoting the proliferation of the infected cell, often bring disaster to the organism [53,54].

Retroviruses that are not normally present in healthy hosts are called exogenous viruses, while DNA sequences in cellular genomes that are homologous to retroviruses are called endogenous retroviruses (ERVs). Retroviruses are allowed to insert multiple copies of proviruses into different sites of the same host genome. Integration of proviruses into the host’s germline cells will result in inherited retroviruses [55]. Notably, the genomes of all vertebrates and especially viviparous mammalians harbor multiple copies of ERVs. Thus, mammalian genomes contain a heavy load (42% in humans) of retroelements, and elements of retroviral origin (ERVs) constitute about 8% of the human genome - a proportion much larger than the sum of all single-copy genes [56-61]. These elements are most probably the proviral remnants of ancestral germ-line infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner [61].

Retroelements including ERVs are normally suppressed from expression or transposition by extensive DNA methylation, RNA interference, heterochromatin formation, etc., to maintain genomic stability of the cell [52-54]. A part of ERV genomes are considered as long terminal repeat (LTR) retrotransposons (e.g., Ty elements), in contrast to non-LTR retrotransposons, like LINE and SINE [58,59,62]. An ERV provirus consists of the typical retroviral coding regions: gag-pro-pol-env, flanked by 5’ and 3’ LTR [57,61]. The genomic stability is enabled due to presence of many regulatory sequences, such as promoters, enhancers, polyadenylation signals and factor-binding sites in the LTRs [57,63]. To date 31 distinct groups and over 100 different ERV families have been found integrated throughout the human chromosomes and represent different copy numbers [59,64].

Some of these genetic elements are expressed at certain stages of the host’s lifetime to the benefit of the host [65-67]. Thus, some env genes are expressed in normal tissues and associated with positive and beneficial physiological functions, such as placentogenesis [68-71]. After binding to cellular receptors they are responsible for cell-cell fusions, like fusions of human placental villous trophoblasts into a multinucleated syncytiotrophoblast responsible for gas and nutrient exchange [69,71]. To date, three ERV-env genes, Syncytin-1, ERV-FRD (Syncytin-2) and env-Pb (or Syncytin-3) have been demonstrated as promoting cell-cell fusions in vitro [60,69,70,72-75]. While this effect is demonstrated in different mammalians, human ERVs (HERVs) are shown to have also immunosuppressive properties [70,76-78]. An additional role is mammalian tissue organization: many of ERV genes are expressed during genome-wide DNA demethylation in gametogenesis and embryonic development. These functions are important for reproduction, while complex interplay between retroelements and gene silencing mechanisms suggests ERVs are integral parts of the genome [54,66,79,80].

It has been suggested that all mammals express ERVs in extraembryonal tissue during trophoblast implantation in order to suppress the local initiation of recognition by the mother’s immune system and allow the growth of the embryo. Because they give birth to live young and their semiallogeneic embryos have no protective rapidly expressed eggshell such as that of birds, all members of the class Mammalia will absolutely require embry­onic and placental ERVs to prevent the initiation of a maternal anti-embryo immune reaction [65,66]. These ERVs, which would be essential for all placental orders, are proposed to be the normal host system for inhibition of the induction of a mother’s embryonic immune recognition. Called syncytins, they also enable embryonal fusion during human trophoblast development [66,79-83]. However, the ERVs are not proposed to control most normal host development or immune cell differentiation but rather are thought to specifically and transiently repress the local development of maternal immune recognition of an embryo [65,84].

The different amount of repeated ERV genes may explain the general tendency of genomes of higher organisms to evolve an ever decreasing gene density with higher order. For example, E. Coli has a ERV gene density of about 2 Kb per gene, Drosophila 4 Kb per gene and mammalian about 30 Kb per gene [65,85]. They are found in most organisms prior to mammalian radiation, but the levels of these genomic agents are relatively low in non-mammals. The increased ERV level in the genome of viviparous mammals is vital for their development in trophoblast stage. The ERVs suppress mother’s immunity in order to provide tolerance for the paternal part of “foreign” embryo [86].  

Taken together, on the first hand vertebrates (including mammals) are frequently-affected from malignant neoplasia compared to other phyla and the most evidenced risk factor is retroviral infection(s). On the other hand, mammals (especially viviparous ones) have in their genome integrated ERVs, which enable the suppression of mother’s immunity from the paternal part of embryo.

Retroviral Genome and Spontaneous Development of Neoplasia in Mammals

The essential role for embryonal ERV genome is the suppression of maternal immunity in order to facilitate its implanting, but in a further life stage a proposed role for the ERV genome is that its reactivation may lead to the development of ERVs-induced malignancies. Thus, the embryonal full immunosupression through an ERV involves many viral genes (such as env and gag), which are reported to be active during development of carcinoma pathologies [65]. For example, the HERV-K sequence of the human teratocarcinoma-derived virus type is reported to be able to make retrovirus like particle and can express gag, pol and env genes [84]. ERV-3 can express env gene in human embryonal placenta, while some HERVs (such as the feline RD1-14, ERV-3, and HERV K10+) are expressed in mammary tumors as well as in placental tissues [87]. Different env genes had a high cDNA expression in endometrial carcinoma (e.g. envH1-3, Syncytin-1, envT, envFc2, ERV-3, Syncytin-2, and envV2) [57]. Regarding tumor parameters, Syncytin-1 and Syncytin-2 were significantly over-expressed in advanced stage pT2 compared to pT1b, suggesting for a prognostic role. In less differentiated endometrial carcinoma, glandular epithelial cells of polyps and hyperplasia Syncytin-1, Syncytin-2, ERV-3, envT or envFc2 were also significantly over-expressed [57]. Additional significantly over-expressed ERV-env genes in endometrial carcinoma and endometrial prestages, like envE and envK have also been identified in a variety of tissues and specific carcinomas [68,88-93]. Strong envK protein expression co-localized to epithelial breast tumor cells and correlated with ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastasis [92,94]. Syncytin-1, Syncytin-2 and Syncytin-3 were proven to be cell fusogenic using ex-vivo assays, and Syncytin-2 also to be immunosuppressive [72,75]. Different authors also have reported about the immunosuppressive and prognostic role of HERVs, associated with increased promoter activity for LTRs [76,95,96].

Such reports may explain the findings of numerous early observations of being able to find viral particles in human tissues, and their association with embryonal and carcinoma development [52,55,56,65,84,87]. In complex, these data support the idea that, apart from beneficiary and essential effect in the suppression of the immune response of the viviparous mammalian mother to the embryo, the genomic retrovirus seems to be a potential risk factor for the development of tumoral disorders. Thus, expression of intercysternal A-type particles (IAPs, a family of ERVs), although normally highly repressed after early embryonal stages, is often observed in various tumor tissues [87]. If these ERVs are a normal host system of immune modulation, it could be expected that tumors would select for the expression of immuno-modulatory ERV or ERV gene products (such as immunosuppressive domain p15E) in order to avoid immunosurveillance. This is observed in different cancers, which affect human breast, urinary, and reproductive systems [97]. These findings are similar to functional analyses showing that 10 different env genes were regulated by methylation in endometrial carcinoma using the RL95-2 cell line. [57]. Under effect of immunosuppressive ERVs, some testicular derived teratocarcinoma cells can differentiate from embryonal stem cells (ES) into several cell types (which characterize parietal trophoectoderm or the 3.5 day blastocyst) [65]. The significant reduction of IAPs levels in differentiated embryonal carcinoma cells (EC) indicates that IAPs expression is tightly linked to DNA methylation, while the switch in gene expression was correlated with efficient de novo methylase activity in pluripotent cells [98,99]. The results obtained in an experimental system established that both EC and pre-implantation mouse embryos are non-permissive for expression of retroviral genomes [52,98,99]. Retroviruses introduced into differentiated derivatives of EC or into postimplantation mouse embryos at day 8 of gestation, however, were able to replicate efficiently. This defines a switch of ear­ly differentiating cells in their ability to support retroviral expression, which is developmentally regulated [98,99]. These findings demonstrate that activity of genomic retroviruses can depend on epigenetic mechanisms. De novo methyl­ation of ERV genomes occurs only after chromosomal integration, while embryonal cells may possess an efficient de novo methy­lation activity that inactivates any DNA which is introduced into the early embryo [54,98,99]. This inactivation may be reversed in a further life stage, leading to an increased risk for neoplasia [57].

