159 results on '"Almstrup K"'
Search Results
102. Testicular germ cell tumours: predisposition genes and the male germ cell niche.
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Gilbert, Duncan, Rapley, Elizabeth, and Shipley, Janet
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LEYDIG cells ,GERM cells ,CELL physiology ,TUMORS ,HORMONE-dependent tumors ,GENOMICS ,CARCINOGENESIS ,PATIENTS - Abstract
Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs. Furthermore, this improved understanding of the mechanisms underlying TGCT development and dissemination has clinical relevance for the management of patients with these tumours. [ABSTRACT FROM AUTHOR]
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- 2011
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103. NANOG promoter methylation and expression correlation during normal and malignant human germ cell development.
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- 2011
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104. Gene expression profiling of rat spermatogonia and Sertoli cells reveals signaling pathways from stem cells to niche and testicular cancer cells to surrounding stroma.
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Ryser, Stephan, Glauser, Dominique, Vigier, Michelle, Yong Qiang Zhang, Tachini, Philippe, Schlegel, Werner, Durand, Philippe, and Irminger-Finger, Irmgard
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GENE expression ,STEM cells ,GERM cells ,TUMORS ,CANCER cells - Abstract
Background: Stem cells and their niches are studied in many systems, but mammalian germ stem cells (GSC) and their niches are still poorly understood. In rat testis, spermatogonia and undifferentiated Sertoli cells proliferate before puberty, but at puberty most spermatogonia enter spermatogenesis, and Sertoli cells differentiate to support this program. Thus, pre-pubertal spermatogonia might possess GSC potential and pre-pubertal Sertoli cells niche functions. We hypothesized that the different stem cell pools at pre-puberty and maturity provide a model for the identification of stem cell and niche-specific genes. We compared the transcript profiles of spermatogonia and Sertoli cells from pre-pubertal and pubertal rats and examined how these related to genes expressed in testicular cancers, which might originate from inappropriate communication between GSCs and Sertoli cells. Results: The pre-pubertal spermatogonia-specific gene set comprised known stem cell and spermatogonial stem cell (SSC) markers. Similarly, the pre-pubertal Sertoli cell-specific gene set comprised known niche gene transcripts. A large fraction of these specifically enriched transcripts encoded trans-membrane, extra-cellular, and secreted proteins highlighting stem cell to niche communication. Comparing selective gene sets established in this study with published gene expression data of testicular cancers and their stroma, we identified sets expressed genes shared between testicular tumors and pre-pubertal spermatogonia, and tumor stroma and pre-pubertal Sertoli cells with statistic significance. Conclusions: Our data suggest that SSC and their niche specifically express complementary factors for cell communication and that the same factors might be implicated in the communication between tumor cells and their micro-enviroment in testicular cancer. [ABSTRACT FROM AUTHOR]
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- 2011
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105. BMP Signaling in the Human Fetal Ovary is Developmentally Regulated and Promotes Primordial Germ Cell Apoptosis.
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Childs, Andrew J., Kinnell, Hazel L ., Collins, Craig S., Hogg, Kirsten, Bayne, Rosemary A . L ., Green, Samira J ., Mcneilly, Alan S., and Anderson, Richard A.
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BONE morphogenetic proteins ,GERM cells ,OVARIES ,APOPTOSIS ,OVUM ,ECOLOGICAL niche - Abstract
Primordial germ cells (PGCs) are the embryonic precursors of gametes in the adult organism., and their development, differentiation, and survival are regulated by a combination of growth factors collectively known as the germ cell niche. Although many candidate niche components have been identified through studies on mouse PGCs, the growth factor composition of the human PGC niche has not been studied extensively. Here we report a detailed analysis of the expression of components of the hone morphogenetic protein (BMP) signaling apparatus in the human fetal ovary, from postmigratory PGC proliferation to the onset of primordial follicle formation. We find developmentally regulated and reciprocal patterns of expression of BMP2 and BMP4 and identify germ cells to he the exclusive targets of ovarian BMP signaling. By establishing long-term cultures of human fetal ovaries in which PGCs are retained within their physiological niche., we find that BMP4 negatively regulates postmigratory PGC numbers in the human fetal ovary by promoting PGC apoptosis. Finally, we report expression of both muscle segment homeobox (MSX)l and MSX2 in the human fetal ovary and reveal a selective upregulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary, as in other systems. These data reveal for the first time growth factor regulation of human PGC development in a physiologically relevant context and have significant implications for the development of cultures systems for the in vitro maturation of germ cells, and their derivation from pluripotent stem cells. [ABSTRACT FROM AUTHOR]
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- 2010
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106. A Distinct Expression Pattern in Mammalian Testes Indicates a Conserved Role for NANOG in Spermatogenesis.
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Kuijk, Ewart W., de Gier, Jeffrey, Chuva de Sousa Lopes, Susana M., Chambers, Ian, van Pelt, Ans M. M., Colenbrander, Ben, and Roelen, Bernard A. J.
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TESTIS ,SPERMATOGENESIS ,GERM cells ,SPERMATOZOA ,ZYGOTES ,MAMMALOGICAL research ,ANIMAL models in research ,MICE ,IMMUNOHISTOCHEMISTRY - Abstract
Background: NANOG is a key player in pluripotency and its expression is restricted to pluripotent cells of the inner cell mass, the epiblast and to primordial germ cells. Spermatogenesis is closely associated with pluripotency, because through this process highly specialized sperm cells are produced that contribute to the formation of totipotent zygotes. Nevertheless, it is unknown if NANOG plays a role in this process. Methodology/Principal Findings: In the current study, NANOG expression was examined in testes of various mammals, including mouse and human. Nanog mRNA and NANOG protein were detected by RT-PCR, immunohistochemistry, and western blotting. Furthermore, eGFP expression was detected in the testis of a transgenic Nanog eGFP-reporter mouse. Surprisingly, although NANOG expression has previously been associated with undifferentiated cells with stem cell potential, expression in the testis was observed in pachytene spermatocytes and in the first steps of haploid germ cell maturation (spermiogenesis). Weak expression in type A spermatogonia was also observed. Conclusions: The findings of the current study strongly suggest a conserved role for NANOG in meiotic and post-meiotic stages of male germ cell development. [ABSTRACT FROM AUTHOR]
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- 2010
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107. Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors.
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TRANSCRIPTION factors ,GERM cells ,GERM cell differentiation ,FETAL tissues ,TESTIS development ,GENE expression ,IMMUNOHISTOCHEMISTRY - Abstract
The article reports on a study to determine the role of GATA-4 transcription factor in early germ cells and during malignant transformation. The study analyzed 10 fetal testis samples and 19 tumor samples using immunohistochemistry to explore the expression of GATA-4, GATA-6, cofactor FOG-2, and downstream target genes during human testis development. The study concludes that the GATA-4 expression occurs in early fetal gonocytes which proves its involvement in early germ cell differentiation.
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- 2010
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108. Intratubular germ cell neoplasms of the testis and bilateral testicular tumors: Clinical significance and management options.
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Risk, Michael C. and Masterson, Timothy A.
