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Cancer/testis antigens and gametogenesis: a review and "brain-storming" session

Cancer Cell International volume 5, Article number: 4 (2005) Cite this article

Abstract

Genes expressed both in normal testis and in malignancies (Cancer/ Testis associated genes – CTA) have become the most extensively studied antigen group in the field of tumour immunology. Despite this, many fundamentally important questions remain unanswered: what is the connection between germ-cell specific genes and tumours? Is the expression of these genes yet another proof for the importance of genome destabilisation in the process of tumorigenesis?, or maybe activation of these genes is not quite random but instead related to some programme giving tumours a survival advantage?

This review collates most of the recent information available about CTAs expression, function, and regulation. The data suggests a programme related to ontogenesis, mostly to gametogenesis. In the "brain-storming" part, facts in conflict with the hypothesis of random CTA gene activation are discussed. We propose a programme borrowed from organisms phylogenetically much older than humans, which existed before the differentiation of sexes. It is a programme that has served as a life cycle with prominent ploidy changes, and from which, as we know, the germ-cell ploidy cycle – meiosis – has evolved. Further work may show whether this hypothesis can lead to a novel anti-tumour strategy.

Introduction

Cancer/Testis (CT) antigens are a group of tumour antigens with gene expression restricted to male germ cells in the testis and to various malignancies. Their function in tumours is enigmatic and a common between testis genes (gametogenesis) and cancer remains elusive. When the causal link is not evident, it is tempting to believe the association is random, and assign it to general aspects of "genome instability in cancer". However, we believe a more direct link may exist. As suggested in this review, possible clues may be found in the common evolutionary pathway between ploidy cycles in meiosis and polyploidy in tumour cells. The latter, along with CT antigen expression, is a characteristic feature of well-progressed tumours. However, before discussing such possibilities, it is necessary to review the established literature.

The search for tumour antigens began in the 1960's with two groups identifying first alpha-fetoprotein (AFP), a serum marker for hepatoma and germ-cell tumours [1], and then carcinoembryonic antigen (CEA), a serum marker for colon and other epithelial cancers [2]. These antigens were discovered using heterogenous sera acquired by immunizing laboratory animals with human tumour material. However, only during the 90's did both cellular [3, 4] and humoral [5] immune responses to human tumours get proper molecular definitions.

The first CTA, MAGEA-1, was identified in 1991 by Boon and colleagues using T-cell epitope cloning, a very complicated and time-consuming method [3]. In 1995 the SEREX (serological expression cloning) technique to identify tumour antigens was developed by Pfreundschuh and colleagues [5], which remains the leading approach to identifying new antigens that elicit humoral immune responses. Besides MAGEA1, BAGE, and GAGE1 discovered by T-cell epitope cloning, SEREX very soon displayed more tumour antigens with a cancer/testis restricted expression profile (SSX2, NY-ESO-1, and SYCP-1). The term "cancer-testis (CT) antigen" was introduced by Chen et al. [6], who recognized this group of genes had little in common except their expression profile.

By initial definition, expression of genes coding for CT antigens should be restricted in normal tissues to male germ cells in the testis and to malignancies of various histological types. However, the criteria proposed in the 90's are not true for all antigens of this group as seen today. Furthermore, for many of the recently discovered gene products with the described expression profile, no T-cell recognized epitopes have hitherto been identified. This is why CTA – "Cancer/Testis Associated" is a more appropriate name for this family of genes (and will be used in this context further in this review), because a lot of its members still need to be proven as possessing antigenic properties in cancer patients.

Attributing genes to the CTA gene family is based on several characteristic features [7, 8]:

  1. 1.

    Predominant expression in germ cells of the testis and generally not in other normal tissues.

  2. 2.

    Expression in a number of malignant tumours of various histological types.

  3. 3.

    Mapping of the gene to the X-chromosome

  4. 4.

    Membership of a multigene family.

  5. 5.

    Antigenic properties in tumour-bearing patients.

Some exceptions to these criteria for certain CTAs will be described and discussed later.

Expression of CTA genes

To date, 89 individual CTA genes or isoforms have been described, which are organised in to 44 families (see additional file 1). From these, 19 families are testis-restricted, and 11 show additional expression in one or two somatic tissues. Nine are expressed in 3–6 tissue types besides testis, and 5 are ubiquitously somatically expressed. With the exception of the testis-restricted CTAs, the others also show expression in the pancreas but at levels as much as 10 × lower than in testis (based on mRNA expression levels from [9]). Expression of CTA was first shown in melanoma and all the classic CTA are expressed in this type of tumour, but since the 1980's, expression in various other tumours has been recognised (additional file 2).

The expression pattern of CTAs during spermatogenesis is of special interest. Functional analysis of these genes during gametogenesis might well give some clues about their possible role in tumours. Their expression is restricted exclusively to spermatogenic germ cells with other tubular cells (e.g. Leydig and Sertoli) being negative. This fits well with the findings of Yuasa et al. [10] who demonstrated that CTAs have much higher expression frequencies in the germ cell cancers (seminomas) than non-seminomas..

Different CTAs are expressed during different stages of spermatogenesis (Fig. 1.), so one may imagine that their functions are versatile, starting from regulation of mitotic cycling in spermatogonia, association with the meiotic cycle in spermatocytes, and finalizing with acrosome maturation in sperm.

Figure 1
figure1

Expression of CTAs during male germ cell development. References for Fig. 1: [25] [27] [28] [37] [40] [42] [53] [92] [93] [94] [95] [96]

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In normal tissues, expression of NY-ESO1, MAGE-A3, -A4, and -A8 through -A11 as well as of several members of the XAGE gene family is found in the placenta. NY-ESO1 and several XAGEs are also expressed in the fetal ovary [11–13].

Regulation of CTA expression

The mechanisms involved in regulation of CTA expression have recently been comprehensively reviewed by Albert Zendman et al [14]. Thus, only a short recitation of some of the main points is provided here.