Endoviral Genome and Epigenetic Mechanisms in Neoplasia

As proposed by Villareal, the viviparous mammals express ERVs in extraembryonal tissue during trophoblast implantation in order to suppress the local initiation of recognition by the mother’s immune system, enable fusion and allow growth of the embryo [65,66,81-83]. After that, regulatory mechanisms suppress ERVs activity possibly due to genomic imprinting. This process consists in expressing of certain genes in a parent-of-origin-specific manner, which achieves monoallelic gene expression without altering the genetic sequence [100,101]. In mammals there are two major mechanisms that are involved in establishing the imprint: DNA methylation and histone modifications [100]. In general, active chromatin is associated with low DNA methylation status and histone acetylation, whereas silenced gene are typically in inactive regions of chromatin exhibiting DNA hyper-methylation and histone deacetylation [101]. The control of expression of specific genes by genomic imprinting is unique to therian mammals. It is now known that there are at least 80 imprinted genes in humans and mice, many of which are ERVs involved in embryonal and placental growth and development [100,102-105]. Experiments in preimplantation embryos and EC cells have shown that early development of mice is associated with variations in methylation and expres­sion of active genes [53,54,99]. Additional findings have demonstrated that DNA methylation is involved in the maintenance of retroviral repression, and that retroviral expression in ES cells is repressed by methylation-dependent as well as methylation-independent mechanisms [106]. These data indicate that failure of the cell to control ERVs can lead to mutations or diseases including neoplasia [52].

In this respects, hypo-methylation and reactivation of LINEs and HERVs may be important in the pathophysiology of cancer [54,107]. However, in many common cancers such as transitional cell carcinoma, specific genes are hyper-methylated, whereas overall DNA methylation is diminished [108]. Analysis of the entire ERV-W 5’LTR (U3/R/U5) has shown a significant hypo-methylation of ERV-W 5’LTR, which is considered as potential molecular mechanism responsible for increased expression of Syncytin-1 in endometrial carcinoma [57]. Additional support for regulation of ERV-W by methylation was observed from luciferase studies using endometrial carcinoma cell lines, where a shut-down of luciferase expression occurred upon methylation of ERV-W 5’LTR containing vectors.

Evidenced data confirmed that methylation of these sequences depends on adequate expression of DNA methyltransferase 1 (Dnmt1) during DNA replication, while transcriptional repression is thought to be mediated by both cis-acting de novo methylation of the integrated proviruses and cell-type-specific trans-acting transcriptional repressors [106,108-110]. In Dnmt1 knockout mouse embryos (lacking maintenance of DNA methylation), unmethylated copies of IAPs are observed along with a significant accumulation of transcripts, suggesting that transcriptionally silent endogenous retroviral elements are reactivated upon loss of genomic methylation [106,111,112]. The genetic decrease of Dnmt1 expression to 10% of wild-type levels and consequent substantial genome-wide hypo-methylation in all tissues resulted at 4 to 8 months of age in development of aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy [107]. These results provide direct evidence that DNA methylation is causally involved in long-term retroviral repression, while DNA hypo-methylation plays a causal role in tumor formation, possibly by promoting chromosomal instability [106,107].

In contrast to these results, methylation-independent mechanisms determine initial retroviral expression in ES cells. Wild-type or Dnmt1−/− ES cells infected with Moloney virus-based vectors were transcriptionally silent, and therefore this silencing was independent of the DNA methylation status of the cells [106]. Because the basal level of expression of the mouse stem cell virus LTR in ES cells is lower than in differentiated cell types and not affected by the methylation status of the ES cells, trans-acting factors must regulate the initial level of expression. These findings demonstrate that epigenetic abnormalities including the aberrant DNA hyper-methylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis [113]. In case of endometrial carcinogenesis the frequencies of aberrant hyper-methylation were 40.4% in hMLH1, 22% in APC, 14% in E-cadherin, and 2.3% in RAR-beta in endometrial cancer specimens. In atypical endometrial hyperplasia the frequencies of aberrant methylation were 14.3% in hMLH1 and 7.3% in APC, whereas normal endometrial cells showed no aberrant hyper-methylation of any of the mentioned genes [113]. The high frequencies of the aberrant DNA hyper-methylation of hMLH1, APC and E-cadherin suggest that the methylation of the DNA mismatch repair may be associated with endometrial carcinogenesis. Methylation analysis of the ERV-K(HML-2) 5’LTR-U3 region demonstrated that CpG-hypo-methylation was linked with transcriptional activity in melanoma cell lines, while in testicular cancer methylation of the 5’-LTR-U3 region of ERV-W, ERV-FRD and ERV-H decreased compared to control tissue [90,114]. Similar to this, analysis of the entire ERV-W 5’LTR demonstrated a significant hypo-methylation of 14 of 20 CpGs in endometrial carcinoma, reducing the overall ERV-W 5’LTR methylation degree for respective patients by 19% [57]. Additional found changes during development of endometrial carcinoma were increased microsatellite instability due to defects in mismatch repair genes, gene mutations in PTEN and p53 and DNA aneuploidy [111,115-117]. These data demonstrate that ERVs contribute to genome wide instability, most likely contributing in tumor initiation and progression [113,118,119].

As above-mentioned, a significant proportion of the human genome consists of stably inherited retroviral sequences that became defective over time [120]. This is possible because among DNA alterations occurring in neoplasia (such as in case of endometrial carcinoma), it is demonstrated that some genome-integrated ERVs still have an open reading frame (ORF) and protein expression [57]. Up to date, there are described at least 19 different fully coding ERV env genes and two ERV env genes with stop codons from 11 different ERV families [68]. Although envE of ERV-E4-1 is not a full length env, due to a stop codon after 428 amino acids, antibodies detected an envE protein in control and tumor tissues [88]. Furthermore, envW2 (which shows a DNA similarity of 93.5% to the ERV-W env, called Syncytin-1) was demonstrated as transcribed, but harbored an N-terminal stop-codon after 117 bp [121]. These findings suggest that aberrant hypo-methylation of Syncytin-1 and other env genes can lead to reactivation of expression, where these env genes could possibly function together in early endometrial prestages and endometrial carcinoma [57].

Especially, the increased sensitivity to epigenetic hypo-methylation of ERV genes is associated to the presence of open reading frames (ORFs) for respective gene promoters [57]. Promoters CpG-methylation is associated with the inability of transcription factor binding, leading therefore to a loss of transcriptional activity [90]. Although the ERV-H family is one of the most common ERVs in the human genome, only three (p59, p60, p62) out of 100 env-containing proviruses have a full length ORF transcribed [77,122]. In a combined qPCR all three ERV-H env p59, p60 and p62 genes represented the highest transcript levels of all ERV env tested for control endometrium, polyps, hyperplasia and endometrial carcinoma [57]. Moreover, the several largely preserved HERV-K(HML-2) element has conserved ORFs for all its proteins in addition to a functional LTR promoter [120,123]. According George et al. this indicates that the gag gene product Pr74Gag of HERV-K(HML-2) is processed to yield p15-MA (matrix), SP1 (spacer peptide of 14 amino acids), p15, p27-CA (capsid), p10-NC (nucleocapsid) and two C-terminally encoded glutamine- and proline-rich peptides, QP1 and QP2, spanning 23 and 19 amino acids, respectively [123]. The LTR promoter activity for nearby genes enables homologous and non-homologous recombination and therefore initiates new mutations [124-127]. Because DNA methylation in general targets copies of transposable elements, it is important for the host to manage the impact of epigenetic regulation of the copies that remain near genes. In mammals, it has been suggested that DNA methylation spreads into the mouse Aprt and rat Afp genes via nearby methylated SINE copies, and this is associated to spreading of heterochromatin (histone H3 trimethylation of lysine 9 (H3K9me3) and DNA methylation) from an ERV LTR to a gene promoter in mouse ES cells [128,129]. In addition, display of differential early transposon and IAPs DNA methylation between their two LTRs suggests that the environment surrounding gene promoters can prevent methylation of the nearby LTR [111].

In summary, silencing of retrotransposons occurs by co-suppression during early embryogenesis, but this process is imperfect and produces a mosaic pattern of retrotransposon expression in somatic cells [130]. Transcriptional interference by active retrotransposons perturbs expression of neighboring genes in somatic cells, in a mosaic pattern corresponding to activity of each retrotransposon. The stochastic nature of retrotransposon activity, and the very large number of genes that may be affected, produce subtle phenotypic variations, which may affect disease risk and be heritable in a non-Mendelian manner [130].

