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Endogenous and the Development of George Kassiotis This information is current as J Immunol 2014; 192:1343-1349; ; of September 26, 2021. doi: 10.4049/jimmunol.1302972 http://www.jimmunol.org/content/192/4/1343 Downloaded from References This article cites 87 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/192/4/1343.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Endogenous Retroviruses and the Development of Cancer George Kassiotis Mammalian include a considerable number of Ultimately, germ-line–integrated ERV sequences degen- endogenous retroviruses (ERVs), relics of ancestral in- erate by accumulation of mutations or recombination events, fectious retroviruses, whose have invaded which destroy their ability to produce infectious (1, the germ-line. The documented ability of infectious ret- 10). For example, recombination between the two LTRs ex- roviruses to cause cancer has greatly contributed to the cises the whole , leaving only a single LTR (referred discovery of ERVs. It also reinforced the concept that to as solo LTR, Fig. 1). These make up the majority (90%) ERVs are causative agents of many , a notion that of all LTR elements. ERVs that have recently invaded the historically has not always stood up to experimental scru- germ-line are more likely to represent full, sometimes in- fectious, copies and are also more likely to be insertionally

tiny. The recent greater appreciation of the complexity Downloaded from of ERV biology and the identification of dedicated host polymorphic between individuals. Inversely, older ERVs have mechanisms controlling ERV activity have revealed novel sustained significantly more damage to their open reading interactions between ERVs and their hosts, with the po- frames (ORFs), rendering them replication defective, and tential to cause or contribute to disease. In this review, they also have reached genetic fixation in their host the involvement of ERVs in cancer initiation and pro- (10).

gression is discussed, as well as their contribution to It is important to note that the ability of ERVs to produce http://www.jimmunol.org/ our understanding of the process of transformation and infectious virions differs substantially between host species. For example, replication-competent endogenous copies of to the invention of innovative preventive and therapeutic murine virus (MLV) or mouse mammary tumor virus cancer treatments. The Journal of Immunology, 2014, (MMTV) can be found in many strains of laboratory mouse (4). 192: 1343–1349. Infectious produced by these ERVs can cause new so- matic infections, as well as transmit vertically to progeny ndogenous retroviruses (ERVs) are remnants of germ- as fully exogenous retroviruses. Replication-competent ERVs have also been found in other species of mammal (11). How-

line integrations of exogenous infectious retroviruses by guest on September 26, 2021 E (1–4). Once in the germ-line of a species, these pro- ever, no replication-competent human ERV (HERV) has been viral DNA copies may amplify their copy number by reinfec- found. HERV ORFs appear to be more defective than murine tion of germ cells (1). ERVs are recognized by their similarity ERVs, and most HERVs are fixed in the human germ-line. in genomic structure with all retroviruses, typically consisting One possible exception is the HML2 group of the HERV-K of a gag, pro, pol, and env flanked by two long-terminal family, which is considered the most recently acquired family repeats (LTRs) (Fig. 1). Certain ERVs may also lose the env (12–14). HERV-K(HML2) proviruses have the most intact and, thus, the ability to infect new cells (Fig. 1). These can ORFs, although none seems to be replication competent, and still propagate efficiently in the germ-line by retrotransposition at least some of them display insertional polymorphism within rather than reinfection (1, 5). the human population (12–14). In addition to ERVs, non- ERVs make up 5.0 and 4.7% of the mouse and human LTR are still active in both humans and genomes, respectively (6, 7), and are part of the group of LTR mice, where frequent somatic retrotransposition can be dem- elements, which also contains the mammalian apparent LTR onstrated (8, 13, 15). retrotransposons (MaLRs) (Fig. 1). LTR elements belong to Given the ability of ERVs and other retroelements to move a larger family of retroelements that also includes non-LTR in the genome, it is perhaps anticipated that these “genomic retrotransposons (8, 9). The latter make up a larger part of the parasites” have been incriminated in the pathological pro- genome [27 and 34% of the mouse and human genomes, cesses leading to cancer, which is also viewed as a “genomic respectively (6, 7)] and can be distinguished into long inter- disease.” Understanding the nature of ERV association with spersed nuclear elements (LINEs) and short interspersed nu- cancer and elucidating the precise mechanisms underlying any clear elements (Fig. 1). such association will be important in reaching a verdict.