Mostly, methylation processes are responsible for the ectopic derepression of CTA genes. Using the demethylating agent, 5-aza-2-deoxycytidine (5DC), expression of several CTAs in cultured tumour cell lines can be induced/upregulated [15]. 5DC entraps DNA methyltransferases in a complex with DNA, which leads to progressive loss of DNA methylation, thereby releasing transcriptional blockage. Such upregulated expression has been reported for several MAGE members – LAGE-1, SSX-2, CAGE, NY-ESO-1. For MAGE-A1, demethylation is necessary and sufficient for gene expression, suggesting demethylation is the primary mechanism of transcription control [16]. In this context, a recent discovery of a CTA, viz. 'Boris', is interesting. Boris is reported as being expressed in several types of malignancies, and normally plays a major role in regulating methylation processes during spermatogenesis – it removes imprinting from genes during the last mitotic division of spermatocytes (reviewed in [17]). Several lines of evidence indicate that expression of some CTAs is dependent not only on demethylation, but on other transcriptional mechanisms.

Histone deacetylase (HDAC) inhibitors, on their own or in combination with 5DC, can also induce CTA expression, including MAGE, SSX, and NY-ESO-1 family members [15]. The CTA-rich region in Xp11.21-22 (e.g. SSX, MAGE-B) may escape X-chromosomal inactivation, but these genes are not normally expressed in females [18]. While global hypomethylation is common and prominent in colorectal cancer, few CTAs have ever been reported as expressed in this type of cancer [19]. Non-demethylation dependent induction of MAGE expression has been demonstrated by Park et al. [20], demonstrating that 40 mM NaCl induces the transcriptional and translational activation of MAGE-B1 and -B2 in specific tissues at hypertonic conditions.

There exist definite expression patterns (sets) of different CTAs in certain tumours. Marked heterogeneity of CTA expression is found in cells of some tumours, which cannot easily be explained by a global demethylation process [21–24]. The mechanisms of ectopic transcriptional activation of CTA genes clearly needs more investigation.

Function

Information regarding the function and cellular localization of CTAs is far less comprehensive. Often the proposed function is based purely on sequence homology with another protein of a known function. The only CTA proteins functionally established in gametogenesis are SCP-1, involved in chromosome pairing during meiosis [7], OY-TES-1 which functions in acrosin packaging in the acrosome of sperm heads [25], SPO11 acting as a meiosis-specific endonuclease [26], and BORIS, which is involved in cancellation of imprinting by epigenetic reprogramming during the final round of mitosis in spermatogenesis [27]. However, contrary to the situation in meiosis where it is rapidly degraded after the meiotic prophase in spermatocytes, SCP-1 expression in tumours is not cell cycle restricted [7]. BORIS is a paralog of CTCF. CTCF is a highly versatile 11 zinc-finger factor involved in various aspects of gene regulation – X chromosome inactivation, reading of imprinting sites, etc. [27]. During spermatogenesis, Boris is expressed later than many other CTA genes ([27]; Fig. 1.).

Suggestions for the functions of other CTAs mostly arose from studies of their homology with some well-known proteins and their domains, TSP50 being protease-like, CT17 phospholipase-like, and CT15 metalloproteinase-like [28]. The CT15 gene encodes a disintegrin and metalloproteinase (ADAM) domain 2, which is a member of the ADAM protein family [29]. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, which have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This member is a subunit of an integral sperm membrane glycoprotein called fertilin, which plays an important role in sperm-egg interactions [30]. It is a membrane metalloproteinase with a possible role in tumour evasion and metastasis.

LDHC, the germ cell-specific member of the lactate dehydrogenase family, escapes from transcriptional repression, resulting in significant expression levels in virtually all tumour types tested. It might contribute to the constitutive activation of an anaerobic pathway in tumours, because its expression in tumours is not dependent on hypoxia [31].

Suggestions as to the role of MAGEs with a CTA expression profile mainly depend on studies of their ubiquitously expressed family members (e.g. Necdin, MAGE-D1, NRAGE, Dlxin-1). In general, the data point to a role for MAGEs via transcriptional regulation in cell cycle control and apoptosis. F.ex, Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor [32]. The high level of homology among members of the MAGE family in both mouse and human suggests an important function both in testis and cancer.

The products of the SSX genes belong to the family of highly homologous synovial sarcoma X (SSX) breakpoint proteins. These proteins may function as transcriptional repressors; SSX1, SSX2 and SSX4 genes have been involved in the t (X;18) translocation characteristically found in all synovial sarcomas [33–35]. This translocation results in the fusion of the synovial sarcoma translocation gene (SYT) on chromosome 18 to one of the SSX genes on chromosome X. The encoded hybrid proteins are probably responsible for transforming activity. In the nucleus of sarcoma cells, both diffuse and speckled localisations of SSX protein have been reported [36, 37].

The HOM-TES-85 protein has structural peculiarities that are shared exclusively with the N-myc oncoprotein. However, functional studies are required for confirmation [38]. Besides, the C-myc proto-oncogene is a normal participant of spermatogenesis (Fig. 2).

Figure 2
figure2

Oncogene expression during spermatogenesis (mainly in mice). From [70].

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BRDT is similar to the RING3 protein family. It possesses 2 bromodomain motifs and a PEST sequence (a proline, glutamic acid, serine, and threonine cluster) characteristic of proteins that undergo rapid intracellular degradation). The bromodomain is found in proteins that regulate transcription [39].

PLU-1, a large multi-domain nuclear protein also has a strong transcriptional repression activity. It is a member of the ARID family of DNA-binding proteins. Plu-1 mRNA and PLU-1 protein are both highly expressed in the mitotic spermatogonia. The expression is reduced in the early prophase I stages (leptotene, zygotene), but reappears at pachytene, still being detectable in diplotene cells. It is located diffusely over the nucleus. PLU-1 might have a role in regulating meiotic transcription, restricted to certain meiotic stages [40].