In other words, the above-mentioned data may support the idea that ERVs incorporated in mammalian genome are an evident risk factor per se in the development of cancers. This agrees with Hayakawa hypothesis which proposed that evolution of viviparity may have increased susceptibility to malignancies [131]. Indeed, true cancers are more frequent among vertebrates, and especially viviparous mammals. The most evidenced risk factor for these pathologies among vertebrates seems to be retroviral infections, which in mammals are incorporated in genome [1,65,66]. Analyses of clinical data in human and experiments in rodents show that ERVs genome activation correlates with immunosupression and the immunosupression strongly correlates with cancer incidence [132]. In general, the development of cancer-like disorders among other phyla needs the stimulant effect of strong pollutants and the development of true cancer among other vertebrata needs the retroviral infections. In contrast to them, viviparous mammals contain the ERVs in their genome and therefore may spontaneously develop the cancer even in absence of environmental oncogenic agents [1,65,133]. Beside this, predator mammals are exposed even to additional ERVs during consumption of their prey, and therefore, they might be more often affected by neoplasia than non-carnivora mammals. If correct, this might be reflected in human life as an epidemiological difference between neoplasia frequencies (and inversely their lifespan) among populations with different nutritional traditions. Consequently, traditionally vegetarian (or even seaside) populations should longer life and be less-affected from neoplasia than traditionally omnivore populations. These lead to the supposition that, if a functional ERV is an essential host system for transient immune suppression and tolerance of “foreign” mammalian embryo, the artificial attempt to eradicate the potential development of cancer in mammalian organism could eradicate the viviparous mammalian self, or at least its natural capacity for viviparous reproduction.

It seems that imprinted ERVs genes after early embryonal stage can be reactivated later in the mammalian life due to epigenetic mechanisms, but their improper epigenetic activation has been associated with many human cancers [53,54]. Therefore, it can be expected that the growth of most tumors can also select for immune suppression, by selecting for ERV or retroviral gene production [65]. The follow­ing ERV production in somatic tissues (including various host genes that affect virus and cellular growth) can eventually yield various retroviral derivatives, leading to the development of tumors in respective mammalian species.

Telomerase as Neoplasia Inducer

The implication of epigenetic mechanisms in the reactivation of ERVs expression agrees with worldwide known fact that the burden of cancer in ageing populations is causing great concern (particularly Europe's growing elderly population) [134]. This seems to contrast with cellular senescence (biological consequence of aging), as long as senescence provoking mechanisms during aging have been proven to act in tumor suppression [135]. The diverse aspects of the senescent phenotype, as are observed for many other cell fates, arise from epigenetic alterations of the chromatin architecture [135]. The pseudo-paradox between cellular senescence and frequent cancers in the elderly population can be resolved due to reflection on the relationship between telomeres and telomerase and cellular aging and cancer [136-139]. Normal human cells progressively lose telomeres with each cell division, leading to a growth arrest known as replicative aging [135,136,140]. Upon specific genetic and epigenetic alterations, normal human cells bypass replicative senescence and continue to proliferate until many telomere ends become uncapped leading to a phenomenon known as crisis [136-139]. In crisis cells have critically shortened telomeres but continue to attempt to divide leading to significant apoptosis and progressive genomic instability [139,140]. Rarely, a human cell escapes crisis and these cells almost universally express the enzyme telomerase, and maintain stable but short telomeres.

Telomerase is a cellular ribonucleoprotein reverse transcriptase (RT) which stabilizes telomere length by adding hexameric (TTAGGG) repeats to the telomeric ends of the chromosomes, thus compensating for the continued erosion of telomeres [137,140-142]. In mammalian genome not only telomerase but also other retrotransposon reverse transcriptases (RTs) synthesize the mentioned hexameric DNA repeats by using the 3′-OH at the end of the chromosome as a primer and telomerase RNA as a template [62,141]. Apart from maintenance of chromosome ends, retrotransposon RTs can repair DNA double-strand breaks of mammalian genome [141-146]. This is because tandem arrays of TTAGGG hexamers are present at both telomeres and intrachromosomal sites (interstitial telomeric sequences - ITSs) [140,145]. In contrast to telomeres that are typically confined to chromosome ends, the retrotranscripts of ERVs and transposons can target a plethora of sites [62]. Mutational analysis of the TTAGGG arrays in the different species suggests that they were inserted as exact telomeric hexamers, further supporting the participation of telomerase in repairing ITSs formation [145]. The functional similarity between RT telomerase and retrotransposon RTs can be demonstrated with finding that loss of telomerase activity may induce alternative lengthening of telomere (ALT) systems [147]. Ty1 elements, which are LTR-retrotransposons in Saccharomyces cerevisiae, are mobilized when DNA lesions are created by the loss of telomere function [141,146]. When telomerase is inactivated, Ty1 retrotransposition increases substantially in parallel with telomere erosion and then partially declines when cells recover from arrest by forming alternative telomere structures [62]. Ty1 cDNA is incorporated into the genome at frequencies high enough to extend telomeres in the absence of telomerase. While Gladyshev and Arkhipova describes retroelements that are similar to telomerases and transpose to telomeres, the work by Morrish et al. shows that artificial disruptions can drive a target-primed (TP) retrotransposon to unprotected chromosome ends [148,149]. These findings highlight similarities between the mechanism of TP retrotransposition and the action of telomerase, because both processes can use a 3' OH for priming reverse transcription at either internal DNA lesions or chromosome ends [141]. In addition, Drosophila telomeres are long tandem arrays of two non-LTR retrotransposons (HeT-A and TART), suggesting that retrotransposon telomeres constitute a robust system for maintaining chromosome ends [150,151]. Successive transpositions of these telomeric elements yield arrays that are functionally equivalent to the arrays generated by telomerase in other organisms [152]. These findings suggest that in established ALT systems, subtelomeric satellite repeats may replace the telomeric minisatellite repeat whilst maintaining the recombination/replication mechanisms for telomere elongation [141,147].

Although HeT-A and TART belong to different subfamilies of non-LTR retrotransposons, they encode very similar retroviral gag proteins, which suggests that gag proteins are involved in their unique transposition targeting [151,152]. They imply a symbiotic relationship between the two elements, with HeT-A gag directing the telomere-specific targeting of the elements, whereas TART provides reverse transcriptase for transposition [152]. The RNA of LTR retrotransposons is used as a template for synthesis of not only RT but also of the structural protein gag, which forms a virus-like particle wherein the RNA is reverse-transcribed [62].

Retromotile enzymes such as telomerase or TP retrotransposons (termed L1s or LINEs), get reactive in mammalian cell lines defective for both telomere capping and non-homologous end joining, suggesting that the chromosome end must be exposed and stabilized to serve as a target for L1 retrotransposition [141,153]. Their activation may be thought of as a mechanism to slow down the rate genomic instability due to dysfunctional telomeres [136]. Introduction of the telomerase catalytic protein component into normal telomerase-negative human cells results in restoration of telomerase activity and extension of cellular lifespan [137,140].

Human cells with introduced telomerase maintain a normal chromosome complement and continue to grow in a normal manner. Unfortunately, the regulation of telomerase activity in human cells plays a significant role in the development of cancer [62,139,140]. The mechanisms for telomerase have not fully defined, but the need for telomere genome repairing during elderly can be associated with reactivation of telomerase. Mechanisms for telomerase reactivation can interfere with reactivation of other RTs, and as consequence with replication of previously-imprinted oncogenic ERVs. Thus, the telomerase activation in cancers includes telomerase catalytic subunit gene (hTERT) amplification and trans-activation of the hTERT promoter by the myc oncogene product [139]. Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. There is accumulating evidence that hTERT favors an immortal phenotype by blocking apoptosis independently of its protective function at the telomere ends [154]. The level of hTERT increases along with colorectal cancer progression, and patients with high hTERT levels showed a significantly worse survival than those with low ones [154-156]. Cancer cells (like aging ones) evade replicative senescence by re-expressing telomerase, which maintains telomere length and hence chromosomal integrity [157]. The attenuation of telomerase activity could be induced by inhibition of hTERT promoter, which would lead cancer cells to senesce and therefore prevent cancer cells from growing indefinitely [154,156]. This demonstrates that telomerase does not drive the oncogenic process; however, its effect is permissive and required for the sustain growth of most advanced cancers [136,138]. This is strongly supported by the fact that telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes epigenetically activated during cellular immortalization and in cancers [139,140,154].