Division of Immunoregulation, Medical Research Council National Institute for Med- Research, The Ridgeway, London NW7 1AA, U.K. E-mail address: gkassio@nimr. ical Research, London NW7 1AA, United Kingdom; and Department of Medicine, mrc.ac.uk Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom Abbreviations used in this article: ERV, endogenous ; HERV, human endog- Received for publication November 4, 2013. Accepted for publication December 10, enous retrovirus; LINE, long interspersed nuclear element; LTR, long-terminal repeat; 2013. MaLR, mammalian apparent long-terminal repeat ; MLV, murine leu- kemia virus; MMTV, mouse mammary tumor virus; ORF, open reading frame. This work was supported by the U.K. Medical Research Council (U117581330). Address correspondence and reprint requests to Dr. George Kassiotis, Division Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 of Immunoregulation, Medical Research Council National Institute for Medical

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302972 1344 BRIEF REVIEWS: ENDOGENOUS RETROVIRUSES IN CANCER

FIGURE 1. Retroelement compo- sition of the mouse genome. The pro- portion of LTR retroelements (MaLRs and ERVs) and non-LTR retrotrans- posons (LINEs and short interspersed nuclear element [SINE]) is depicted. The typical genomic structure of dis- tinct ERVs, adopted from Ref. 90, is also shown. ORF overlap has been re- moved for simplicity. Downloaded from ERVs and cancer: a historical perspective avian leukosis virus in domestic fowl. The latter work by Historically, ERVs have been linked to the development of R. Weiss in London, England was one of the earliest sug- cancer as a result of the transforming nature of retroviral in- gestions of the existence of ERVs and is reviewed elsewhere fection, a property that was also a major contributor to the (11, 17). The leukemogenic potential of these ERVs also rein- discovery of ERVs (11, 16, 17). Furthermore, the study of forced the association with cancer. However, at least for the retroviral infection in models has greatly contributed laboratory mouse, ERVs appear to have far-reaching effects. http://www.jimmunol.org/ to the delineation of the process of cellular transformation and First, many murine ERVs are still very much active and, thus, laid the foundation of modern (18). a significant source of mutation of the murine germ-line. It is The one animal that supported the study of retroviral in- estimated that 1 in 10 spontaneous phenotypes that have been fection and discovery of ERVs, as well as their association with described in mice are caused by insertional mutagenesis by an cancer, is arguably the mouse (11, 16, 17). Records of spon- ERV (21, 22). Second, active ERV retrotransposition in the taneous tumors observed in mice date back to the 1890s and mouse germ-line and intensive inbreeding involved in the es- include mice that were caught in the wild or supplied by tablishment of laboratory mice have resulted in extensive insertional ERV polymorphisms among mouse strains (4). mouse fanciers, who had been breeding selected phenotypic by guest on September 26, 2021 traits (16). Cancer research scientists both in Europe and Insertional ERV polymorphism is a considerable part of all North America around that time had been obtaining mice structural variants among mouse strains identified by genome from mouse farms, which often kept family records of the sequence comparisons and undoubtedly will affect the phe- selected breeds (16). This collaboration fertilized the early notypic outcome of a given single-gene mutation in distinct notion of “heritable” cancer, which was later investigated ex- inbred mouse strains (23). tensively at the Bussey Institute of Harvard University in Similarly to the first inbred mouse strain, DBA, bred for and Boston, Massachusetts. There, C.C. Little and his mentor, named after its coat color, which is the result of a germ-line W.E. Castle, carried out seminal work on cancer genetics with integration of an MLV provirus (24), selection of certain phe- mice likely originally obtained from a nearby mouse farm run notypic characteristics by early mouse fanciers and experimental by Miss A. Lathrop, who had also made important observa- may have inadvertently