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TESTICULAR cancer ,TUMORS ,GERM cells ,CANCER treatment ,CANCER patient medical care - Abstract
Objectives: Intratubular germ cell neoplasia (ITGCN) is the precursor lesion for invasive testicular germ cell tumors (TGCTs) of adolescents and young adults. The rising incidence of these tumors has prompted a rigorous investigation of the etiology, diagnosis and management of ITGCN. Bilateral testicular cancer is closely linked with ITGCN, as patients with unilateral testicular cancer are at the highest risk for a future malignancy in the contralateral testicle. Methods: A literature review directed at ITGCN and bilateral testis cancer was performed using the Medline/PubMed database. Our review focused on the pathogenesis, risk factors, diagnosis and treatment regimens utilized. Results: Major advances have been made in the understanding of ITGCN over the past 30 years. There is evidence that TGCTs arise from ITGCN, ITGCN is closely related to fetal gonocytes, and that events in pre- and perinatal period may result in abnormal persistence of fetal gonocytes leading to ITGCN and subsequent TGCT. Controversy exists regarding the need to biopsy men at increased risk of TGCT, as well as the best approach to managing patients with known ITGCN. Bilateral testicular cancer has excellent outcomes in the current era of platinum-based chemotherapy. Conclusion: The optimal management of patients at risk for ITGCN and future TGCT is still a matter of debate. Individualization of management, including biopsy and treatment, should be based on risk factors for TGCT, compliance with potential surveillance, and patient preferences particularly with regard to fertility. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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109. The Multicopy Gene Sly Represses the Sex Chromosomesin the Male Mouse Germline after Meiosis.
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Cocquet, Julie, Ellis, Peter J. I., Yamauchi, Yasuhiro, Mahadevaiah, Shantha K., Affara, Nabeel A., Ward, Monika A., and Burgoyne, Paul S.
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SEX chromosomes ,LABORATORY mice ,GERM cells ,CELL division ,DNA microarrays ,GENE targeting - Abstract
Studies of mice with Y chromosome long arm deficiencies suggest that the male-specific region (MSYq) encodes information required for sperm differentiation and postmeiotic sex chromatin repression (PSCR). Several genes have been identified on MSYq, but because they are present in more than 40 copies each, their functions cannot be investigated using traditional gene targeting. Here, we generate transgenic mice producing small interfering RNAs that specifically target the transcripts of the MSYq-encoded multicopy gene Sly (Sycp3-like Y-linked). Microarray analyses performed on these Sly-deficient males and on MSYq-deficient males show a remarkable up-regulation of sex chromosome genes in spermatids. SLY protein colocalizes with the X and Y chromatin in spermatids of normal males, and Sly deficiency leads to defective repressive marks on the sex chromatin, such as reduced levels of the heterochromatin protein CBX1 and of histone H3 methylated at lysine 9. Sly-deficient mice, just like MSYq-deficient mice, have severe impairment of sperm differentiation and are near sterile. We propose that their spermiogenesis phenotype is a consequence of the change in spermatid gene expression following Sly deficiency. To our knowledge, this is the first successful targeted disruption of the function of a multicopy gene (or of any Y gene). It shows that SLY has a predominant role in PSCR, either via direct interaction with the spermatid sex chromatin or via interaction with sex chromatin protein partners. Sly deficiency is the major underlying cause of the spectrum of anomalies identified 17 y ago in MSYq-deficient males. Our results also suggest that the expansion of sex-linked spermatid-expressed genes in mouse is a consequence of the enhancement of PSCR that accompanies Sly amplification. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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110. New Insight into Molecular and Hormonal Connection in Andrology.
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Francomano, Davide, Sanguigni, Valerio, Capogrosso, Paolo, Deho, Federico, and Antonini, Gabriele
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CELL physiology ,SPERMATOGENESIS ,TESTIS physiology ,ANDROLOGY ,SERTOLI cells ,GERM cells ,LEUCOCYTES ,GLYCOCALYX - Abstract
Hormones and cytokines are known to regulate cellular functions in the testes. These biomolecules induce a broad spectrum of effects on various level of spermatogenesis, and among them is the modulation of cell junction restructuring between Sertoli cells and germ cells in the seminiferous epithelium. Cytokines and androgens are closely related, and both correct testicular development and the maintenance of spermatogenesis depend on their function. Cytokines also play a crucial role in the immune testicular system, activating and directing leucocytes across the endothelial barrier to the inflammatory site, as well as in increasing their adhesion to the vascular wall. The purpose of this review is to revise the most recent findings on molecular mechanisms that play a key role in male sexual function, focusing on three specific molecular patterns, namely, cytokines, miRNAs, and endothelial progenitor cells. Numerous reports on the interactions between the immune and endocrine systems can be found in the literature. However, there is not yet a multi-approach review of the literature underlying the role between molecular patterns and testicular and sexual function. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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111. Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice.
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Wieckowski, Margaux, Ranga, Stéphanie, Moison, Delphine, Messiaen, Sébastien, Abdallah, Sonia, Granon, Sylvie, Habert, René, Rouiller-Fabre, Virginie, Livera, Gabriel, and Guerquin, Marie-Justine
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POLLUTANTS ,GERM cells ,LEYDIG cells ,TESTIS physiology ,SOMATIC cells ,ENDOCRINE disruptors - Abstract
For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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112. Expression of Pluripotent Stem Cell Markers in the Human Fetal Testis.
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Kerr, Candace L., Hill, Christine M., Blumenthal, Paul D., and Gearhart, John D.
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STEM cells ,EMBRYONIC stem cells ,SPERMATOGENESIS ,GERMPLASM ,GERM cells ,EMBRYOLOGY - Abstract
Human primordial germ cells (PGCs) have proven to be a source of pluripotent stem cells called embryonic germ cells (EGCs). However, the developmental potency of these cells in the fetal gonad still remains elusive. Thus, this study provides a comprehensive analysis of pluripotent and germ cell marker expression in human fetal testis 7-15 weeks postfertilization (pF) and compares this expression to their ability to derive EGCs. Although the majority of germ cells expressed stem cell markers stage-specific embryonic antigen (SSEA) 1, SSEA4, EMA-1, and alkaline phosphatase, only a small percentage of those (<1%) expressed OCT4, CKIT, and NANOG. Specifically, the number of OCT4
+ /CKIT+ /NANOG+ cells significantly increased in the developing cords during weeks 7-9, followed by a gradual decline into week 15 pF. By week 15 pF, the remaining OCT4+ /CKIT+ /NANOG+ cells were found in the cords surrounding the periphery of the testis, and the predominant germ cells, CKIT+ cells, no longer expressed OCT4 or NANOG. Based on morphology and early germ cell marker expression, including VASA, PUM2, and DAZL, we suggest these cells are mitotically active gonocytes or prespermatogonia. Importantly, the number of OCT4+ cells correlated with an increase in the number of EGC colonies derived in culture. Interestingly, two pluripotent markers, Tra-1-60 and Tra-1-81, although highly expressed in EGCs, were not expressed by PGCs in the gonad. Together, these results suggest that PGCs maintain expression of pluripotent stem cell markers during and after sexual differentiation of the gonad, albeit in very low numbers. [ABSTRACT FROM AUTHOR]- Published
- 2008
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113. TCam-2 but not JKT-1 cells resemble seminoma in cell culture.
- Author
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Eckert, D., Nettersheim, D., Heukamp, L. C., Kitazawa, S., Biermann, K., and Schorle, H.