Telomerase is cross-linked with different interplaying signaling pathways that regulate cell proliferation, DNA damage repair, and also cell death [154]. With the extension of life span get epigenetically increased the probability for genetic instability, oncogenic activation and/or onco-suppressor gene inactivation (i.e. p53, pRB, ras, TRF1, TPP1 and Rap1): the cancer transformation can be then induced in predisposed cells, depending on their genetic context, by the activation of telomere maintenance [117,138,140,142,158]. Induction of telomere dysfunction by deficiency in the telomerase RNA component (mTER) in a p53 mutant mouse background results in significant levels of breast adenocarcinomas and colon carcinomas [158-160]. The study of these proteins demonstrates that telomere dysfunction, even if telomeres are of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromosomal aberrations and initiation of neoplastic lesions [142].

As suggested, the telomerase activation due to epigenetic mechanisms is associated with potential reactivation of previously-imprinted ERV genes, leading to the spontaneous development of cancers in aged mammals [140,156]. While DNA methylation is thought to be a general mechanism used by cells to silence foreign ERV genome and other transposable elements, hypo-methylation and genome expression opens a "window of opportunity" for retrotransposition and recombination that contribute to inherited disease including neoplasia [54,106]. Target of the hypo-methylation are not only reduced telomeres, but also intersticial ERV genomes (especially some genome-integrated ERVs with an ORF and protein expression) [57,123]. In the control of mentioned elements, epigenetic mechanisms involve mammalian DNA methyltransferases (DNMTs) [161]. In general, chromosomal subtelomeric regions are heavily methylated, but this modification is decreased in DNMT-deficient cells. Mouse ES cells genetically deficient for dnmt1, or both dnmt3a and dnmt3b have dramatically elongated telomeres compared with wild-type controls [161]. Lack of DNMTs also resulted in increased telomeric recombination as indicated by the presence of ALT-associated promyelocytic leukaemia bodies. This increased telomeric recombination may lead to telomere-length changes, although these results do not exclude a potential involvement of telomerase and telomere-binding proteins in the aberrant telomere elongation observed in DNMT-deficient cells [161]. Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity.

According to Prindull, foreign, silenced, potentially oncogenic DNA sequences, i.e. regular components of the mammalian genome such as ERVs, could conceivably be activated for expression in neoplastic transformation by epigenomic lineage leukemia deregulations [162]. This supports the concept that evolutionary interplay between retroviruses and host defenses among mammalian placentas may have contributed to the local genomic imprinting [66,79-83]. It is not excluded that every affected tissue by such processes develops embryonal-like growth abilities. This speculation can be supported by the fact that only placental tissue from normal early pregnancies possesses consistent telomerase activity [163]. During the pregnancy progression, this activity attenuates due to hyper-methylation of retroviral genome [57]. In a later life stage telomerase and other RTs get hypo-methylated in order to escape senescence, leading not only to genome repair but also to ERVs replication. Consequently, the occurrence of telomere dysfunction (like the reoccurred ERV genome replication) may be an early and potentially highly frequent genetic aberration event in the development of neoplasia [158].

Recent findings demonstrate that telomerase-induced carcinogenesis is associated with telomere end-to-end associations (telomere fusions) [158]. Human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. These fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage [158]. Defects in telomere maintenance have been suggested to play significant roles in the initiation of genomic instability via breakage–fusion–bridge cycles and aneuploidy, which are associated with the development of human cancers [164,165]. In a human mammary epithelial cell culture model, late-passage human mammary epithelial cell escape a stress-associated senescence-like barrier and acquire genomic alterations, including telomere fusions [166]. In this respect, there are found small regions of LTR and non-LTR retrotransposon elements from interstitial chromosomal regions within fusion junctions in human breast invasive tissue [158]. Similar retrotransposon elements are present at Drosophila chromosome ends and have been reported to integrate at dysfunctional mammalian telomeres in a Chinese hamster ovary cell line [149,167]. These results provide direct evidence that telomere fusions are present in mammalian tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in neoplasia.

The telomere fusion at genomic level seems to be analogue to the embryonal one at the cellular level, as both telomerase and certain ERVs called syncytins are retroelements and show fusogenic functions [57,158]. For example, syncytin, the Env protein of HERV-W human endogenous retroviruses and putative mediator of trophoblast fusion, was also found to mediate fusion between breast cancer cells and endothelial cells [168,169]. If de-methylation occurred during tumorigenesis, this could lead to chromatin opening and availability of transcription factor binding sites (in the ERV-W 5’LTR), thus inducing Syncytin-1 expression via the cAMP response element [57]. The env gene of ERV-R (ERV-3) has been shown to be expressed in most tissues, like testis, skin, thymus and placenta and in various carcinomas, like glioma, breast, or Wilm’s tumor [68]. In contrast to the three known fusogenic ERV-env proteins (Syncytin-1, Syncytin-2 and Syncytin-3), ERV-3 is considered a cytoplasmic protein due to the lack of a leader sequence, a membrane spanning domain and a fusion peptide [170]. As cell fusion plays an essential role in fertilization, formation of placenta, immune response, tissue repair, and regeneration, increasing recognition of cell fusion in somatic cell dynamics has revitalized the century-old hypothesis that cell fusion may contribute to the initiation and progression of cancer [57]. Experimental and clinical studies suggest for a potentially multifaceted involvement of cell fusion in different stages of tumor progression, including aneuploidy and tumor initiation, origin of cancer stem cells, multidrug resistance, and the acquisition and diversification of metastatic abilities. Spontaneous cell fusion in tissue culture or in animal models has been reported for a large variety of tumor cells [171,172]. While fusion efficiency can be proportional to the malignant level of tumor cells, colonization preference (organotropizm) can also be determinate by cell fusion [121,173]. For example, fusion of myeloma cells with B lymphocytes resulted in a hybrid cell metastasizing to the spleen and liver, yet fusion with macrophages led to metastasis to lung [174]. Importantly, fusion of tumor cells with resident cells in a secondary organ may allow disseminated tumor cells to survive in a hostile microenvironment as minimal residual diseases and emerge as overt metastasis after accumulation of additional oncogenic alternations [57]. In a recent study, untransformed mammary cells were found to persist in the lungs as small clusters until inducible activation of oncogenes stimulated the formation of pulmonary metastases [69]. Overall, accumulating evidence has suggested a plausible involvement of cell fusion in several aspects of cancer progression.

Rigorous genetic studies in animal tumor models will be needed to definitely demonstrate the extent of cell fusion to tumor initiation, drug resistance and metastasis [168]. Further investigations should discover the specific role of telomerase in placenta and its interaction with embryonal ERV genome and compare them with investigations in neoplasia development. As long as with the extension of life span the probability to get in contact with (endogenous) carcinogens increases, chemo-preventive therapies for the up-regulation of telomerase activity, able to prolong the life of cell cultures in a phenotypically youthful state, could have important applications in research and medicine [138]. On the contrary the therapeutic down-regulation of telomerase activity may be used in cancer therapy. The desperate natural or pharmacological intervention for the modulation of the living rate could lead to cancerous development of the target cells and therefore to the decreasing of their living rate [138]. Because of the unknown state of the enormous cell number of the human organism, is it safe to extend the human lifespan by therapeutic agents? Virus DNA gave rise to those of eukaryotes, and ERVs incorporation in their genome was essential for the mammalians’ evolution/existence [65,175]. Consequently (and based on the actual opportunities), either mammals should remain mammalian organisms with a relative life span expectation, or they, (beside providing of healthy environment and lifestyle), should eradicate the ERVs from their genome giving up viviparous reproduction form once and for all in order to live quite much longer. Would have Shakespeare said: ”To live longer with the fear of cancer or not” if he knew about ERVs? 


In this work we propose that ERV genome in mammals is a potential risk factor for the spontaneous development of neoplasia, especially in the late adulthood. This genome could be reactivated due to epigenetic mechanisms, maybe as an attempt of longevity for aging organism. Because of the unknown state of the enormous cell number of the mammalian organism, the attempt to extend the lifespan could be not safe, and therefore, a potential hearth of neoplasia.

According to actual knowledge, neoplasia is caused by environmental factors (including retroviral infections) or oncogenic mutations. Our hypothesis suggests that integrated ERVs (which are essential for reproduction of mammals) can be at the same time risk factor per se in the development of spontaneous neoplasia. Epigenetic mechanisms serve to escape cellular senescence and aging due to telomerase activation, but these processes can be associated with re-expression of ERV genome and tumor growth. This is possible because both telomerase and ERVs are of reverse-transcription origin, under control of the same epigenetic mechanisms, and exercise similar functions in genome ends and interstitial genome. With respect to human medicine, our suggestion stresses out the role of detection of neoplastic alterations at the early stages. However, the eradication of this risk may affect our natural reproduction and mammalian being.