The protein encoded by the SPANX gene targets the nucleus and associates with nuclear vacuoles and the redundant nuclear envelope in sperm cells [41]. In situ hybridization of human testis sections showed SPAN-X mRNA expression in round and elongated spermatids [42]. These redundant nuclear envelopes have a unique structure of limited chromatin sheets continued as annulate lamellae. Both these enigmatic structures have also been described in intact lymphomas [43] and irradiated lymphomas [44].

The protein encoded by IL13RA1 gene is a subunit of the interleukin-13 receptor. This subunit forms a receptor complex with IL-4 receptor alpha, a subunit shared by IL-13 and IL-4 receptors. This subunit serves as a primary IL-13-binding subunit of the IL-13 receptor, and may also be a component of IL-4 receptors. This protein binds tyrosine kinase TYK2, and thus may mediate the signalling processes that lead to the activation of JAK1, STAT3 and STAT6 induced by IL-13 and IL-4 [45].

SGY-1 (soggy-1), a secreted protein related to the Dickkopf protein family, is involved in suppressing the Wnt signal-transduction pathway controlling transcription activation of genes such as c-myc, c-jun, Fra, and cyclin D1 by preventing the accumulation of beta-catenin [46, 47]. Wnt proteins are implicated in a wide variety of biologic processes including cell fate determination and patterning in early embryos, and in cell growth and/or differentiation in certain adult mammalian tissues [48]. Wnts can induce proliferation in different types of stem cells [49, 50]. The importance of Wnt signalling during tumorigenesis has been recently emphasised [51, 52].

NY-ESO-1 is one of the most immunogenic and therapeutically promising CTAs but functional studies on this gene are severely lagging behind its practical application. Unlike the majority of CTA genes, NY-ESO-1 stops its expression in well-progressed tumours, so it can be used as a marker to follow the early progression of testicular tumorigenesis [53].

CAGE [54] and HAGE [55] code for proteins with helicase-like features. Probably, it might be involved in recombination exchange in testis and recombination DNA repair in tumours.

TPX-1 is now seen as an integral protein of the outer dense fibres and the acrosome of spermatids in rats [56].

In summary, we see that the functions of individual CTA, when known, are very diverse, including, for example, both activators and repressors of proliferation and transcription.

Immunogenicity

Immunogenicity in cancer patients is elicited only by short peptide sequences of CTA epitopes, which are presented on the tumour cell surface by HLA Class I molecules in the case of cytotoxic T lymphocyte (CTL) mediated immune responses and by HLA Class II molecules on the surface of APC (antigen presenting cells), in the case of T-helper cell (TH) mediated immune responses. Identification of these epitopes is one of the main goals of CTA research. Knowledge of epitopes recognized by the immune system allows the creation of the tumour-specific vaccines. In the vaccination process, T-cell epitopes are often administered together with different adjuvants or cytokines, or delivered using peptide pulsed autologous dendritic cells, all of which are aimed at enhancing the immune reaction [57]. Currently efforts are being made to identify HLA class II restricted epitopes in order to promote TH responses, which are required to support the activity of CTLs, and provide a more "complete" immune response. However, vaccines designated to prime the immune system against tumours expressing various CTA have so far shown only partial clinical success [57–59].

Since the technique used to identify candidate tumour antigens has changed from T-cell epitope cloning [3, 60], and SEREX (serological analysis of cDNA expression libraries) [5, 61, 62] to differential gene expression analysis by various techniques like RDA (representative difference analysis) [63], DD (differential display) [64] and SSH (suppression subtractive hybridization) [65] – and even further to bioinformatics – we cannot really be sure about the adequate use of the definition "antigen" in relation to CTA gene products. Whilst the former two techniques are dependent on the immunogenicity of specific epitopes in cancer patients, the latter ones are simply based on mRNA expression levels or even sequence homologies detected via search engines and provide no answer about immunoreactivity. In additional file 1, one can see that an immune response is documented against only 19 of 44 CTAs. Immune recognition of the majority of these CTAs is cancer-related, occurring spontaneously in cancer patients, not in cancer-free individuals. The exceptions to this are humoral immune responses to MAGEB1/CT3.1 in systemic lupus erythematosus patients [66] and to SPA17/CT22 in vasectomised men [67].

CTA can be considered to be tumour specific. There exists the blood-testis barrier [68], which prevents the immune system from contacting with CTA gene products. Besides this, germinative cells do not express HLA class Ia molecules [69], so they cannot present their expressed proteins to the immune system. For these reasons, the immune system never comes into contact with these proteins and recognizes them as "non-self" structures.

Brain-storming

The function of most CTAs is unknown, although some role in regulation of gene expression (both activating and repressing) seems likely [8]. Are CTAs oncogenes? By definition, oncogenes are normal cellular genes participating in proliferation cascades, which are abnormally activated in tumours [70]. Therefore, with the exception of one (HOM-TES-85, which has structural homology with the myc-oncogene) CTAs can not formally be regarded as oncogenes. Are CTAs simply activated by the imbalanced genome, due to its instability in tumours? Some, such as SSX, whose ectopic expression is caused by the SYT-SSX fusion due to translocation t (X;18) in synovial sarcomas, certainly are. However, a large number of CTA genes are only located on the X-chromosome and this chromosome is not a specific site of chromosome breaks and translocations usually associated with tumours [71]. However, the chromosome region 20q13.2 containing the BORIS gene is commonly amplified or exhibits moderate gains of material in many human cancers. This has strengthened the idea that this region contains a major oncogene [72, 73]. A preliminary report using RT-PCR has found that BORIS expression is detectable in over half of ~200 cancer cell lines studied, representing most of the major forms of human tumours, discussed in [17]. However, this observation awaits further confirmation. Theoretically, the aberrant expression of the amplified (by chance) Boris, which by analogy with CTCF may demethylate CTA genes located on X-chromosome, may in turn activate a large body of CTA genes in human malignancies. However, why are other gametogenesis-related CTA genes also activated from other chromosomes? It does not look like a chance event and therefore amplification of "Boris" may still not be random.