contributed to the high ERV tions on the spontaneous incidence of cancers in her mice (19, activity in laboratory mice, rendered polymorphic by subse- 20). This work at the Bussey Institute also included the ge- quent inbreeding. Although this situation is ideal for the study netics of coat color and transplant rejection and generated the of ERVs in particular, it is something that should be considered first inbred mouse strains, which proved an invaluable tool not in the interpretation of studies involving mice. only in the dissection of cancer genetics and transplantation, Potential mechanistic links between ERVs and cancer but also later in all other fields of experimental biology (20). Little’s work also led to the discovery by J.J. Bittner at the With the possible exception of rare acutely oncogenic variants, Jackson Laboratory in Bar Harbor, Maine of the “milk factor,” a exogenous infectious retroviruses cause cancer principally by vertically transmitted extrachromosomal agent causing mammary insertional mutagenesis, a process that has led to the identi- cancers in mice (16). This, of course, was MMTV, the proto- fication of numerous cellular or tumor-suppressor typic b-retrovirus responsible for the majority of mammary genes (16, 18). This well-established transforming potential tumors in mice, and its transmission via milk seemed to argue ofexogenousretrovirusesisalsosharedbyatleastthoseERVs against Mendelian cancer inheritance. However, several years that retain infectivity, such as the infectious copies of MMTV later, the Dutch investigators P. Bentvelzen and J.H. Daams or MLV in certain mouse strains (3, 4, 16, 18). However, the discovered germ-line–integrated copies of MMTV proviruses, only contribution of the germ-line copy of these infectious which were indeed inherited as Mendelian traits in the GR retroviruses is transmission to progeny, which, in the case of mouse strain and that encoded fully infectious MMTV (16, 17). both MMTV and MLV, can also be achieved by vertical Also notable are the independent parallel discoveries of transmission via milk. Thus, the germ-line copies of infectious endogenous copies of MLV in inbred mouse strains and of ERVs may not directly participate in the process of cellular The Journal of Immunology 1345 transformation. Instead, it is new somatic integrations as a from controversy (28). The strong link between MMTV result of cellular infection with virions encoded by infectious infection and mammary tumor in mice inspired an exhaustive, ERVs that mediate the mutagenic effect. However, in contrast but as yet unsuccessful, quest for a retrovirus causing human to mechanisms necessitating somatic infections by infectious . The lack of convincing evidence, despite major retroviruses, the sheer number and repetitive nature of ERVs efforts in identifying human tumor viruses, led to scientists in the genome and, consequently, their presence in every cell referring to the elusive target as “rumor viruses” (28). may trigger additional pathogenic mechanisms that do not Although the discovery of human T-lymphotropic virus 1 require the production of infectious virions (25, 26); these are unequivocally proved the existence of a tumor-inducing discussed separately (Fig. 2). exogenous human retrovirus, no HERV provirus with the Transformation by insertional mutagenesis. The process of trans- potential to produce an infectious retrovirus has been discovered. formation by endogenous copies of infectious MMTV and One of the most convincing evidence for infectious HERVs MLV almost invariably involves insertional activation of would be finding new somatic HERV integrations, and oncogenes, such as Wnt1 or Notch1, among many others, or genome sequencing and analysis tools are sufficiently de- disruption of tumor-suppressor genes, and it has been described veloped today to provide a certain degree of validity, even extensively in the mouse (27). However, the search for infectious of negative findings. In this regard, data from cancer genome retroviruses, endogenous or otherwise, which may be causing sequencing identified .180 LINE-1 somatic integrations in cancer in humans through a similar mechanism, was not free human cancer cells (29). In contrast, the same data identified