Acknowledgements and Authors Contribution

This work is dedicated to my lovely parents, both affected by tumor disorders (E.Mingomataj). Authors cordially thank Ms. Alkerta Ibranji for the manuscript’s editing and helpful discussions. Both authors contributed equally to this work.


1. Robert J. Comparative study of tumorigenesis and tumor immunity in invertebrates and nonmammalian vertebrates. Dev Comp Immunol 2010; 34: 915-25.
2. Falkmer S, Marklund S, Mattsson PE, Rappe C. Hepatomas and other neoplasms in the atlantic hagfish (Myxine glutinosa): a histopathologic and chemical study. Ann NY Acad Sci 1978; 298: 342–55.
3. Falkmer S. The tumor pathology of Myxine glutinosa. In: Jorgensen JM, Lombolt JP, Weber RE, Malte H, (Eds). The biology of hagfishes. Chapman and Hall; London: 1998, pp. 101–7.
4. Ostrander GK, Cheng KC, Wolf JC, Wolfe MJ. Shark cartilage, cancer and the growing threat of pseudoscience. Cancer Res 2004; 64: 8485–91.
5. Smith AC. Comparative pathology: human disease counterparts in marine animals. Arch Pathol Lab Med 2000; 124: 348–52.
6. Brown ER, Hazdra JJ, Keith L, Greenspan I, Kwapinski JBG, Beamer P. Frequency of Fish Tumors Found in a Polluted Watershed as Compared to Nonpolluted Canadian Waters. Cancer Res1973; 33: 189–98.
7. Groff JM. Neoplasia in fishes. Vet Clin North Am Exot Anim Pract 2004; 7: 705–56.
8. Holzschu D, Lapierre LA, Lairmore MD. Comparative pathogenesis of epsilon-retroviruses. J Virol 2003; 77: 12385–91.
9. LaPierre LA, Casey JW, Holzschu DL. Walleye retroviruses associated with skin tumors and hyperplasias encode cyclin D homologs. J Virol 1998; 72: 8765–71.
10. Rahn JJ, Gibbs PD, Schmale MC. Patterns of transcription of a virus-like agent in tumor and non-tumor tissues in bicolor damselfish. Comp Biochem Physiol C Toxicol Pharmacol 2004; 138: 401–9.
11. Campbell CE, Gibbs PD, Schmale MC. Progression of infection and tumor development in damselfish. Mar Biotechnol (NY) 2001; 3(Suppl. 1): S107–14.
12. Paul TA, Quackenbush SL, Sutton C, Casey RN, Bowser PR, Casey JW. Identification and characterization of an exogenous retrovirus from atlantic salmon swim bladder sarcomas. J Virol 2006; 80: 2941–8.
13. Stacy BA, Parker JM. Amphibian oncology. Vet Clin North Am Exot Anim Pract 2004; 7: 673–95.
14. Pfeiffer CJ, Asashima M, Hirayasu K. Ultrastructural characterization of the spontaneous papilloma of Japanese newts. J Submicrosc Cytol Pathol 1989; 21: 659–68.
15. Masahito P, Nishioka M, Ueda H, Kato Y, Yamazaki I, Nomura K, et al. Frequent development of pancreatic carcinomas in the Rana nigromaculata group. Cancer Res 1995; 55: 3781–4.
16. Masahito P, Nishioka M, Kondo Y, Yamazaki I, Nomura K, Kato Y, et al. Polycystic kidney and renal cell carcinoma in Japanese and Chinese toad hybrids. Int J Cancer 2003; 103: 1–4.
17. Harshbarger JC, Chang SC, DeLanney LE, Rose FL, Green DE. Cutaneous mastocytomas in the neotenic caudate amphibians Ambystoma mexicanum (axolotl) and Ambystoma tigrinum (tiger salamander) J Cancer Res Clin Oncol 1999; 125: 187–92.
18. Naegele RF, Granoff A, Darlington RW. The presence of the Lucke herpesvirus genome in induced tadpole tumors and its oncogenicity: Koch-Henle postulates fulfilled. Proc Natl Acad Sci USA 1974; 71: 830–4.
19. Granoff A. Herpesvirus and the Lucke tumor. Cancer Res 1973; 33: 1431–3.
20. McKinnell RG, Carlson DL. Lucke renal adenocarcinoma, an anuran neoplasm: studies at the interface of pathology, virology, and differentiation competence. J Cell Physiol 1997; 173: 115–8.
21. Balls M. Lymphosarcoma in the South African clawed toad, Xenopus laevis: a virus tumor. Ann NY Acad Sci 1965; 126: 256–73.
22. Kambol R, Kabat P, Tristem M. Complete nucleotide sequence of an endogenous retrovirus from the amphibian, Xenopus laevis. Virology 2003; 311: 1–6.
23. Pereira ME, Viner TC. Oviduct adenocarcinoma in some species of captive snakes. Vet Pathol 2008; 45: 693–7.
24. Quackenbush SL, Work TM, Balazs GH, Casey RN, Rovnak J, Chaves A, et al. Three closely related herpesviruses are associated with fibropapillomatosis in marine turtles. Virology 1998; 246: 392–9.
25. Jones AG. Sea turtles: old viruses and new tricks. Curr Biol 2004; 14(19): R842–3.
26. Literak I, Robesova B, Majlathova V, Majlath I, Kulich P, Fabian P, et al. Herpesvirus-associated papillomatosis in a green lizard. J Wildl Dis 2010; 46: 257–61.
27. Payne LN. Retrovirus-induced disease in poultry. Poult Sci 1998; 77: 1204–12.
28. Hatai H, Ochiai K, Nagakura K, Imanishi S, Ochi A, Kozakura R, et al. A recombinant avian leukosis virus associated with fowl glioma in layer chickens in Japan. Avian Pathol 2008; 37: 127–37.
29. Jarosinski KW, Tischer BK, Trapp S, Osterrieder N. Marek’s disease virus: lytic replication, oncogenesis and control. Expert Rev Vaccines 2006; 5: 761–72.
30. Osterrieder N, Kamil JP, Schumacher D, Tischer BK, Trapp S. Marek’s disease virus: from miasma to model. Nat Rev Microbiol 2006; 4: 283–94.
31. Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer 2011; 11: 135-41.
32. Withrow SJ, Wilkins RM. Cross talk from pets to people: translational osteosarcoma treatments. ILAR J 2010; 51: 208-13.
33. Peters EC, Halas JC, McCarty HB. Calicoblastic neoplasms in Acropora palmata, with a review of reports on anomalies of growth and form in corals. J Natl Cancer Inst 1986; 76: 895–912.
34. Work TM, Aeby GS, Coles SL. Distribution and morphology of growth anomalies in Acropora from the Indo-Pacific. Dis Aquat Organ 2008; 78: 255–64.
35. Berry LW, Westlund B, Schedl T. Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors. Development 1997; 124: 925–36.
36. Schertel C, Conradt B. C. elegans orthologs of components of the RB tumor suppressor complex have distinct pro-apoptotic functions. Development 2007; 134: 3691–701.
37. Walker C, Bottger SA, Mulkern J, Jerszyk E, Litvaitis M, Lesser M. Mass culture and characterization of tumor cells from a naturally occurring invertebrate cancer model: applications for human and animal disease and environmental health. Biol Bull 2009; 216: 23–39.
38. Usheva LN, Frolova LT. A connective tissue tumor in the mussel Mytilus trossulus from a polluted region of Nakhodka Bay, the Sea of Japan. Ontogenez 2000; 31: 63–70.
39. Ciocan C, Sunila I. Disseminated neoplasia in blue mussels, Mytilus galloprovincialis, from the Black Sea, Romania. Mar Pollut Bull 2005; 50: 1335–9.
40. Ciocan CM, Moore JD, Rotchell JM. The role of ras gene in the development of haemic neoplasia in Mytilus trossulus. Mar Environ Res 2006; 62(Suppl S): 147–50.
41. Muttray AF, Schulte PM, Baldwin SA. Invertebrate p53-like mRNA isoforms are differentially expressed in mussel haemic neoplasia. Mar Environ Res 2008; 66: 412–21.
42. Scharrer B, Lochhead MS. Tumors in the invertebrates: a review. Cancer Res 1950; 10: 403–19.
43. Sparks AK. Review of tumors and tumor-like conditions in protozoa, coelenterata, platyhelminthes, annelida, sipunculida, and arthropoda, excluding insects. Natl Cancer Inst Monogr 1969; 31: 671–82.
44. Basto R, Brunk K, Vinadogrova T, Peel N, Franz A, Khodjakov A, et al. Centrosome amplification can initiate tumorigenesis in flies. Cell 2008; 133: 1032–42.
45. Vogt G. How to minimize formation and growth of tumours: potential benefits of decapod crustaceans for cancer research. Int J Cancer 2008; 123: 2727–34.