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CELL culture ,CANCER cells ,GERMPLASM ,GERM cells ,CELL lines ,GENE expression ,CANCER ,CYTOLOGICAL research ,TISSUES - Abstract
Of all malignancies diagnosed in men between 17 and 45 years of age, 60% are germ cell tumors (GCT). GCT arise from carcinoma in situ cells, which are thought to originate from a transformed fetal germ cell, the gonocyte. Seminoma together with embryonal carcinoma represent the most frequent subtypes of GCT. However, the nature of the molecular pathways involved in seminoma formation remains elusive. Therefore, analysis of appropriate cell culture systems is an important prerequisite for further understanding of the etiology of this tumor entity. Although several cell lines for embryonal carcinoma have been established and analyzed, so far only two cell lines from seminoma patients have been reported. In the present study, we have analyzed these seminoma cell lines (TCam-2 and JKT-1) and compared the gene-expression profiles with those of normal tissue and of seminoma and embryonal carcinoma by using DNA Array technology. We have found that TCam-2 clusters with the group of classical seminoma, whereas JKT-1 clusters with the group of embryonal carcinoma. Using reverse transcription/polymerase chain reaction, Western blot, and immunohistochemistry, we have confirmed the seminoma-like nature of TCam-2, whereas JKT-1 lacks expression for most of the genes detectable in GCTs, thus making doubtful the germ cell nature of this cell line. The data represent the first genome-wide expression analysis of the two cell lines and comparison/clustering with subgroups of germ cell tumors. Only TCam-2 seems to represent a suitable in vitro model for seminoma. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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114. Sequence variation in the human transcription factor gene POU5F1.
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Hussain, Shehnaz K., Sequerra, Reynaldo, Bertucci, Caterina, Hastings, Noel C., Rieder, Mark, and Schwartz, Stephen M.
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NUCLEOTIDE sequence ,TRANSCRIPTION factors ,GENE expression ,STEM cells ,GERM cells ,ONCOGENES ,EMBRYOLOGY ,DNA - Abstract
Background: POU5F1 expression is required to maintain stem cell pluripotency and for primordial germ cells to retain proliferative capability in embryonic development. Recent evidence suggests that POU5F1 may also be a testicular germ cell carcinoma (TGCC) oncogene, and POU5F1 variation may influence TGCC risk. As an important first step to a genetic association study, we sought to identify all common sequence variants in an 11.3 kb region containing POU5F1, and to describe the linkage disequilibrium patterns, using DNA from individuals of African-descent (AD) and European-descent (ED). Results: A higher number of polymorphisms was observed in the AD (n = 102) versus ED (n = 82) population. Among the 41 observed haplotypes, 21 (51%) and 12 (29%) were unique to the AD and ED populations, respectively, while 8 (20%) were observed in both. The number of tagging polymorphisms necessary to explain at least 80% of common variation (minor allele frequency ≥ 0.10) due to the remaining untyped polymorphisms was 17 for an AD and 10 for an ED population, providing a 4.0- and 7.0-fold gain in genotyping efficiency for characterizing nucleotide variation, respectively. Conclusion: POU5F1 is highly polymorphic, however a smaller subset of polymorphisms can tag the observed genetic variation with little loss of information. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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115. Chromosomes and Expression in Human Testicular Germ-Cell Tumors.
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LOOIJENGA, LEENDERT H. J., GILLIS, AD. J. M., STOOP, HANS J., HERSMUS, REMKO, and OOSTERHUIS, J. WOLTER
- Subjects
GENETICS ,GERM cells ,TUMORS ,EPIDEMIOLOGY ,GENOMICS ,TESTIS ,TERATOMA ,GONADS ,SPERMATOGENESIS - Abstract
Human germ-cell tumors (GCTs) are a heterogeneous group of neoplasms. Based on epidemiology, anatomical site of presentation, histology, chromosomal constitution, and pattern of genomic imprinting, GCTs are classified into five entities. Within the testis, three types of GCTs can be diagnosed: type I (teratomas and yolk-sac tumors of neonates and infants); type II (seminomas and nonseminomas); type III (spermatocytic seminomas). Here the focus is on the type II GCTs, the most frequent type in the adult testis (so-called TGCTs). They can also be diagnosed in dysgenetic gonads (an incomplete or defective formation of the gonad, caused by a disturbed process of migration of the germ cells and/or their correct organization in their fetal gonadal ridge), the anterior mediastinum, and pineal/suprasellar region. In the testis, they originate from the malignant counterpart of primordial germ cells/gonocytes, referred to as carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU). CIS/ITGCNU and seminomatous cells are characterized by expression of OCT3/4 and NANOG, while in addition embryonal carcinoma expresses SOX2, all identified as transcription factors related to pluripotency in embryonic stem (ES) cells. With the exception of teratomas, most histological elements of TGCTs are sensitive for (cisplatin-based) chemotherapy; CIS/ITGCNU and seminoma cells are also sensitive to DNA damage induced by irradiation. Similar observations have been made for ES cells and their derivates. Moreover, the genetic constitution of TGCTs (low incidence of mutations and frequent uniparental disomies) can also be linked to characteristics of ES cells, likely related to their specific inability to repair DNA damage and their high sensitivity to apoptotic cell death. The unusual presence of wild-type P53 in TGCTs is explained by specific expression of a cluster of micro-RNAs (miRNAs), that is, hsa-miR 371–373, also expressed in ES cells, which prevents P53-driven cellular senescence upon oncogenic stress. Many characteristics of human TGCTs reflect the nonmalignant counterparts from which they originate. Demonstration of these characteristics, in combination with the knowledge of the abnormal niche of these cells, normally occupied by spermatogonia, allows an informative method for (early) diagnosis. The conclusion is that TGCTs are embryonic cancers found in adults. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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116. From Gonocytes to Testicular Cancer.
- Author
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RAJPERT‐DE MEYTS, EWA and HOEI‐HANSEN, CHRISTINA E.
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GENETICS ,TUMORS ,TESTICULAR cancer ,GERM cells ,CANCER ,GENETIC polymorphisms ,ENDOCRINE disruptors ,AGE groups ,COMPARATIVE studies - Abstract
Testicular germ-cell tumors occur primarily in young individuals, and the tumors in this age group (seminomas or nonseminomas) are derived from a preinvasive precursor cell called carcinoma in situ (CIS) or intratubular germ-cell neoplasia. These tumors have been a growing problem, especially in highly developed industrialized countries. A hypothesis was put forward that CIS originates from arrested fetal germ cells, thus testicular cancer is a developmental disease of germ-cell differentiation. This notion was supported by comparative studies of the gene expression at the protein and RNA level, which demonstrated a close similarity of CIS to primordial germ cells and gonocytes with many features of embryonic stem cells. The arrest of germ-cell differentiation is thus the key first event, which may be followed by malignant transformation and overt germ-cell cancer in young adult age, usually after puberty. In most cases the arrest/delay of germ-cell differentiation is caused by testicular dysgenesis, a multifactorial and complex syndrome that has a broad spectrum of phenotypes ranging from moderate impairment of spermatogenesis to severe disorders of sexual development and differentiation. The most severe cases are a result of inherited genetic aberrations, but the etiology of the common sporadic testicular cancer must involve environmental factors, including maternal lifestyle and possibly an early exposure to endocrine disruptors. The effects of environmental factors are likely modulated by genomic variation (polymorphisms), thus explaining the individual susceptibility and population-level differences in the incidence of testicular cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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117. The epigenome of testicular germ cell tumors.