only a single somatic integration of a small HERV fragment, Downloaded from which was likely the result of a microhomology-mediated DNA repair mechanism rather than genuine retrotransposition (29). Nevertheless, it is conceptually possible that infectious retroviruses derived from HERV precursors do arise sponta-

neously. These may not cause generalized infection within an http://www.jimmunol.org/ individual or even transmission between individuals and, therefore, would elude detection. Indeed, the HERV-K (HML2) family comprises insertionally polymorphic provi- ruses with various degrees of inactivation that collectively, but not individually, contain the complete information for a rep- lication-competent recombinant retrovirus (30, 31). Recom- bination between defective HERV-K(HML2) proviruses was

shown to occur naturally (14, 32) and may be facilitated by by guest on September 26, 2021 exogenous retroviruses, as in the case of HIV-1 infection (33). Although such recombination events restoring ERV infectiv- ity would be exceptionally rare, recent mouse studies (34, 35) showed that the probability of infectious MLVs arising from defective ERV precursors can be significantly elevated when innate and adaptive immune responses are defective. This process ultimately leads to development of in mice and additionally seems to be controlled by environmental parameters, such as the intestinal microbiota (34). Therefore, it is possible that infectious HERVs do arise and contribute to cancer development in specific situations involving immu- nodeficiency. Tumor-promoting retroviral proteins. Although most, if not all, ERVs have accumulated replication-inactivating mutations, many still contain intact ORFs that produce retroviral proteins (36, 37). These ERV-derived proteins may serve as a source of Ag for the and, for certain ERVs, also a source of superantigen, with examples including MMTV in mice (38) and HERV-K18 in humans (39). ERV-encoded proteins are unlikely to be distinguished by the immune system from all other host proteins and, thus, are expected to contribute to T or B cell AgR repertoire– selection processes, as well as peripheral regulatory mechanisms, FIGURE 2. Potential mechanisms of ERV-mediated transformation. as part of “self” (40, 41). Nevertheless, immune reactivity to Nonallelic homologous recombination between ERVs creates chromosomal ERV products can often occur spontaneously in infection or rearrangements. New ERV integrations may disrupt a host gene. ERV tran- cancer and is considered the driving force of several auto- scriptional derepression can activate downstream genes. Accumulated incomplete ERV replication intermediates activate innate immunity or dysregulate non- immunedisordersinmice(42).ImmunereactivitytoERV coding RNA networks. Certain retroviral proteins (e.g., envelope) mediate products can also be induced experimentally in mice and immunosuppression and may also be involved in cellular fusion. nonhuman primates (43, 44), suggesting that immunological 1346 BRIEF REVIEWS: ENDOGENOUS RETROVIRUSES IN CANCER tolerance to ERV-derived proteins is not complete. ERV the replication of exogenous retroviruses and may have similar proteins may also retain biological function, which was pro- roles against ERVs (59, 60). This potential role against ERVs posed to contribute to cellular transformation (45). Indeed, is thought to be at the center of the pathogenic mechanism expression of HERV-encoded proteins has been detected, by initiated when these pathways are not operative. Indeed, Ab straining, in a variety of human cancers (25). Although mutations in the genes encoding these enzymes lead to au- certain HERV proteins can also be expressed in healthy, toimmune or autoinflammatory human conditions associated nontransformed tissue, some show exclusive expression in with elevated production of type I IFNs (61). Notably, tumors (25, 28). However, direct mechanisms of contribution SAMHD1 mutations were also identified in a variety of hu- to cancer development have been proposed for only few of man cancers (62–64), suggesting that SAMHD1 is a tumor- these proteins. suppressor gene, although the precise mechanism connecting Examples include two accessory proteins, Rec and Np9, SAMHD1 mutations with cancer development is not clear. produced as alternative splicing products of the HERV-K In addition to the effect of generic ERV transcripts and (HML2) env gene. These proteins are frequently found in replication intermediates, noncoding RNAs of certain ERVs transformed cells from testicular germ cell tumors but not in can have more direct effects on genome function. Repression of healthy cells (25). Rec, in particular, interacts with the cellular several proto-oncogenes, as well as other cellular genes, relies factor PLZF, and its overexpression in mice can on the premRNA splicing factor PSF (65). In turn, PSF ac- induce early seminomas (46). tivity is negatively regulated by binding to noncoding RNAs,

The envelope proteins of several ERVs may also contribute one of which is transcribed from a HERV-K11 provirus (66), Downloaded from to the development of cancer through their fusogenic or im- thus potentially linking HERV transcription with proto- munosuppressive properties. Both properties of expressed activation. retroviral envelope proteins can also serve physiological pro- ERVs additionally influence genome function without pro- cesses in the host (3). For example, products of the host ducing an RNA transcript (57, 67–69). They provide promoter syncytin genes, which are derived from retroviral env genes, are activity, numerous binding sites for transcription or other essential for placentation, by mediating cell fusion of syncytial DNA binding factors, or homology sites for DNA recom- http://www.jimmunol.org/ cell layers, and for maternal tolerance of the fetus, by im- bination. Indeed, ERV LTRs are perfect docking sites for munosuppression (47). Expression of syncytins, which is nor- DNA-binding factors, which are critically involved in cancer mally restricted to the placenta, was found in human cancer, and development (2). One such factor is p53, an important tumor it is hypothesized that syncytin-mediated cell fusion partici- suppressor maintaining genome integrity and preventing mu- pates in transformation or (48, 49). tation, often referred to as the “guardian of the genome” (70). Seminal work by T. Heidmann further defined the im- One in three of all p53 binding sites identified in a human munosuppressive domain within the transmembrane subunit line were within the LTRs of two HERV families,