46. Lightner DV, Brock JA. A lymphoma-like neoplasm arising from hematopoietic tissue in the white shrimp, Penaeus vannamei Boone (Crustacea: Decapoda) J Invertebr Pathol 1987; 49: 188–93.
47. Sparks AK, Morado JF. A putative carcinoma-like neoplasm in the hindgut of a red king crab, Paralithodes camtschatica. J Invertebr Pathol 1987; 50: 45–52.
48. Wellings SR. Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--A review. Natl Cancer Inst Monogr 1969; 31: 59–128.
49. Jangoux M. Diseases of Echinodermata. IV. Structural abnormalities and general considerations on biotic diseases. Dis Aquat Org 1987; 3: 221–9.
50. Sparks AK. Noncommunicable Diseases. Academic Press; New York: 1972, Invertebrate Pathology.
51. Fontaine AR. Pigmented tumor-like lesions in an ophluroid echinoderm. Natl Cancer Inst Monogr 1969; 31: 255–61.
52. Liu Y. Endogenous retroviruses: remnants of germline infection or created in the cell? Creat Res Soc Quarterly 2008; 44: 241.
53.  Druker R, Whitelaw E. Retrotransposon-derived elements in the mammalian genome: a potential source of disease. J Inher Metab Dis 2004; 27: 319-30.
54.  Schulz WA, Seinhoff C, Flori AR. Methylation of endogenous retroelements in health and disease. Curr Topics Microbiol Immunol 2006; 310: 211-50.
55. Jaenisch RF. Germline integration and Mendelian transmission of the exogenous Moloney leukemia virus. Proc Natl Acad Sci USA 1976; 73: 1260-4.
56. Lewin B. Genes VIII, Pearson Education, Inc., Upper Saddle River, NJ, 2004, pp. 505.
57. Strissel PL, Ruebner M, Thiel F, Wachter D, Ekici AB, Wolf F, Thieme F, Ruprecht K,  Beckmann MW, Strick R. Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: Emergence of new molecular targets. Oncotarget 2012; 3(10): 1204-19.
58. Bannert N, Kurth R. Retroelements and the human genome: new perspectives on an old relation. Proc Natl Acad Sci USA. 2004; 101 (Suppl 2): 14572-9.
59. Stoye JP. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat Rev Microbiol 2012; 10(6): 395-406.
60. Taruscio D, Mantovani A. Factors regulating endogenous retroviral sequences in human and mouse. Cytogenet Genome Res 2004; 105(2-4): 351-62.
61. De Parseval N, Heidmann T. Human endogenous retroviruses: from infectious elements to human genes. Cytogenet Genome Res 2005; 110(1-4): 318-32.
62. Belfort M, Curcio MJ, Lue NF. Telomerase and retrotransposons: reverse transcriptases that shaped genomes. Proc Natl Acad Sci USA 2011; 108(51): 20304-10.
63. Khodosevich K, Lebedev Y, Sverdlov E. Endogenous retroviruses and human evolution. Comp Funct Genomics 2002; 3(6): 494-8.
64. Tristem M. Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the human genome mapping project database. J Virol 2000; 74(8): 3715-30.
65. Villarreal LP. On Viruses, Sex, and Motherhood. J Virol 1997; 71: 859-65.
66. Haig D. Retroviruses and the placenta. Curr Biol 2012; 22(15): R609-13.
67. Holder BS, Tower CL, Abrahams VM, Aplin JD. Syncytin 1 in the human placenta. Placenta 2012; 33(6): 460-6.
68. de Parseval N, Lazar V, Casella JF, Benit L, Heidmann T. Survey of human genes of retroviral origin: identification and transcriptome of the genes with coding capacity for complete envelope proteins. J Virol 2003; 77(19): 10414-22.
69. Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset FL. An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 2000; 74(7): 3321-9.
70. Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC Jr., McCoy JM. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000; 403(6771): 785-9.
71. Ruebner M, Strissel PL, Langbein M, Fahlbusch F, Wachter DL, Faschingbauer F, Beckmann MW, Strick R. Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes. J Mol Med (Berl) 2010; 88(11): 1143-56.
72. Blaise S, de Parseval N, Heidmann T. Functional characterization of two newly identified Human Endogenous Retrovirus coding envelope genes. Retrovirology 2005; 2: 19.
73. Langbein M, Strick R, Strissel PL, Vogt N, Parsch H, Beckmann MW, Schild RL. Impaired cytotrophoblast cell-cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol Reprod Dev 2008; 75(1): 175-83.
74. Ruebner M, Langbein M, Strissel PL, Henke C, Schmidt D, Goecke TW, Faschingbauer F, Schild RL, Beckmann MW, Strick R. Regulation of the human endogenous retroviral Syncytin-1 and cell-cell fusion by the nuclear hormone receptors PPARgamma/RXRalpha in placentogenesis. J Cell Biochem 2012; 113(7): 2383-96.
75. Blaise S, de Parseval N, Bénit L, Heidmann T. Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytins 2, a gene conserved on primate evolution. Proc Natl Acad Sci USA 2003; 100(22): 13013-8.
76. Mangeney M, de Parseval N, Thomas G, Heidmann T. The full-length envelope of an HERV-H human endogenous retrovirus has immunosuppressive properties. J Gen Virol 2001; 82(Pt 10): 2515-8.
77. De Parseval N, Casella J, Gressin L, Heidmann T. Characterization of the three HERV-H proviruses with an open envelope reading frame encompassing the immunosuppressive domain and evolutionary history in primates. Virology 2001; 279(2): 558-69.
78. Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, Heidmann O, Letzelter C, Richaud A, Ducos B, Heidmann T. Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA 2007; 104(51): 20534-9.
79.  Mallet F, Oliver B, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B. The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci USA 2004; 101: 1731-6.
80. Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M, Rabreau M, Evain-Brion D, Mallet F. Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cel Biol 2003; 23: 3566-74.
81. Caceres M, NISC Comparative Sequencing Program, Thomas JW. The gene of proviral origin syncytin-1 is specific to hominoids and is inactive in old world monkeys. J Heredity 2006; 97: 100-6.
82.  Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, Heidmann T. Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae. Proc Natl Acad Sci USA 2005; 102: 725-30.
83.  Levine KL, Steiner B, Johnson K, Aronoff R, Quinton TJ, Linial ML. Unusual features of integrated cDNAs generated by infection with genome-free retroviruses. Mol Cell Biol 1990; 10: 1891-900.
84. Temin HM. The protovirus hypothesis: speculations on the signifi­cance of RNA-directed DNA synthesis for normal development and for carcinogenesis. J Natl Cancer Inst 1971; 46: 3–7.
85. Szathmary E, Smith JM. The major evolutionary transitions. Nature 1995; 374: 227-32.
86. Venables PJ, Brookes SM, Grif?ths D, Weiss RA, Boyd MT. Abundance of an endogenous retroviral envelope protein in placental trophoblasts suggests a biological function. Virology 1995; 211: 589–92.
87. Djaffar I, Dianoux L, Leibovich S, Kaplan L, Emanoil-Ravier R, Peries J. Detection of IAP related transcripts in normal and transformed rat cells. Biochem Biophys Res Commun 1990; 169: 222–31.
88. Turbeville MA, Rhodes JC, Hyams DM, Distler CM, Steele PE. Characterization of a putative retroviral env-related human protein. Pathobiology 1997; 65(3): 123-8.
89. Wang-Johanning F, Liu J, Rycaj K, Huang M, Tsai K, Rosen DG, Chen DT, Lu DW, Barnhart KF, Johanning GL. Expression of multiple human endogenous retrovirus surface envelope proteins in ovarian cancer. Int J Cancer 2007; 120(1): 81-90.
90. Gimenez J, Montgiraud C, Pichon JP, Bonnaud B, Arsac M, Ruel K, Bouton O, Mallet F. Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control. Nucleic Acids Res 2010; 38(7): 2229-46.