- Author
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Lind, Guro E., Skotheim, Rolf I., and Lothe, Ragnhild A.
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GENE expression ,CANCER ,GERM cells ,DNA ,TUMORS ,METHYLATION - Abstract
Gene expression is tightly regulated in normal cells, and epigenetic changes disturbing this regulation are a common mechanism in the development of cancer. Testicular germ cell tumor (TGCT) is the most common malignancy among young males and can be classified into two main histological subgroups: seminomas, which are basically devoid of DNA methylation, and nonseminomas, which in general have methylation levels comparable with other tumor tissues, as shown by restriction landmark genome scanning (RLGS). In general, DNA methylation seems to increase with differentiation, and among the nonseminomas, the pluripotent and undifferentiated embryonal carcinomas harbor the lowest levels of DNA promoter hypermethylation, whereas the well-differentiated teratomas display the highest. In this regard, TGCTs resemble the early embryogenesis. So far, only a limited number of tumor suppressor genes have been shown to be inactivated by DNA promoter hypermethylation in more than a minor percentage of TGCTs, including MGMT, SCGB3A1, RASSF1A, HIC1, and PRSS21. In addition, imprinting defects, DNA hypomethylation of testis/cancer associated genes, and the presence of unmethylated XIST are frequent in TGCTs. Aberrant DNA methylation has the potential to improve current diagnostics by noninvasive testing and might also serve as a prognostic marker for treatment response. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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118. Comprehensive analysis of gene expression in testes producing haploid germ cells using DNA microarray analysis.
- Author
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Ike, Akiko, Tokuhiro, Keizo, Hirose, Mika, Nozaki, Masami, Nishimune, Yoshitake, and Tanaka, Hiromitsu
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GENE expression ,TESTIS ,MALE reproductive organs ,HAPLOIDY ,GERM cells ,DNA microarrays ,ANDROLOGY - Abstract
The comprehensive changes in testicular gene expression before and after haploid germ cell differentiation were examined using microarray analysis. Approximately 14 000 expressed sequence tag (EST) clones of Mouse FANTOM Array ver.1 were hybridized with probes generated from mRNA of adult and juvenile (17 days postpartum) testes before the onset of spermiogenesis. Of 1315 genes that exhibited reproducible changes in expression ( p < 0.05), 46% exhibited an increase of twofold or more in adults compared to juveniles, and 22% a decrease of twofold or more. The analysis not only confirmed the reported haploid-specific expression of several known genes, but also provided new information on the differential expression of various other genes, including upregulated genes such as Allc and Skd3 and downregulated genes such as hbb b1, before or after the onset of spermiogenesis. Based on the fundamental difference in expression profiles, and molecular functions of the encoded products, the genes were classified into several groups: postmeiotically upregulated genes encoding various enzymes, structural and regulatory proteins, and chaperones, and downregulated genes encoding haemoglobins and oxidation/reduction-related proteins or the machinery associated with protein synthesis, such as ribosomal proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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119. Culture adaptation of embryonic stem cells echoes germ cell malignancy.
- Author
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Harrison, Neil J., Baker, Duncan, and Andrews, Peter W.
- Subjects
EMBRYONIC stem cells ,GENETIC transformation ,GERM cells ,CELL culture ,TERATOCARCINOMA ,TUMORS - Abstract
Teratocarcinomas are a subset of tumours that result from the neoplastic transformation of primordial germ cells. Such germ cell tumours (GCT) are histologically heterogeneous, reflecting a capacity for differentiation (pluripotency) of their embryonal carcinoma (EC) stem cells. However, malignant evolution of these tumours may ultimately correlate with a decrease in pluripotency, because this would tend to increase the propensity of EC cells for self-renewal. Human embryonic stem (ES) cells, derived from early blastocysts, closely resemble EC cells and, on prolonged culture in vitro, acquire progressive genetic changes that show striking similarity to those seen in GCT (e.g. gain of material from chromosome 12). In parallel, these abnormal ES cells show enhanced population growth rates and plating efficiencies, indicative of their adaptation to culture conditions. Understanding the mechanisms that drive such culture adaptation of ES cells may also provide insights into the development and progression of GCT. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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120. Improved gene expression signature of testicular carcinoma in situ.
- Author
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Almstrup, Kristian, Leffers, Henrik, Lothe, Ragnhild A., Skakkebæk, Niels E., Sonne, Si B., Nielsen, John E., Meyts, Ewa Rajpert-De, and Skotheim, Rolf I.
- Subjects
GENE expression ,GERM cells ,TESTICULAR cancer ,ANDROLOGY ,DNA microarrays ,IMMOBILIZED nucleic acids - Abstract
The carcinoma in situ (CIS) stage is the common precursor of testicular germ cell tumours (TGCTs) that arise in young adults. Within the past decade genome wide gene expression tools have been developed and have greatly advanced the insight into the biology of TGCTs. Two independent data sets on global gene expression in testicular CIS have been previously published. We have merged the two data sets on CIS samples ( n = 6) and identified the shared gene expression signature in relation to expression in normal testis. Among the top-20 highest expressed genes, one-third was transcription factors and the list included some ‘novel’ CIS markers (i.e. DOCK11 and ANXA3). Genes related to biological terms ‘nucleic acid binding’ and ‘translational activity’ (e.g. transcription factors and ribosomal proteins, respectively) were consistently and significantly over-represented. Some of the significantly over-expressed genes in CIS cells were selected for validation by RT-PCR ( IFI16, DOCK11, and ANXA3), immunohistochemistry (HLXB9), or in situ hybridization ( IFI16). High-level analysis utilizing the Ingenuity pathway analysis tool indicated that networks relating to ‘gene expression in cancer’ and ‘embryonic development’ were significantly altered and could collectively affect cellular pathways like the WNT signalling cascade, which thus may be disrupted in testicular CIS. The merged CIS data from two different microarray platforms, to our knowledge, provide the most precise CIS gene expression signature to date. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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121. Relevance of microRNAs in normal and malignant development, including human testicular germ cell tumours.
- Author
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Looijenga, L. H. J., Gillis, A. J. M., Stoop, H., Hersmus, R., and Oosterhuis, J. W.
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GERM cells ,MESSENGER RNA ,TESTICULAR cancer ,DISEASES in men ,ANDROLOGY ,EMBRYOLOGY - Abstract
The dogma of genome functionality has recently been challenged by identification of non-protein-encoding RNAs, including mi(cro)RNAs. These relatively small sequences interact with mRNA and in the mammalian system, are involved in fine-tuning the process of translation. miRNAs have been found to be of crucial importance for normal development, including stem cell formation. Recent interesting fundamental observations will be discussed in this paper, as well as their impact on the genesis of human germ cell tumours (GCTs), in particular those of the adult testis, seminomas and non-seminomas (type II), and spermatocytic seminomas (type III). miRNA cluster 371–373 is specifically involved in inhibition of cellular senescence induced by oncogenic stress in the type II GCTs. This explains the unusual presence of wild type P53, characteristic of this type of solid cancer. Specific sets of differentiating miRNA were found to characterize the various differentiation lineages within the GCTs, which simulate normal embryonic development. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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122. DNA damage response in human testes and testicular germ cell tumours: biology and implications for therapy.