Diversity of functions, including genes involved in ontogenesis suggest that CTAs are activated either as a result of the genome instability (however, why testicular genes?) or as part of a complex program. Also from this point, this looks like a program related to gametogenesis. The same idea was proposed by Old [8].

If CTAs generally do not enhance tumour growth except by stimulating proliferation, like oncogenes, another possibility is that they could do it by stimulating DNA repair or inhibiting apoptosis (combination of all three is possible). Indeed, some CTAs have relation to the DNA repair factors by homologous recombination. These are SPO11, SYCP1, helicase-like CAGE and HAGE acting in meiotic prophase of gametogenesis. In turn, homologous recombination in tumours was shown to act anti-apoptotically [74].

Are these CTAs restricted only to prophase of meiosis, where recombination takes place? It appears not. For example, some are associated with the spermatogonial stage (Plu-1 mRNA and PLU-1), and some with maturation of the acrosome (see Fig. 1). It is a program again, and why only male gametogenesis? But it also occurs in oogenesis [8]. Thus, prophase of meiosis (pairing and recombination) may be still the most important.

So, ectopic activation of CTA genes is not entirely random, being induced from the sexual X-chromosome but also from loci on other chromosomes, relating to gametogenesis. However, it is curious then that the very common proto-oncogenes of proliferatives cascades also participate in gametogenesis, e.g. myc, ras, jun, etc. This can be seen in Fig 2, (taken from the Janis Erenpreiss [70]). He and others postulated a link between gametogenesis and cancerogenesis before CTAs were revealed [75–77].

In turn, Old [8] looked at the problem from a new angle and suggested that CTAs provide a causal link between gametogenesis and cancer. This seems plausable, but does this illegitimate program in tumours embrace, even mosaically, only gametogenesis? May be only the DNA recombination repair component is common? But the CTA genes are repressing a wide Wnt family, which also functions in early embryogenesis.

The program sounds more like an ontogenetic (life-cycle) one. Let us remember the experiments by Mintz and Illmeisee [19] who cloned normal genetic mosaic mice by introducting the nuclei of malignant teratocarcinoma into enucleated eggs. Both gametic, parthenogenetic and trophoblastic theories of cancer have also been proposed in the past [8, 70] and can be viewed as embryonal or ontogenetic theories of cancer.

Another question is whether CTA genes govern a life-cycle-like program with its key events similar to meiosis? In turn, to which process does meiosis provide a key – recombination and reduction division? Are tumours capable of these? We also have to consider why X-chromosomes are involved, and not Y-chromosomes, which are responsible for sex? Perhaps this is because the X-chromosome is better conserved evolutionary and appeared prior to sex discrimination.

So, this looks like an ontogenetic program, which evolutionary preceded sexual (amphimictic) life-cycle, with the key in recombination and reduction division; but what is it? The answer is evident – ancient ploidy cycles [78, 79]. In general, ploidy cycles are displayed as a cyclic increase and reduction of ploidy (chromosome number), and these involve the pairing of homologous chromosomes and their segregation, omitting one round of DNA replication.

There may be reduction of ploidy 2n-n (sexual meiosis) or from nx to 2n DNA numbers, in the asexual ploidy cycles characteristic for a few protists, as in Amoebae and foraminiferans [80, 81] as well as part of ontogenetic programs in the more developed taxons [82, 83]. Contrary to gametic reduction in sexual meiosis, the reduction of ploidy in polyploid somatic cells is called "somatic reduction".

In this context, expression of some CTAs by the placenta is of interest because trophoblast and decidua are the only mammalian tissue capable of endoreduplication creating enormously large ploidies [84]. an ability shared by many tumour cells. The latest studies on a silver fox revealed somatic reduction in the giant cells of a trophoblast [85].

Now let us return to DNA recombination repair in tumours as a means of survival, as already mentioned. Repair by homologous recombination can protect malignant tumour cells from apoptosis. In particular, as shown in our laboratory, endopolyploid cells employ this mechanism [86]. Likewise, expression of CTAs – endopolyploidy – is a hallmark of malignant tumour progression where there is deficient TP53 function [87].

In turn, some giant tumour cells show the capability to segregate their genomes and return to mitosis ([86, 88–91], see Fig. 3).

Figure 3
figure3

Reductional mitotic divisions generating low ploidy cells from one large polyploid cell. Non-treated Burkitt's lymphoma cell line, DNA staining with Toluidine-blue. × 2,500.

Full size image

Conclusion

A hypothesis is put forward that activation of at least some of the CTA genes in p53-deficient human tumours could be due to the genetic program running "relic" ploidy cycles in tumour cells. This hypothesis offers new opportunities for the design of novel tumour treatment strategies. In particular, passive therapy using CTAs to prime the host immune system against the tumour could be replaced with gene therapy aimed to block the function of CTA gene products or even their expression. This approach is promising, because normally only the germ cells in the testis express CTA genes and they are well protected by the blood-testis barrier. Thus, there should not be any problem with tumour-specific priming, and respectively we would predict there to be no side effects.

References

  1. 1.

    Abelev GI, Perova SD, Khramkova NI, Postnikova ZA, Irlin IS: Production of embryonal alpha-globulin by transplantable mouse hepatomas. Transplantation. 1963, 1: 174-180.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Gold P, Freedman SO: Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965, 122: 467-481. 10.1084/jem.122.3.467.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  3. 3.

    van der BP, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den EB, Knuth A, Boon T: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991, 254: 1643-1647.

    Article  Google Scholar 

  4. 4.

    Traversari C, van der BP, Van den EB, Hainaut P, Lemoine C, Ohta N, Old L, Boon T: Transfection and expression of a gene coding for a human melanoma antigen recognized by autologous cytolytic T lymphocytes. Immunogenetics. 1992, 35: 145-152. 10.1007/BF00185107.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M: Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A. 1995, 92: 11810-11813.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  6. 6.

    Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO, Tsang S, Williamson B, Stockert E, Pfreundschuh M, Old LJ: A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci U S A. 1997, 94: 1914-1918. 10.1073/pnas.94.5.1914.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. 7.