91. Wang-Johanning F, Frost AR, Jian B, Azerou R, Lu DW, Chen DT, Johanning GL. Detecting the expression of human endogenous retrovirus E envelope transcripts in human prostate adenocarcinoma. Cancer 2003; 98(1): 187-97.
92. Wang-Johanning F, Radvanyi L, Rycaj K, Plummer JB, Yan P, Sastry KJ, Piyathilake CJ, Hunt KK, Johanning GL. Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res 2008; 68(14): 5869-77.
93. Yi JM, Kim HS. Molecular phylogenetic analysis of the human endogenous retrovirus E (HERV-E) family in human tissues and human cancers. Genes Genet Syst 2007; 82(1): 89-98.
94. Wang-Johanning F, Rycaj K, Plummer JB, Li M, Yin B, Frerich K, Garza JG, Shen J, Lin K, Yan P, Glynn SA, Dorsey TH, Hunt KK, Ambs S, Johanning GL. Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J Natl Cancer Inst 2012; 104(3): 189-210.
95. Larsen JM, Christensen IJ, Nielsen HJ, Hansen U, Bjerregaard B, Talts JF, Larsson LI. Syncytin immunoreactivity in colorectal cancer: potential prognostic impact. Cancer Lett 2009; 280(1): 44-9.
96. De Parseval N, Alkabbani H, Heidmann T. The long terminal repeats of the HERV-H human endogenous retrovirus contain binding sites for transcriptional regulation by the Myb protein. J Gen Virol 1999; 80(Pt 4): 841-5.
97. Stoger H, Wilders-Truschnig M, Samonigg H, Schmid M, Bauernhofer T, Tiran A, Tas M, Drexhage HA. The presence of immunosuppressive 'p15E-like' factors in the serum and urine of patients suffering from malign and benign breast tumours. Clin Exp Immunol 1993; 93: 437-41.
98. Hojman-Montes de Oca F, Dianoux L, Peries J, Emanoil­ Ravicovitch R. Intracisternal A particles: RNA expression and DNA methylation in murine teratocarcinoma cell lines. J Virol 1983; 46: 307-10.
99. Jaenisch R, Harbers K, Milner D, Stewart C, Stuhlmann H. Expression of Retroviruses During Early Mouse Embryogenesis. In: Neth, Gallo, Greaves, Moore, Winkler (Eds), Haematology and Blood Transfusion, Vol. 28, Modern Trends in Human Leukemia V, Springer-Verlag, Berlin Heidelberg, 1983.
100. Isles AR, Holland AJ. Imprinted genes and mother-offspring interactions. Early Human Development 2005; 81: 73–7.
101. Fu Y, Nachtigal MW. Analysis of epigenetic alterations to proprotein convertase genes in disease. Methods Mol Biol 2011; 768: 231-45.
102. Haig D. Parental antagonism, relatedness asymmetries, and genomic imprinting. Proc Royal Society London Series B-Biological Sciences 1997; 264(1388): 1657–62.
103. Haig D. The kinship theory of genomic imprinting. Annu Rev Ecol Systematics 2000; 31(1388): 9–32.
104. McElroy, J, Kim JJ, Harry DE, Brown SR, Dekkers JC, Lamont SJ. Identification of trait loci affecting white meat percentage and other growth and carcass traits in commercial broiler chickens. Poultry Science 2006; 85: 593–605.
105. Tycko B, Morison IM. Physiological functions of imprinted genes. J Cell Physiol 2002; 192: 245–58.
106. Cherry SR, Biniszkiewicz D, van Parijs L, Baltimore D, Jaenisch R. Retroviral expression in embryonic stem cells and hematopoietic stem cells. Mol Cell Biol 2000; 20(20): 7419-26.
107. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenish R. Introduction of tumors in mice by genomic hypomethylation Science 2003; 300(5618): 489-92.
108. Kimura F, Seifert HH, Flori AR, Santourlidis S, Steinhoff C, Swiatkowski S, Mahotka C, Gerharz CD, schulz WA. Decrease of DNA methyltransferase 1 expression relative to cell proliferation in transitional cell carcinoma. Int J Cancer 2003; 104(5): 568-78.
109. Hoeben RC, Migchielsen AA, van der Jagt RC, van Ormondt H, van der Eb AJ. Inactivation of the Moloney murine leukemia virus long terminal repeat in murine fibroblast cell lines is associated with methylation and dependent on its chromosomal position. J Virol 1991; 65: 904–12.
110. Loh TP, Sievert LL, Scott RW. Evidence for a stem cell-specific repressor of Moloney murine leukemia virus expression in embryonal carcinoma cells. Mol Cell Biol 1990; 10: 4045–57.
111. Rebollo R, Miceli-Royer K, Zhang Y, Farivar S, Gagnier L, Mager DL. Epigenetic interplay between mouse endogenous retroviruses and host genes. Genome Biol 2012; 13: R89 [Epub ahead of print]
112. Walsh CP, Chaillet JR, Bestor TH: Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 1998; 20: 116-7.
113. Banno K, Yanokura M, Susumu N, Kawaguchi M, Hirao N, Hirasawa A, Tsukazaki K, Aoki D. Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer. Oncol Rep 2006; 16(6): 1189-96.
114. Stengel S, Fiebig U, Kurth R, Denner J. Regulation of human endogenous retrovirus-K expression in melanomas by CpG methylation. Gen Chromosom Cancer 2010; 49(5): 401-11.
115. Martin A, Troadec C, Boualem A, Rajab M, Fernandez R, Morin H, Pitrat M, Dogimont C, Bendahmane A. A transposon-induced epigenetic change leads to sex determination in melon. Nature 2009; 461: 1135-8.
116. Salvesen HB, Stefansson I, Kretzschmar EI, Gruber P, MacDonald ND, Ryan A, Jacobs IJ, Akslen LA, Das S. Significance of PTEN alterations in endometrial carcinoma: a population-based study of mutations, promoter methylation and PTEN protein expression. Int J Oncol 2004; 25(6): 1615-23.
117. Saldaña-Meyer R, Recillas-Targa F. Transcriptional and epigenetic regulation of the p53 tumor suppressor gene. Epigenetics 2011; 6(9): 1068-77.
118. Maksakova IA, Romanish MT, Gagnier L, Dunn CA, van de Lagemaat LN, Mager DL. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet 2006; 2: e2.
119. Okuda T, Sekizawa A, Purwosunu Y, Nagatsuka M, Morioka M, Hayashi M, Okai T. Genetics of endometrial cancers. Obstet Gynecol Int 2010; 2010: 984013.
120. Lavie L, Kitova M, Maldener E, Meese E, Mayer J. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J Virol 2005; 79(2): 876-83.
121. Roebke C, Wahl S, Laufer G, Stadelmann C, Sauter M, Mueller-Lantzsch N, Mayer J, Ruprecht K. An N-terminally truncated envelope protein encoded by a human endogenous retrovirus W locus on chromosome Xq22.3. Retrovirol 2010; 7: 69.
122. Lindeskog M, Mager DL, Blomberg J. Isolation of a human endogenous retroviral HERV-H element with an open env reading frame. Virology 1999; 258(2): 441-50.
123. George M, Schwecke T, Beimforde N, Hohn O, Chudak C, Zimmermann A, Kurth R, Naumann D, Bannert N. Identification of the protease cleavage sites in a reconstituted Gag polyprotein of an HERV-K(HML-2) element. Retrovirol 2011; 8: 30.
124. Cohen CJ, Lock WM, Mager DL. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 2009; 448: 105-14.
125. Romanish MT, Lock WM, van de Lagemaat LN, Dunn CA, Mager DL. Repeated recruitment of LTR retrotransposons as promoters by the anti-apoptotic locus NAIP during mammalian evolution. PLoS Genet 2007, 3: e10.
126. Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JW, Su AI. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 2009; 10: R130.
127. Ekram MB, Kang K, Kim H, Kim J. Retrotransposons as a major source of epigenetic variations in the mammalian genome. Epigenetics 2012; 7: 370-82.
128. Yates PA, Burman RW, Mummaneni P, Krussel S, Turker MS: Tandem B1 elements located in a mouse methylation center provide a target for de novo DNA methylation. J Biol Chem 1999; 274: 36357-61.  
129. Rebollo R, Karimi MM, Bilenky M, Gagnier L, Miceli-Royer K, Zhang Y, Goyal P, Keane TM, Jones S, Hirst M, Lorincz MC, Mager DL. Retrotransposon-induced heterochromatin spreading in the mouse revealed by insertional polymorphisms. PLoS Genet 2011; 7: e1002301.