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Bartkova, J., Rajpert-De Meyts, E., Skakkebæk, N. E., Lukas, J., and Bartek, J.
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DNA damage ,GENETIC mutation ,GERM cells ,IMMUNOHISTOCHEMISTRY ,TESTICULAR cancer ,ANDROLOGY - Abstract
DNA damage response (DDR) is emerging as a physiological anti-cancer barrier in early stages of cancer development, as shown for several types of solid cancers derived from somatic cells. Here we discuss our recently published and unpublished results on the exceptional paucity of such constitutive activation of the DDR machinery in human testicular germ cell tumours (TGCTs), including their common pre-invasive stage of carcinoma in situ (CIS). Our conclusions are supported by immunohistochemical analyses of multiple markers of activated DNA damage signalling, such as the phosphorylated ATM and Chk2 checkpoint kinases and phosphorylated histone H2AX. We propose that the unique lack of DDR activation in TGCTs reflects the biology of their cell of origin, the gonocyte. Furthermore, we propose that the lack of DDR activation avoids the pressure to select for mutations in DDR genes such as p53 or ATM, and the resulting intact DDR machinery may have implications for the exceptional curability of TGCTs by DNA damaging therapies. [ABSTRACT FROM AUTHOR]
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- 2007
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123. Testicular cancer trends as ‘whistle blowers’ of testicular developmental problems in populations.
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Skakkebæk, N. E., Rajpert-De Meyts, E., Jørgensen, N., Main, K. M., Leffers, H., Andersson, A.-M., Juul, A., Jensen, T. K., and Toppari, J.
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GERM cells ,TESTICULAR cancer ,DISEASES in men ,CRYPTORCHISM ,HUMAN abnormalities ,ANDROLOGY - Abstract
Recently a worldwide rise in the incidence of testicular germ cell cancer (TGCC) has been repeatedly reported. The changing disease pattern may signal that other testicular problems may also be increasing. We have reviewed recent research progress, in particular evidence gathered in the Nordic countries, which shows strong associations between testicular cancer, undescended testis, hypospadias, poor testicular development and function, and male infertility. These studies have led us to suggest the existence of a testicular dysgenesis syndrome (TDS), of which TGCC, undescended testis, hypospadias/disorders of sex differentiation and male fertility problems may be symptoms with varying penetration. In spite of their fetal origin, most of the TDS symptoms, including TGCC and poor semen quality, can only be diagnosed in adulthood. Data from a Danish–Finnish research collaboration strongly suggest that trends in TGCC rates of a population may be ‘whistle blowers’ of other reproductive health problems. As cancer registries are often of excellent quality – in contrast to registries for congenital abnormalities – health authorities should consider an increase in TGCC as a warning that other reproductive health problems may also be rising. [ABSTRACT FROM AUTHOR]
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- 2007
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124. Genomic and expression profiling of human spermatocytic seminomas: pathogenetic implications.
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Looijenga, Leendert H. J., Stoop, Hans, Hersmus, Remko, Gillis, Ad J. M., and Oosterhuis, J. Wolter
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GERM cells ,TESTICULAR cancer ,DISEASES in men ,CARCINOGENESIS ,PATHOLOGY ,ANDROLOGY - Abstract
Traditionally, germ cell tumours (GCTs) have been classified based on their histological appearance, i.e. the differentiation of lineages. Various subtypes of seminomas have been identified in a number of classification systems, including anaplastic and spermatocytic seminoma. Here we present conclusive evidence that spermatocytic seminomas are GCTs with a separate pathogenesis from seminoma, and should therefore not be considered as a variant of seminoma. Moreover, the different putative animal models, either spontaneous or induced, are discussed in the context of their value as model for human GCTs. The canine seminomas are currently considered as the most informative model for human spermatocytic seminomas. [ABSTRACT FROM AUTHOR]
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- 2007
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125. Epigenetic transgenerational toxicology and germ cell disease.
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Skinner, Michael K.
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GERM cells ,TESTICULAR cancer ,DISEASES in men ,ANDROLOGY ,METHYLATION ,DNA - Abstract
The ability of an environmental exposure (i.e. endocrine disruptor) during sex determination to reprogramme the male germline and promote an epigenetic transgenerational disease phenotype suggests that environmental factors and compounds may permanently alter the germline epigenome. This epigenetic transgenerational phenomenon will be discussed with respect to adult-onset germline disease (e.g. testicular cancer). A thorough literature review is not provided, rather a perspective is provided on how this epigenetic transgenerational toxicology should be considered in germ cell disease and testicular cancer. [ABSTRACT FROM AUTHOR]
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- 2007
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126. Current approaches for detection of carcinoma in situ testis.
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Hoei-Hansen, Christina E., Olesen, Inge A., Jorgensen, Niels, Carlsen, Elisabeth, Holm, Mette, Almstrup, Kristian, Leffers, Henrik, and Rajpert-De Meyts, Ewa
- Subjects
TESTICULAR cancer ,DISEASES in men ,GERM cells ,ANDROLOGY ,BIOPSY ,CLINICAL pathology - Abstract
Testicular germ cell tumours have a favourable prognosis if detected early, but are potentially lethal in a subset of patients. Multi-modality treatment is often necessary, thus the preferable time of diagnosis is at the pre-invasive, but unfortunately often asymptomatic precursor stage of carcinoma in situ (CIS). This review describes current possible approaches for the detection of CIS. At present, an open testicular biopsy is the only definitive way of establishing the presence of CIS. The tissue section should be of an adequate size, be properly fixed, and evaluation be supported by at least one solid immunohistochemical marker, for example PLAP, OCT-3/4 or AP-2γ. Determination of who should be offered testicular biopsies is based on clinical and ultrasonic examination along with the evaluation of risk factors. A surgical biopsy is an invasive procedure with potential complications, although rare. Therefore, a noninvasive and equally reliable method is needed. Testicular ultrasound is risk-free, painless and at present the only noninvasive method of aid for andrologists when CIS is suspected. The presence of testicular microlithiasis is, in some cases, indicative of pre-malignant changes, especially in males with additional risk factors. Promising results have recently been obtained with a novel noninvasive detection method based on immunocytological AP-2γ-staining of CIS cells in semen. This method could be a supporting method in andrology centres where careful follow-up is possible. In conclusion, one difficulty is to determine in which males CIS should be suspected; secondly, there does not as yet exist an optimal noninvasive method of diagnosis that is more acceptable than an open surgical biopsy. [ABSTRACT FROM AUTHOR]
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- 2007
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127. JKT-1 is not a human seminoma cell line.
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de Jong, Jeroen, Stoop, Hans, Gillis, Ad J. M., Gurp, Ruud J. H. L. M. van, van Drunen, Ellen, Beverloo, H. Berna, Lau, Yun-Fai Chris, Schneider, Dominik T., Sherlock, Jon K., Baeten, John, Hatakeyama, Shingo, Ohyama, Chikara, Oosterhuis, J. Wolter, and Looijenga, Leendert H. J.