    Tureci O, Sahin U, Zwick C, Koslowski M, Seitz G, Pfreundschuh M: Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens. Proc Natl Acad Sci U S A. 1998, 95: 5211-5216. 10.1073/pnas.95.9.5211.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Old LJ: Cancer/testis (CT) antigens - a new link between gametogenesis and cancer. Cancer Immun. 2001, 1: 1-

    CAS  PubMed  Google Scholar 

  9. 9.

    Scanlan MJ, Simpson AJ, Old LJ: The cancer/testis genes: review, standardization, and commentary. Cancer Immun. 2004, 4: 1-

    PubMed  Google Scholar 

  10. 10.

    Yuasa T, Okamoto K, Kawakami T, Mishina M, Ogawa O, Okada Y: Expression patterns of cancer testis antigens in testicular germ cell tumors and adjacent testicular tissue. J Urol. 2001, 165: 1790-1794. 10.1097/00005392-200105000-00102.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Jungbluth AA, Chen YT, Stockert E, Busam KJ, Kolb D, Iversen K, Coplan K, Williamson B, Altorki N, Old LJ: Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues. Int J Cancer. 2001, 92: 856-860. 10.1002/ijc.1282.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    De Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora JP, De Smet C, Brasseur F, van der BP, Lethe B, Lurquin C, .: Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics. 1994, 40: 360-369.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Zendman AJ, Van Kraats AA, Weidle UH, Ruiter DJ, Van Muijen GN: The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's sarcoma. Int J Cancer. 2002, 99: 361-369. 10.1002/ijc.10371.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Zendman AJ, Ruiter DJ, Van Muijen GN: Cancer/testis-associated genes: identification, expression profile, and putative function. J Cell Physiol. 2003, 194: 272-288. 10.1002/jcp.10215.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Shichijo S, Yamada A, Sagawa K, Iwamoto O, Sakata M, Nagai K, Itoh K: Induction of MAGE genes in lymphoid cells by the demethylating agent 5-aza-2'-deoxycytidine. Jpn J Cancer Res. 1996, 87: 751-756.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    De Smet C, Lurquin C, Lethe B, Martelange V, Boon T: DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol. 1999, 19: 7327-7335.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. 17.

    Klenova EM, Morse HCIII, Ohlsson R, Lobanenkov VV: The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Semin Cancer Biol. 2002, 12: 399-414. 10.1016/S1044-579X(02)00060-3.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Miller AP, Willard HF: Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation. Proc Natl Acad Sci U S A. 1998, 95: 8709-8714. 10.1073/pnas.95.15.8709.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  19. 19.

    Mintz B, Illmensee K: Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci U S A. 1975, 72: 3585-3589.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  20. 20.

    Park JH, Lee SW: Hypertonicity induction of melanoma antigen, a tumor-associated antigen. Mol Cells. 2002, 13: 288-295.

    CAS  PubMed  Google Scholar 

  21. 21.

    Coulie PG, Van den Eynde BJ, van der BP, Van Pel A, Boon T: Antigens recognized by T-lymphocytes on human tumours. Biochem Soc Trans. 1997, 25: 544-548.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Dalerba P, Ricci A, Russo V, Rigatti D, Nicotra MR, Mottolese M, Bordignon C, Natali PG, Traversari C: High homogeneity of MAGE, BAGE, GAGE, tyrosinase and Melan-A/MART-1 gene expression in clusters of multiple simultaneous metastases of human melanoma: implications for protocol design of therapeutic antigen-specific vaccination strategies. Int J Cancer. 1998, 77: 200-204. 10.1002/(SICI)1097-0215(19980717)77:2<200::AID-IJC5>3.0.CO;2-U.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Sahin U, Tureci O, Chen YT, Seitz G, Villena-Heinsen C, Old LJ, Pfreundschuh M: Expression of multiple cancer/testis (CT) antigens in breast cancer and melanoma: basis for polyvalent CT vaccine strategies. Int J Cancer. 1998, 78: 387-389. 10.1002/(SICI)1097-0215(19981029)78:3<387::AID-IJC22>3.0.CO;2-2.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Zendman AJ, de Wit NJ, van Kraats AA, Weidle UH, Ruiter DJ, van Muijen GN: Expression profile of genes coding for melanoma differentiation antigens and cancer/testis antigens in metastatic lesions of human cutaneous melanoma. Melanoma Res. 2001, 11: 451-459. 10.1097/00008390-200110000-00003.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Ono T, Kurashige T, Harada N, Noguchi Y, Saika T, Niikawa N, Aoe M, Nakamura S, Higashi T, Hiraki A, Wada H, Kumon H, Old LJ, Nakayama E: Identification of proacrosin binding protein sp32 precursor as a human cancer/testis antigen. Proc Natl Acad Sci U S A. 2001, 98: 3282-3287. 10.1073/pnas.041625098.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  26. 26.

    Romanienko PJ, Camerini-Otero RD: Cloning, characterization, and localization of mouse and human SPO11. Genomics. 1999, 61: 156-169. 10.1006/geno.1999.5955.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, Mannan P, Larsson E, Kanduri C, Vostrov AA, Cui H, Niemitz EL, Rasko JE, Docquier FM, Kistler M, Breen JJ, Zhuang Z, Quitschke WW, Renkawitz R, Klenova EM, Feinberg AP, Ohlsson R, Morse HCIII, Lobanenkov VV: BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci U S A. 2002, 99: 6806-6811. 10.1073/pnas.092123699.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  28. 28.

    Shan J, Yuan L, Xiao Q, Chiorazzi N, Budman D, Teichberg S, Xu HP: TSP50, a possible protease in human testes, is activated in breast cancer epithelial cells. Cancer Res. 2002, 62: 290-294.

    CAS  PubMed  Google Scholar 

  29. 29.