130. Whitelaw E, Martin DI. Retrotransposons as epigenetic mediators of phenotypic variation in mammals. Nat Genet 2001; 27(4): 361-5.
131. Hayakawa S. No cancer in cancers: evolutionary trade-off between successful viviparity and tumor escape from the adaptive immune system. Med Hypotheses 2006; 66: 888–9.
132. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329–60.
133. Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, Biggar RJ. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS 2006; 20: 1645–54.
134. Verdecchia A, Mariotto A, Capocaccia R, Gatta G, Micheli A, Sant M, Berrino F. Incidence and prevalence of all cancerous diseases in Italy: trends and implications. Eur J Cancer 2001; 37: 1149-57.
135. Simboeck E, Ribeiro JD, Teichmann S, Di Croce L. Epigenetics and senescence: learning from the INK4-ARF locus. Biochem Pharmacol 2011; 82: 1361-70.
136. Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol 2011; 21: 349-53.
137. Shay JW, Wright WE. Telomeres and telomerase: implications for cancer and aging. Radiat Res 2001; 155(1 Pt 2): 188-93.
138. Aragona M, Maisano R, Panetta S, Giudice A, Morelli M, La Torre I, La Torre F. Telomere length maintenance in aging and carcinogenesis. Int J Oncol 2000; 17: 981-9.
139. Hahn WC, Meyerson M. Telomerase activation, cellular immortalization and cancer. Ann Med 2001; 33: 123-9.
140. Tzuckerman M, Selig S, Skorecki K. Telomeres and telomerase in human health and disease. J Pediatr Endocrinol Metab 2002; 15(3): 229-40.
141. Curcio MJ, Belfort M. The beginning of the end: Links between ancient retroelements and modern telomerases. Proc Natl Acad Sci USA 2007; 104(22): 9107-8.
142. Donate LE, Blasco MA. Telomeres in cancer and ageing. Philos Trans R Soc Lond B Biol Sci 2011; 366(1561): 76-84.
143. Eickbush TH. Telomerase and retrotransposons: which came first? Science 1997; 277: 911–2.
144. Nakamura TM, Cech TR. Reversing time: origin of telomerase. Cell 1998: 587–90.
145. Nergadze SG, Santagostino MA, Salzano A, Mondello C, Giulotto E. Contribution of telomerase RNA retrotranscription to DNA double-strand break repair during mammalian genome evolution. Genome Biol 2007; 8(12): R260.
146. Scholes DT, Kenny AE, Gamache ER, Mou Z, Curcio MJ. Activation of a LTR-retrotransposon by telomere erosion. Proc Natl Acad Sci USA 2003; 100(26): 15736-41.
147. Fajkus J, Sýkorová E, Leitch AR. Telomeres in evolution and evolution of telomeres. Chromosome Res 2005; 13(5): 469-79.
148. Gladyshev EA, Arkhipova IR. Telomere-associated endonuclease-deficient Penelope-like retroelements in diverse eukaryotes. Proc Natl Acad Sci USA 2007; 104: 9352–7.
149. Morrish TA, Garcia-Perez JL, Stamato TD, Taccioli GE, Sekiguchi J, Moran JV. Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres. Nature 2007; 446: 208–12.
150. Pardue ML, DeBaryshe PG. Retrotransposons provide an evolutionarily robust non-telomerase mechanism to maintain telomeres. Annu Rev Genet 2003; 37: 485-511.
151. Rashkova S, Athanasiadis A, Pardue ML. Intracellular targeting of Gag proteins of the Drosophila telomeric retrotransposons. J Virol 2003; 77(11): 6376-84.
152. Rashkova S, Karam SE, Kellum R, Pardue ML. Gag proteins of the two Drosophila telomeric retrotransposons are targeted to chromosome ends. J Cell Biol 2002; 159(3): 397-402.
153. Kopera HC, Moldovan JB, Morrish TA, Garcia-Perez JL, Moran JV. Similarities between long interspersed element-1 (LINE-1) reverse transcriptase and telomerase. Proc Natl Acad Sci USA 2011; 108(51): 20345-50.
154. Lamy E, Goetz V, Erlacher M, Herz C, Mersch-Sundermann V. hTERT: another brick in the wall of cancer cells. Mutat Res 2012; pii: S1383-5742(12)00070-1. [Epub ahead of print]
155. Bertorelle R, Briarava M, Rampazzo E, Biasini L, Agostini M, Maretto I, Lonardi S, Friso ML, Mescoli C, Zagonel V, Nitti D, De Rossi A, Pucciarelli S. Telomerase is an independent prognostic marker of overall survival in patients with colorectal cancer. Br J Cancer 2013; 108(2): 278-84.
156. Wang Z, Xu J, Geng X, Zhang W. Analysis of DNA methylation status of the promoter of human telomerase reverse transcriptase in gastric carcinogenesis. Arch Med Res 2010; 41(1): 1-6.
157. Taka T, Huang L, Wongnoppavich A, Tam-Chang SW, Lee TR, Tuntiwechapikul W. Telomere shortening and cell senescence induced by perylene derivatives in A549 human lungcancer cells. Bioorg Med Chem 2013; 21(4): 883-90.
158. Tanaka H, Abe S, Huda N, Tu L, Beam MJ, Grimes B, Gilley D. Telomere fusions in early human breast carcinoma. Proc Natl Acad Sci USA 2012; 109(35): 14098-103.
159. Rudolph KL, Millard M, Rosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 2001; 28: 155–9.
160. Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA, Castrillon DH, Horner JW, Weiler SR, Carrasco RD, DePinho RA. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc Natl Acad Sci USA 2002; 99: 8191–6.
161. Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, Blasco MA. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 2006; 8(4): 416-24.
162. Prindull G. Final checkup of neoplastic DNA replication: evidence for failure in decision-making at the mitotic cell cycle checkpoint G(1)/S. Exp Hematol 2008; 36: 1403-16.
163. Ruey-Jien C, Chien-Ts C, Su-Cheng H, Song-Nan C, Chang-Yao H. Telomerase activity in gestational trophoblastic disease and placental tissue from early and late human pregnancies Hum Reprod 2002; 17: 463-8.
164. Calado RT, Young NS. Telomere diseases. N Engl J Med 2009; 361: 2353–65.
165. Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis 2010; 31: 9–18.
166. Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 2001; 409: 633–7.
167. Capkova Frydrychova R, Biessmann H, Mason JM. Regulation of telomere length in Drosophila. Cytogenet Genome Res 2008; 122: 356–64.
168. Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Cancer Res 2009; 69(22): 8536-9.
169. Duelli D, Lazebnik Y. Cell-to-cell fusion as a link between viruses and cancer. Nat Rev Cancer 2007; 7(12): 968–76.
170. Rote NS, Chakrabarti S, Stetzer BP. The role of human endogenous retroviruses in trophoblast differentiation and placental development. Placenta 2004; 25(8-9): 673-83.
171. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90.
172. Ben-Arie A, Goldchmit C, Laviv Y, Levy R, Caspi B, Huszar M, Dgani R, Hagay Z. The malignant potential of endometrial polyps. Eur J Obstet Gynecol Reprod Biol 2004; 115(2): 206-10.
173. Wethington SL, Herzog TJ, Burke WM, Sun X, Lerner JP, Lewin SN, Wright JD. Risk and predictors of malignancy in women with endometrial polyps. Ann Surg Oncol 2011; 18(13): 3819-23.
174. De Parseval N, Heidmann T. Physiological knockout of the envelope gene of the single-copy ERV-3 human endogenous retrovirus in a fraction of the Caucasian population. J Virol 1998; 72(4): 3442-5.
175. Villarreal LP, DeFilippis VR. A hypothesis for DNA viruses as the origin of eukaryotic replication proteins. J Virol 2000; 74: 7079-84.

Source(s) of Funding


Competing Interests

Nothing to declare.


This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.


Author Comments
2 comments posted so far

Cordially Thanks to Reviewers Posted by Dr. Ervin Mingomataj on 20 Apr 2013 04:44:12 PM GMT

Horrible Scenario Posted by Dr. Ervin Mingomataj on 27 Feb 2013 06:22:28 PM GMT


What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)