of the envelope protein of several retroviruses, as well as its which, when bound by p53, could activate transcription of by guest on September 26, 2021 potential role in tumor growth (50). Overexpression of Moloney downstream genes (71). Thus, ERV LTRs may also partici- MLV transmembrane subunit in murine tumor cell lines led pate in the tumor-suppressing p53 response. to tumor growth in recipient mice that would otherwise im- However, ERV LTRs may also promote cellular transfor- munologically reject them (51). Equally, knockdown of env mation by in cis activation of downstream oncogenes. Tran- transcripts in B16 melanoma and Neuro-2a neuroblastoma scriptional derepression of the CSF1R gene, encoding CSF-1 cell lines, both of which produce infectious MLVs derived receptor, by a demethylated MaLR LTR acting as an alter- from ERV precursors, rendered them susceptible to immune native promoter was linked with survival of cancer B cells in rejection in vivo (52, 53). Thus, ERV-encoded immunosup- Hodgkin’s (72). This study revealed how loss of pressive domains may contribute to cancer development by epigenetic silencing of retroelement LTRs contributes directly establishing the immunosuppression necessary for tumor to tumor growth. growth and, in addition to syncytins, the env of HERV-E (54) Lastly, the repetitive nature of ERVs provides an ideal and HERV-H (55) was shown to possess immunosuppressive substrate for nonallelic homologous DNA recombination (2, potential. 32, 56), which results in a variety of chromosomal rear- ERV effects on genome function. For every ERV with the ability rangements. Recombination between ERVs is responsible for to produce proteins or virions, there are many more that are notable germ-line genomic rearrangements leading to known transcriptionally silenced or may produce only noncoding human genetic disorders (32). Such recombination events can RNA transcripts. Both noncoding RNA transcription from also occur in somatic cells, resulting in chromosomal trans- ERVs and their repetitive presence in the genome as DNA locations, which, in turn, underpin cellular transformation. elements have enormous potential to affect genome function Examples include recurrent chromosomal translocations in hu- (56). Although some of the complex effects of ERVs on genome man prostate cancer, which create fusions between a HERV-K function benefit the host and have been co-opted during provirus and an otherwise dormant oncogene of the ETS evolution, others may be pathogenic (56, 57). (E26 transformation–specific) family (73). Further study of The cell possesses an array of enzymes involved in DNA chromosomal translocations in cancer is expected to add to metabolism, and some of these are considered essential for the list of ERVs driving these translocations. preventing accumulation of intermediates from incomplete ERV replication cycles. These include TREX1, an Elevated ERV activity in cancers: harmful cause or useful consequence? ssDNA exonuclease, and SAMHD1, an enzyme involved in It is evident that ERVs possess properties that might cause or the regulation of cytosolic deoxyribo-NTPs (58) that may also contribute to cancer development, and the activity of many exert nuclease activity (59, 60). These enzymes interfere with ERVs is frequently elevated in transformed cells. There are The Journal of Immunology 1347 numerous examples of ERV protein expression or virion pro- the possibility of targeted against duction in mouse and human cancer cells (74, 75). However, ERVs. both ERV proteins and virions also can be seen in either certain healthy tissues, such as the placenta (76–78), or in infection and Conclusions other nonneoplastic diseases. Therefore, elevated ERV activity, The tumorigenic mechanisms used by exogenous retroviruses, even if restricted to cancer cells, should not be taken to signify namely insertional mutagenesis and acquisition of oncogenes, causality. Rather, most of this activity is likely to represent lack helped to pave the way to understanding cellular-transformation of ERV regulation under these conditions. events. This increased understanding of the complex processes ERV activity in a cell is regulated by both cell-intrinsic of transformation no longer required infection with retro- factors and external signals (1, 3, 34, 79). Epigenetic silenc- viruses, because similar genomic insults are generated by a ing seems to be a major way in which the cell prevents variety of other mechanism. However, this increased under- transcription of repetitive elements, including ERVs (1, 3). standing of genome structure and function has also highlighted Global DNA hypomethylation, leading to epigenetic dere- the potential importance of ERVs, the ultimate genomic pression, is a hallmark of cellular transformation and a major parasites, although obtaining compelling evidence remains a contributor to oncogene activation. In the altered epigenetic challenge. Just as their predecessors, exogenous retroviruses, landscape of transformed cells, ERV derepression should be did in the past, ERVs may illuminate additional mechanistic expected as a consequence (80). details of cancer initiation and progression, as well as offer

Nevertheless, causal or otherwise, characteristic patterns of new prospects for cancer immunotherapy. Downloaded from ERV expression are often seen in various tumors (25), offering a unique approach to immunotherapy, trials of which already Acknowledgments have been contemplated (44). Largely tumor-restricted ex- I thank Jonathan Stoye at National Institute for Medical Research for helpful pression was proposed for several ERVs, including HERV-K discussion and critical reading of the manuscript. (HML6) in melanomas, HERV-K(HML2) in germ-cell car- cinomas, HERV-E in renal cell , or even syncytin- Disclosures http://www.jimmunol.org/ 1 in diverse cancers (81, 82). HERV expression in some of The author has no financial conflicts of interest. these cases also was demonstrated to lead to immune reactivity against HERV-derived epitopes (83, 84). Of note, hemato- References poietic transplantation in patients with renal cell 1. Dewannieux, M. and T. Heidmann. 2013. 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