    Scanlan MJ, Gordon CM, Williamson B, Lee SY, Chen YT, Stockert E, Jungbluth A, Ritter G, Jager D, Jager E, Knuth A, Old LJ: Identification of cancer/testis genes by database mining and mRNA expression analysis. Int J Cancer. 2002, 98: 485-492. 10.1002/ijc.10276.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Gupta SK, Alves K, Palladino LO, Mark GE, Hollis GF: Molecular cloning of the human fertilin beta subunit. Biochem Biophys Res Commun. 1996, 224: 318-326. 10.1006/bbrc.1996.1027.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Koslowski M, Tureci O, Bell C, Krause P, Lehr HA, Brunner J, Seitz G, Nestle FO, Huber C, Sahin U: Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Res. 2002, 62: 6750-6755.

    CAS  PubMed  Google Scholar 

  32. 32.

    Kuwako K, Taniura H, Yoshikawa K: Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor. J Biol Chem. 2004, 279: 1703-1712. 10.1074/jbc.M308454200.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    de Bruijn DR, dos Santos NR, Kater-Baats E, Thijssen J, van den BL, Stap J, Balemans M, Schepens M, Merkx G, van Kessel AG: The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RAB3IP, and a novel nuclear protein, SSX2IP. Genes Chromosomes Cancer. 2002, 34: 285-298. 10.1002/gcc.10073.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Yang K, Lui WO, Xie Y, Zhang A, Skytting B, Mandahl N, Larsson C, Larsson O: Co-existence of SYT-SSX1 and SYT-SSX2 fusions in synovial sarcomas. Oncogene. 2002, 21: 4181-4190. 10.1038/sj.onc.1205569.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Storlazzi CT, Mertens F, Mandahl N, Gisselsson D, Isaksson M, Gustafson P, Domanski HA, Panagopoulos I: A novel fusion gene, SS18L1/SSX1, in synovial sarcoma. Genes Chromosomes Cancer. 2003, 37: 195-200. 10.1002/gcc.10210.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    dos Santos NR, de Bruijn DR, Balemans M, Janssen B, Gartner F, Lopes JM, de Leeuw B, Geurts K: Nuclear localization of SYT, SSX and the synovial sarcoma-associated SYT-SSX fusion proteins. Hum Mol Genet. 1997, 6: 1549-1558. 10.1093/hmg/6.9.1549.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    dos Santos NR, de Bruijn DR, Kater-Baats E, Otte AP, van Kessel AG: Delineation of the protein domains responsible for SYT, SSX, and SYT-SSX nuclear localization. Exp Cell Res. 2000, 256: 192-202. 10.1006/excr.2000.4813.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Tureci O, Sahin U, Koslowski M, Buss B, Bell C, Ballweber P, Zwick C, Eberle T, Zuber M, Villena-Heinsen C, Seitz G, Pfreundschuh M: A novel tumour associated leucine zipper protein targeting to sites of gene transcription and splicing. Oncogene. 2002, 21: 3879-3888. 10.1038/sj.onc.1205481.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Pivot-Pajot C, Caron C, Govin J, Vion A, Rousseaux S, Khochbin S: Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Mol Cell Biol. 2003, 23: 5354-5365. 10.1128/MCB.23.15.5354-5365.2003.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Madsen B, Tarsounas M, Burchell JM, Hall D, Poulsom R, Taylor-Papadimitriou J: PLU-1, a transcriptional repressor and putative testis-cancer antigen, has a specific expression and localisation pattern during meiosis. Chromosoma. 2003, 112: 124-132. 10.1007/s00412-003-0252-6.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Westbrook VA, Schoppee PD, Diekman AB, Klotz KL, Allietta M, Hogan KT, Slingluff CL, Patterson JW, Frierson HF, Irvin WPJ, Flickinger CJ, Coppola MA, Herr JC: Genomic organization, incidence, and localization of the SPAN-x family of cancer-testis antigens in melanoma tumors and cell lines. Clin Cancer Res. 2004, 10: 101-112.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Westbrook VA, Diekman AB, Klotz KL, Khole VV, Kap-Herr C, Golden WL, Eddy RL, Shows TB, Stoler MH, Lee CY, Flickinger CJ, Herr JC: Spermatid-specific expression of the novel X-linked gene product SPAN-X localized to the nucleus of human spermatozoa. Biol Reprod. 2000, 63: 469-481.

    CAS  PubMed  Google Scholar 

  43. 43.

    Ultrastructural pathology of cell and matrix. Edited by: Ghadially FN. 2004, London, Butterworths, 1: 3

    Google Scholar 

  44. 44.

    Erenpreisa J, Ivanov A, Cragg M, Selivanova G, Illidge T: Nuclear envelope-limited chromatin sheets are part of mitotic death. Histochem Cell Biol. 2002, 117: 243-255. 10.1007/s00418-002-0382-6.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Aman MJ, Tayebi N, Obiri NI, Puri RK, Modi WS, Leonard WJ: cDNA cloning and characterization of the human interleukin 13 receptor alpha chain. J Biol Chem. 1996, 271: 29265-29270. 10.1074/jbc.271.46.29265.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, Brown DE, Guyot D, Mays G, Leiby K, Chang B, Duong T, Goodearl AD, Gearing DP, Sokol SY, McCarthy SA: Functional and structural diversity of the human Dickkopf gene family. Gene. 1999, 238: 301-313. 10.1016/S0378-1119(99)00365-0.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Karim R, Tse G, Putti T, Scolyer R, Lee S: The significance of the Wnt pathway in the pathology of human cancers. Pathology. 2004, 36: 120-128. 10.1080/00313020410001671957.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Bergstein I, Eisenberg LM, Bhalerao J, Jenkins NA, Copeland NG, Osborne MP, Bowcock AM, Brown AM: Isolation of two novel WNT genes, WNT14 and WNT15, one of which (WNT15) is closely linked to WNT3 on human chromosome 17q21. Genomics. 1997, 46: 450-458. 10.1006/geno.1997.5041.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JRIII, Nusse R: Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003, 423: 448-452. 10.1038/nature01611.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL: A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003, 423: 409-414. 10.1038/nature01593.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Polakis P: Wnt signaling and cancer. Genes Dev. 2000, 14: 1837-1851.