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CELL lines ,GERM cells ,TESTIS tumors ,DISEASES in men ,FLOW cytometry ,IMMUNOHISTOCHEMISTRY ,ANDROLOGY - Abstract
The JKT-1 cell line has been used in multiple independent studies as a representative model of human testicular seminoma. However, no cell line for this specific tumour type has been independently confirmed previously; and therefore, the seminomatous origin of JKT-1 must be proven. The genetic constitution of the JKT-1 cells was determined using flow cytometry and spectral karyotyping, as well as array comparative genomic hybridization and fluorescent in situ hybridization. Marker profiling, predominantly based on differentially expressed proteins during normal germ cell development, was performed by immunohistochemistry and Western blot analyses. Moreover, genome wide affymetrix mRNA expression and profiling of 157 microRNAs was performed, and the status of genomic imprinting was determined. A germ cell origin of the JKT-1 cells was in line with genomic imprinting status and marker profile (including positive staining for several cancer-testis antigens). However, the supposed primary tumour, from which the cell line was derived, being indeed a classical seminoma, was molecularly proven not to be the origin of the cell line. The characteristic chromosomal anomalies of seminoma, e.g. gain of the short arm of chromosome 12, as well as the informative marker profile (positive staining for OCT3/4, NANOG, among others) were absent in the various JKT-1 cell lines investigated, irrespective of where the cells were cultured. All results indicate that the JKT-1 cell line is not representative of human seminoma. Although it can originate from an early germ cell, a non-germ cell derivation cannot be excluded. [ABSTRACT FROM AUTHOR]
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- 2007
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128. Prenatal development of murine gonads with special reference to germ cell differentiation: a morphological and immunohistochemical study.
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Zayed, A. E., Abd-Elnaeim, M. M., Abd-Elghaffar, S. Kh., Hild, A., Brehm, R., and Steger, K.
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GONADS ,GERM cells ,CELL differentiation ,SERTOLI cells ,SEXUAL dimorphism in animals ,IMMUNOHISTOCHEMISTRY ,LABORATORY mice - Abstract
The prenatal differentiation of male and female gonads of the mouse was investigated both morphologically and immunohistochemically. Sexual dimorphism could be detected as early as 12 days post-coitum (dpc) by the appearance of the primary elements of the tunica albuginea and positive immunoreactivity for anti-Muellerian hormone in the Sertoli cells of the male gonad. Male germ cells passed two waves of mitotic activity, a first wave between 12 and 14 dpc, which is followed by apoptosis of the old germ cell generation, and a second wave between 17 and 20 dpc. Oct-4 was expressed as a juxtanuclear ring in the cytoplasm of germ cells up to 17 dpc. Subsequently, it was down-regulated and completely disappeared in 20 dpc full-term fetuses. By contrast, M2A antigen revealed only a weak immunoreaction in some germ cells of 14 dpc gonads, but exhibited strong signals in all germ cells of 20 dpc full-term fetuses. Therefore, we postulate that, in the mouse, prenatal germ cells represent two populations: the first is immunopositive for Oct-4 and disappeared in full-term fetuses, whereas the second appeared in 14 dpc and is immunopositive for M2A antigen. [ABSTRACT FROM AUTHOR]
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- 2007
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129. The Stem Cell Identity of Testicular Cancer.
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Clark, Amander T.
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TESTICULAR cancer ,EMBRYONIC stem cells ,GERM cells ,TUMORS ,STEM cells - Abstract
Testicular germ cell tumors account for 1% of all cancers, and are the most common malignancies to affect males between the ages of 15 and 34. Understanding the pathogenesis of testis cancer has been challenging because the molecular and cellular events that result in the formation of germ cell tumors are hypothesized to occur during human fetal development. In this review, the molecular pathways involved in human testis cancer will be presented based on our research in human embryonic stem cells (hESCs), and also research using animal models. Testis germ cell tumors are unique in that the normal germ cell from which the tumor is derived has distinct stem cell characteristics that are shared with pluripotent hESCs. In particular, normal fetal germ cells express the core pluripotent transcription factors NANOG, SOX2 and OCT4. In contrast to hESCs:, the germ line is not pluripotent. As a result, germ cell tumorigenesis may arise from loss of germ line-specific inhibitors which in normal germ cells prevent overt pluripotency and self-renewal and when absent in abnormal germ cells, result in the conversion to germ line cancer stem cells. At the conclusion of this review, a model for the molecular events involved in germ cell tumor forrnation and the relationship between germ cell tumorigenesis and stem cell biology will be presented. [ABSTRACT FROM AUTHOR]
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- 2007
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130. Towards a non-invasive method for early detection of testicular neoplasia in semen samples by identification of fetal germ cell-specific markers.
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C.E. Hoei-Hansen
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TESTICULAR diseases ,GERM cells ,SEMEN ,ALKALINE phosphatase - Abstract
BACKGROUND: Testicular germ cell tumours (TGCTs) originate from a common precursor, carcinoma in situ (CIS). Diagnosis at the CIS stage is desirable as it minimizes the necessary treatment. A detailed clinical evaluation of an approach to detect CIS cells in the ejaculate using primordial germ cell/gonocyte markers is presented. METHODS: Immunocytological staining for AP-2γ [and in some cases, OCT-3/4, NANOG or placental alkaline phosphatase (PLAP)] was performed in semen samples from 294 infertile patients and 209 patients with TGCTs or other diseases. RESULTS: Presence of AP-2γ-stained cells was detected in 50% of participants with CIS and in 33.9% of TGCT patients before treatment (non-seminomas: 56.6%, seminomas: 17.4%). OCT-3/4 results were similar to those of AP-2γ, whereas NANOG and PLAP stainings were unsuitable. Sensitivity was 54.5% for participants harbouring pre-invasive CIS but reduced in participants with overt TGCTs, perhaps because of obstruction. Assay specificity was 93.6%, positive predictive value (PPV) 83.3% and negative predictive value (NPV) 60.3%. CONCLUSIONS: Immunocytological semen analysis based on expression of fetal germ cell markers in exfoliated cells has auxiliary diagnostic value, as it detects some patients with CIS/incipient tumour, but a negative result does not exclude TGCT. Further effort is needed to improve this assay, for example, by employing a more sensitive biochemical method of detection. [ABSTRACT FROM AUTHOR]
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- 2007
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131. Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers.
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Hoei-Hansen, Christina E., Kraggerud, Sigrid M., Abeler, Vera M., Kærn, Janne, Rajpert-De Meyts, Ewa, and Ragnhild A. Lothe
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GERM cells ,CARCINOGENESIS ,MOLECULAR genetics ,IMMUNOFLUORESCENCE ,IN situ hybridization ,ONCOGENES - Abstract
Background: Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. Results: We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2γ) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13—40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. Conclusion: This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females. [ABSTRACT FROM AUTHOR]
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- 2007
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132. Diagnostic value of markers M2A, OCT3/4, AP-2γ, PLAP and c-KIT in the detection of extragonadal seminomas.
- Author
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Biermann, K., Klingmüller, D., Koch, A., Pietsch, T., Schorle, H., Büttner, R., and Zhou, H.
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GONADS ,TUMORS ,CANCER ,HISTOPATHOLOGY ,GERM cells - Abstract
Aims: To compare the suitability of new seminoma markers including transcription factors AP-2γ, OCT3/4 and M2A for detection of metastatic and extragonadal seminomas with the two well-known markers c-KIT and PLAP. Materials and methods: The immunohistochemical distribution of PLAP, c-KIT, M2A, AP-2γ and OCT3/4 was examined in two pineal germinomas, 28 metastatic seminomas and 10 of their testicular primaries. Evaluation of specificity was achieved by additional tissue array studies on 75 malignancies other than germ cell tumours (GCT). Clinical data including serum PLAP were available in 18 patients. Results: Compared with other markers, significantly better staining results were observed with antibodies to M2A and AP-2γ in all seminomatous GCT. In contrast, the staining pattern with antibodies to c-KIT, PLAP and OCT3/4 was variable or absent. The lowest specificity was obtained with c-KIT, which was expressed in a variety of non-GCT. The only M2A+ mesothelioma expressed no other seminoma markers. No correlation between serum PLAP level and tissue PLAP expression was found. Conclusions: M2A and AP-2γ are the most sensitive markers for seminoma metastases or primary extragonadal seminomas. Combination of these markers provides highly specific and clear results for detection of a seminomatous GCT. [ABSTRACT FROM AUTHOR]
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- 2006
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133. CDH1 (E-cadherin) in testicular germ cell neoplasia: suppressed translation of mRNA in pre-invasive carcinoma in situ but increased protein levels in advanced tumours.
- Author
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Sonne, Si B., Hoei-Hansen, Christina E., Nielsen, John E., Herlihy, Amy S., Andersson, Anna-Maria, Almstru, Kristian, Daugaard, Gedske, Skakkebaek, Niels E., Leffers, Henrik, and Meyts, Rajpert-De
- Subjects
CADHERINS ,GERM cells ,TUMORS ,TESTIS ,PROTEINS - Abstract
E-cadherin (CDH1) is a transmembrane glycoprotein involved in cellular adhesion. In our recent microarray studies of testicular germ cell tumours (TGCTs) and the common precursor carcinoma in situ (CIS), CDH1 mRNA was highly expressed in CIS and embryonal carcinoma. It has previously been reported that the CDH1 protein is not expressed in CIS. To resolve the discrepancy, we performed a detailed analysis of the expression of CDH1 mRNA and protein in a series of normal and neoplastic testes. High expression of CDH1 mRNA in CIS was confirmed by real-time PCR and in situ hybridisation. At the protein level, however, CDH1 was only detected with one of three tested antibodies, but Western blotting analysis with this antibody showed additional bands, suggesting unspecific staining. The levels of a CDH1 protein fragment in serum samples from 58 patients with TGCTs were analysed by ELISA; we found significantly higher levels in patients with advanced disease (stage II/III) when compared to healthy individuals and patients with stage I TGCT. In conclusion, despite high mRNA levels, the CDH1 protein is not expressed in CIS, suggesting translational suppression of CDH1 protein expression. CDH1 serum levels may be a serological marker for staging of TGCT patients. [ABSTRACT FROM AUTHOR]
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- 2006
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134. Expression of SpanX proteins in normal testes and in testicular germ cell tumours.
- Author
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Salemi, Michele, Calogero, Aldo E., Castiglione, Roberto, Tricoli, Dario, Asero, Paola, Romeo, Rosa, Rappazzo, Giancarlo, and Vicari, Enzo
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PROTEINS ,TESTIS ,GERM cells ,EMBRYONAL tumors ,CYTOPLASM ,CANCER ,IMMUNOHISTOCHEMISTRY - Abstract
We investigated the expression of the SpanX protein family in cells of normal testes and in testicular germ cell tumours, mainly seminomas and embryonal carcinomas, using an immunohistochemical approach. Most of the normal germ cells, belonging to spermatogonial and primary spermatocytic classes, showed a strong nuclear positivity. In contrast, post-meiotic germ cells showed diffused cytoplasmic and sometimes also perinuclear localization of the signal. The vast majority of cells were also positive in eight seminomas, six embryonal cell carcinomas and one teratocarcinoma. In all seminomas, nuclei were either exclusively or preferentially labelled; whereas, the nuclear signal intensity decreased in parallel with the appearance of some cytoplasmic staining in embryonal carcinomas. In conclusion, these data suggest that the SpanX protein family is not exclusively expressed post-meiotically and that seminomas and embryonal carcinomas may originate from SpanX-positive carcinoma-in-situ cell. [ABSTRACT FROM AUTHOR]
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- 2006
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135. Spatial expression of germ cell markers during maturation of human fetal male gonads: an immunohistochemical study.
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Katharina Pauls, Hubert Schorle, Wiebke Jeske, Ralph Brehm, Klaus Steger, Nicolas Wernert, Reinhard Büttner, and Hui Zhou
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GERM cells ,IMMUNOHISTOCHEMISTRY ,BIOMARKERS ,GONADS - Abstract
BACKGROUND: The aim of the present study was to examine fetal male germ cells for expression of proteins associated with differentiation and maturation and to compare them with morphologically defined subpopulations. METHODS: Testes of 61 fetuses from week 12 of gestation to the newborn period were selected. Immunohistochemistry was performed using antibodies to proteins associated with differentiation of germ cells (c-KIT, AP-2γ) or pluripotency (OCT3/4), oncofetal protein M2A and spermatogonial marker MAGE-A4. RESULTS: Two subtypes of fetal germ cells were detected by quantification and immunohistochemistry. Nearly all germ cells with morphological criteria of gonocytes and intermediate cells co-expressed OCT3/4, c-KIT, M2A and AP-2γ. Starting from week 12, their number increased up to week 18/19 and then declined continuously during further development. After week 25, pre-spermatogonia were predominant and expressed MAGE-A4 selectively. CONCLUSIONS: Fetal male germ cells are comprised of two major groups with distinct immunohistochemical phenotypes. Germ cells that are predominantly found before week 25 of gestation co-express oncofetal proteins OCT3/4, c-KIT, M2A and AP-2γ. After week 25, most germ cells have lost their pluripotent potential and acquire a spermatogonial phenotype defined by expression of MAGE-A4. [ABSTRACT FROM AUTHOR]
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- 2006
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136. From embryonic stem cells to testicular germ cell cancer – should we be concerned?
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Almstrup, Kristian, Sonne, Si Brask, Hoei-Hansen, Christina E., Ottesen, Anne Marie, Nielsen, John E., Skakkebæk, Niels E., Leffers, Henrik, and Meyts, Ewa Rajpert-De
- Subjects
EMBRYONIC stem cells ,TESTICULAR diseases ,CANCER cells ,ETIOLOGY of cancer ,GERM cells - Abstract
Since the discovery of testicular carcinoma in situ (CIS) – the precursor cell for the vast majority of germ cell tumours – it has been proposed that CIS cells could be derived from transformed primordial germ cells or gonocytes. Here, we review recent discoveries not only substantiating that initial hypothesis but also indicating that CIS cells have a striking phenotypic similarity to embryonic stem cells (ESC). Many cancers have been proposed to originate from tissue-specific stem cells [so-called ‘cancer stem cells’ (CSC)] and we argue that CIS may be a very good example of a CSC, but with exceptional features due to the retention of embryonic pluripotency. In addition, considering the fact that pre-invasive CIS cells are transformed from early fetal cells, possibly due to environmentally induced alterations of the niche, we discuss potential risks linked to the uncontrolled therapeutic use of ESC. [ABSTRACT FROM AUTHOR]
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- 2006
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137. Genomic and gene expression signature of the pre-invasive testicular carcinoma in situ.