    CAS  PubMed  Google Scholar 

  52. 52.

    Taipale J, Beachy PA: The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001, 411: 349-354. 10.1038/35077219.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Satie AP, Rajpert-De Meyts E, Spagnoli GC, Henno S, Olivo L, Jacobsen GK, Rioux-Leclercq N, Jegou B, Samson M: The cancer-testis gene, NY-ESO-1, is expressed in normal fetal and adult testes and in spermatocytic seminomas and testicular carcinoma in situ. Lab Invest. 2002, 82: 775-780.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Cho B, Lim Y, Lee DY, Park SY, Lee H, Kim WH, Yang H, Bang YJ, Jeoung DI: Identification and characterization of a novel cancer/testis antigen gene CAGE. Biochem Biophys Res Commun. 2002, 292: 715-726. 10.1006/bbrc.2002.6701.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Martelange V, De Smet C, De Plaen E, Lurquin C, Boon T: Identification on a human sarcoma of two new genes with tumor-specific expression. Cancer Res. 2000, 60: 3848-3855.

    CAS  PubMed  Google Scholar 

  56. 56.

    O'Bryan MK, Sebire K, Meinhardt A, Edgar K, Keah HH, Hearn MT, De Kretser DM: Tpx-1 is a component of the outer dense fibers and acrosome of rat spermatozoa. Mol Reprod Dev. 2001, 58: 116-125. 10.1002/1098-2795(200101)58:1<116::AID-MRD14>3.0.CO;2-8.

    Article  PubMed  Google Scholar 

  57. 57.

    Stevanovic S: Identification of tumour-associated T-cell epitopes for vaccine development. Nat Rev Cancer. 2002, 2: 514-520. 10.1038/nrc841.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, Santiago D, Ferrara CA, Matsuo M, Selvakumar A, Dupont B, Chen YT, Hoffman EW, Ritter G, Old LJ, Gnjatic S: Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol. 2004, 172: 3289-3296.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Ehlken H, Schadendorf D, Eichmuller S: Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells. Int J Cancer. 2004, 108: 307-313. 10.1002/ijc.11537.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Wang RF, Rosenberg SA: Human tumor antigens recognized by T lymphocytes: implications for cancer therapy. J Leukoc Biol. 1996, 60: 296-309.

    CAS  PubMed  Google Scholar 

  61. 61.

    Sahin U, Tureci O, Pfreundschuh M: Serological identification of human tumor antigens. Curr Opin Immunol. 1997, 9: 709-716. 10.1016/S0952-7915(97)80053-2.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Tureci O, Sahin U, Pfreundschuh M: Serological analysis of human tumor antigens: molecular definition and implications. Mol Med Today. 1997, 3: 342-349. 10.1016/S1357-4310(97)01081-2.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Hubank M, Schatz DG: Identifying differences in mRNA expression by representational difference analysis of cDNA. Nucleic Acids Res. 1994, 22: 5640-5648.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  64. 64.

    Liang P, Pardee AB: Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992, 257: 967-971.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED, Siebert PD: Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci U S A. 1996, 93: 6025-6030. 10.1073/pnas.93.12.6025.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  66. 66.

    McCurdy DK, Tai LQ, Nguyen J, Wang Z, Yang HM, Udar N, Naiem F, Concannon P, Gatti RA: MAGE Xp-2: a member of the MAGE gene family isolated from an expression library using systemic lupus erythematosus sera. Mol Genet Metab. 1998, 63: 3-13. 10.1006/mgme.1997.2639.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Lea IA, Adoyo P, O'Rand MG: Autoimmunogenicity of the human sperm protein Sp17 in vasectomized men and identification of linear B cell epitopes. Fertil Steril. 1997, 67: 355-361. 10.1016/S0015-0282(97)81923-1.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Bart J, Groen HJ, van der Graaf WT, Hollema H, Hendrikse NH, Vaalburg W, Sleijfer DT, de Vries EG: An oncological view on the blood-testis barrier. Lancet Oncol. 2002, 3: 357-363. 10.1016/S1470-2045(02)00776-3.

    Article  PubMed  Google Scholar 

  69. 69.

    Fiszer D, Kurpisz M: Major histocompatibility complex expression on human, male germ cells: a review. Am J Reprod Immunol. 1998, 40: 172-176.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Erenpreiss JO: Current concepts of malignant growth. Part A. From a Normal Cell to Cancer. 1993, Riga, Zvaigzne publishers

    Google Scholar 

  71. 71.

    Kufe D, Pollock R, Weicheselbaum R, Bast R, Gansler T, Holland J, Frie E: Cancer Medicine. 2003, Hamilton (Canada), BC. Decker Inc., 6

    Google Scholar 

  72. 72.

    Tanner MM, Grenman S, Koul A, Johannsson O, Meltzer P, Pejovic T, Borg A, Isola JJ: Frequent amplification of chromosomal region 20q12-q13 in ovarian cancer. Clin Cancer Res. 2000, 6: 1833-1839.

    CAS  PubMed  Google Scholar 

  73. 73.

    Hidaka S, Yasutake T, Takeshita H, Kondo M, Tsuji T, Nanashima A, Sawai T, Yamaguchi H, Nakagoe T, Ayabe H, Tagawa Y: Differences in 20q13.2 copy number between colorectal cancers with and without liver metastasis. Clin Cancer Res. 2000, 6: 2712-2717.

    CAS  PubMed  Google Scholar 

  74. 74.

    Raderschall E, Stout K, Freier S, Suckow V, Schweiger S, Haaf T: Elevated levels of Rad51 recombination protein in tumor cells. Cancer Res. 2002, 62: 219-225.

    CAS  PubMed  Google Scholar 

  75. 75.

    Erenpreis YG: The function of nucleic acids in the differentiation of neoplastic processes. 1964, New York, Daniel Davey a. Co

    Google Scholar 

  76. 76.

    Erenpreiss JG: Gametogenesis as a molecular model of cancerogenesis: A current view of the embryological theory of cancer. Proc Latv Acad Sci Part B. 1992, 3: 55-63.

    Google Scholar 

  77. 77.

    Vinnitsky VB: Oncogerminal hypothesis of tumour growth. perimental Oncology. 1989, 11: 59-66.

    Google Scholar 

  78. 78.

    Cleveland LR: The origin and evolution of meiosis. Science. 1947, 105: 287-289.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Kondrashov AS: The asexual ploidy cycle and the origin of sex. Nature. 1994, 370: 213-216. 10.1038/370213a0.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Raikov IB: The Protozoan Nucleus. Morphology and Evolution. 1982, Wien-New York, Springer Verlag

    Google Scholar 

  81. 81.

    Raikov IB: Meiosis in protists: recent advances and persisting problems. r J Protistol. 1995, 31: 1-7.

    Article  Google Scholar 

  82. 82.

    Nagl W: Endopolyploidy and Polyteny in Differentiation and Evolution. 1978, Amsterdam-New York-Oxford, North-Holland Pub.,

    Google Scholar 

  83. 83.

    Kondrashov AS: Evolutionary genetics of life cycles. nu Rev Ecol Syst ,. 1997, 391-435. 10.1146/annurev.ecolsys.28.1.391.

    Google Scholar 

  84. 84.

    Zybina EV, Zybina TG: Polytene chromosomes in mammalian cells. Int Rev Cytol. 1996, 165: 53-119.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Zybina TG, Zybina EV, Kiknadze II, Zhelezova AI: Polyploidization in the trophoblast and uterine glandular epithelium of the endotheliochorial placenta of silver fox (Vulpes fulvus Desm.), as revealed by the DNA content. Placenta. 2001, 22: 490-498. 10.1053/plac.2001.0675.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Ivanov A, Cragg MS, Erenpreisa J, Emzinsh D, Lukman H, Illidge TM: Endopolyploid cells produced after severe genotoxic damage have the potential to repair DNA double strand breaks. J Cell Sci. 2003, 116: 4095-4106. 10.1242/jcs.00740.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Buglioni S, D'Agnano I, Vasselli S, Perrone DR, D'Angelo C, Brenna A, Benevolo M, Cosimelli M, Zupi G, Mottolese M: p53 nuclear accumulation and multiploidy are adverse prognostic factors in surgically resected stage II colorectal cancers independent of fluorouracil-based adjuvant therapy. Am J Clin Pathol. 2001, 116: 360-368. 10.1309/V7UW-UT2E-JVYH-DGWK.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Baroja A, de la HC, Alvarez A, Ispizua A, Bilbao J, de Gandarias JM: Genesis and evolution of high-ploidy tumour cells evaluated by means of the proliferation markers p34(cdc2), cyclin B1, PCNA and 3[H]-thymidine. Cell Prolif. 1996, 29: 89-100. 10.1046/j.1365-2184.1996.00990.x.

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Baroja A, de la HC, Alvarez A, Vielba R, Sarrat R, Arechaga J, de Gandarias JM: Polyploidization and exit from cell cycle as mechanisms of cultured melanoma cell resistance to methotrexate. Life Sci. 1998, 62: 2275-2282. 10.1016/S0024-3205(98)00208-2.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Erenpreisa JA, Cragg MS, Fringes B, Sharakhov I, Illidge TM: Release of mitotic descendants by giant cells from irradiated Burkitt's lymphoma cell line. Cell Biol Int. 2000, 24: 635-648. 10.1006/cbir.2000.0558.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Illidge TM, Cragg MS, Fringes B, Olive P, Erenpreisa JA: Polyploid giant cells provide a survival mechanism for p53 mutant cells after DNA damage. Cell Biol Int. 2000, 24: 621-633. 10.1006/cbir.2000.0557.

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Saburi S, Nadano D, Akama TO, Hirama K, Yamanouchi K, Naito K, Tojo H, Tachi C, Fukuda MN: The trophinin gene encodes a novel group of MAGE proteins, magphinins, and regulates cell proliferation during gametogenesis in the mouse. J Biol Chem. 2001, 276: 49378-49389. 10.1074/jbc.M108584200.

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Jungbluth AA, Busam KJ, Kolb D, Iversen K, Coplan K, Chen YT, Spagnoli GC, Old LJ: Expression of MAGE-antigens in normal tissues and cancer. Int J Cancer. 2000, 85: 460-465. 10.1002/(SICI)1097-0215(20000215)85:4<460::AID-IJC3>3.3.CO;2-E.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Jungbluth AA, Chen YT, Busam KJ, Coplan K, Kolb D, Iversen K, Williamson B, Van Landeghem FK, Stockert E, Old LJ: CT7 (MAGE-C1) antigen expression in normal and neoplastic tissues. Int J Cancer. 2002, 99: 839-845. 10.1002/ijc.10416.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Meuwissen RL, Offenberg HH, Dietrich AJ, Riesewijk A, van Iersel M, Heyting C: A coiled-coil related protein specific for synapsed regions of meiotic prophase chromosomes. EMBO J. 1992, 11: 5091-5100.

    PubMed Central  CAS  PubMed  Google Scholar 

  96. 96.

    Tapparel C, Reymond A, Girardet C, Guillou L, Lyle R, Lamon C, Hutter P, Antonarakis SE: The TPTE gene family: cellular expression, subcellular localization and alternative splicing. Gene. 2003, 323: 189-199. 10.1016/j.gene.2003.09.038.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully thank Denys Wheatley and Jamie Honeychurch for his help in editing the article.

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    Martins Kalejs & Jekaterina Erenpreisa

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  1. Martins Kalejs
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Kalejs, M., Erenpreisa, J. Cancer/testis antigens and gametogenesis: a review and "brain-storming" session. Cancer Cell Int 5, 4 (2005). https://doi.org/10.1186/1475-2867-5-4

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Keywords

  • CTA genes
  • gametogenesis
  • polyploidy

Cancer Cell International

ISSN: 1475-2867

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