- Author
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Almstrup, Kristian, Ottesen, Anne Marie, Sonne, Si Brask, Hoei-Hansen, Christina E., Leffers, Henrik, Rajpert-De Meyts, Ewa, and Skakkebaek, Niels E.
- Subjects
TESTICULAR diseases ,CANCER ,GENOMES ,GENE expression ,GERM cells ,DNA microarrays ,COMPARATIVE genomic hybridization ,EMBRYONIC stem cells - Abstract
Testicular cancer is the most common malignancy among men in the reproductive age and the incidence is increasing, probably caused by environmental factors. Most testicular cancers are testicular germ cell tumours and all originate from a carcinoma in situ (CIS) pattern. In this review, we focus on the pre-invasive CIS and its possible fetal origin by reviewing recent data originating from DNA microarrays and comparative genomic hybridisations. A comparison of gene expression and genomic aberrations reveal chromosomal “hot spots” with mutual clustering of gene expression and genomic amplification. Some of the genes found in the hot spots may be involved in creating the CIS phenotype. On the other hand, many genes that are highly expressed in CIS are not present in the hot-spot areas. The gene expression profile of CIS thus most likely reflects the combined result of genomic amplification and increased transcriptional activation and/or deficiency in the epigenetic silencing of specific loci. Amplification of chromosome 12p, appears to be a good genomic marker of the transition from the pre-malignant to malignant CIS cell; this is consistent with recent findings of propagation advantages in cultured undifferentiated embryonic stem cells after spontaneous amplification in similar regions. The gene expression profile of CIS cells has remarkable similarity to that of embryonic stem cells and supports our long-standing hypothesis of an early developmental origin of CIS and testicular germ cell cancer. [ABSTRACT FROM AUTHOR]
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- 2005
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138. Genetic basis of human testicular germ cell cancer: insights from the fruitfly and mouse.
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Browne, Catherine M., Hime, Gary R., Koopman, Peter, and Loveland, Kate L.
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GERM cells ,CANCER ,ETIOLOGY of diseases ,GENETICS ,GENETIC mutation ,FLIES ,MICE - Abstract
The prevalence of tumours of the germ line is increasing in the male population. This complex disease has a complex aetiology. We examine the contribution of genetic mutations to the development of germ line tumours in this review. In particular, we concentrate on fly and mouse experimental systems in order to demonstrate that mutations in some conserved genes cause pathologies typical of certain human germ cell tumours, whereas other mutations elicit phenotypes that are unique to the experimental model. Despite these experimental systems being imperfect, we show that they are useful models of human testicular germ cell tumourigenesis. [ABSTRACT FROM AUTHOR]
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- 2005
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139. Transcription Factors GATA-4 and GATA-6, and their Potential Downstream Effectors in Ovarian Germ Cell Tumors.
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Mannisto, Susanna, Butzow, Ralf, Salonen, Jonna, Leminen, Arto, Heikinheimo, Oskari, and Heikinheimo, Markku
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OVARIAN tumors ,GERM cells ,GERMPLASM ,ONCOLOGY ,CRYOBIOLOGY - Abstract
Ovarian germ cell tumors (GCTs) are histologically heterogeneous neoplasms originating from activated germ cells, the oocyte stem cells. These rare tumors often contain many different tissues mixed together, and malignant components are occasionally hidden within benign tissues thus complicating the diagnosis. The reasons for the variable differentiation of germ cells are still largely unknown. As transcription factors GATA-4 and GATA-6 as well as their downstream factors (e.g. HNF-4, BMP-2 and Ihh) are essential for normal yolk sac development, we studied their expression in 19 ovarian GCTs. Endodermal markers were expressed distinctively in different GCT types. The malignant endoderm in yolk sac tumors expressed all factors of endodermal development included in the study. Dysgerminomas, on the contrary, expressed only GATA-4 and, in a minority of cases, Ihh and BMP-2. The results suggest that GATA-4 and GATA-6 detected in the ovarian GCTs have retained their normal function. The fact that GATA-6 and HNF-4 are expressed exclusively in endodermal tissues indicates that these transcription factors play a role in the differentiation of germ cells towards the endodermal phenotype. Analysis of the nuclear transcription factors in tumor tissue could serve as a new informative diagnostic tool for ovarian GCTs. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2005
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140. Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation.
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Ong, C., Hasthorpe, S., and Hutson, J. M.
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SPERMATOGENESIS ,CRYPTORCHISM ,GERM cells ,TESTICULAR diseases ,PEDIATRICS ,HORMONE therapy ,CRYPTORCHISM surgery ,HYPOTHALAMUS physiology ,SPERMATOZOA physiology ,SPERMATOZOA ,TESTIS ,TESTIS tumors ,NEOPLASTIC cell transformation - Abstract
Germ cell development is an active process in normal testes during the first 4 years after birth, with transformation of the neonatal gonocytes into adult dark spermatogonia and then primary spermatocytes. The hormonal regulation of these changes is not fully understood, with evidence both for and against a role for gonadotrophins and androgens. Early surgical intervention in infancy aims to prevent or reverse germ cell maldevelopment. Although hormonal treatment for maldescent has been shown to be ineffective, there is still controversy over whether it may be useful as an adjunct to surgery to stimulate germ cells. Current evidence suggests that hormonal therapy may not stimulate transformation of neonatal gonocytes but may trigger prepubertal mitosis of primary spermatocytes. Further studies are required to determine the role of hormone treatment on germ cell development. [ABSTRACT FROM AUTHOR]
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- 2005
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141. Testicular germ-cell tumours in a broader perspective.
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Oosterhuis, J. Wolter and Looijenga, Leendert H. J.
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GERM cells ,TUMORS ,TESTIS ,GERMPLASM ,EMBRYOLOGY ,HEREDITY - Abstract
The germ-cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating germ cell. Recent progress begins to explain the apparent unpredictable development of germ-cell tumours and offers a basis for understanding their exquisite sensitivity to therapy. [ABSTRACT FROM AUTHOR]
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- 2005
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142. Mammalian male germ cells are fertile ground for expression profiling of sexual reproduction.
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Wrobel, Gunnar and Primig, Michael
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SPERMATOGENESIS ,GERM cells ,EMBRYOLOGY ,MALE reproductive organs ,LABORATORY rodents - Abstract
Analyzes consolidated high density oligonucleotide microarray data from rodent total testis and purified germ cell samples. Impact of the data on the understanding of the transcriptional program governing male germ cell differentiation; Expression of large number of loci during spermatogenesis; Expression profiling of mammalian spermatogenesis; Consolidated expression profiling of spermatogenesis in mouse and rat.
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- 2005
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143. The Role of DND1 in Cancers.
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Zhang, Yun, Godavarthi, Jyotsna D., Williams-Villalobo, Abie, Polk, Shahrazad, and Matin, Angabin
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GERMINOMA ,OVARIAN tumors ,GENETIC mutation ,RNA-binding proteins ,GERM cells ,MICRORNA ,TERATOMA ,MESSENGER RNA ,TESTIS tumors ,CARRIER proteins - Abstract
Simple Summary: The Dead-End (DND1) protein can interact with different messenger RNAs (mRNAs) in the cell. It uses multiple mechanisms to regulate expression of proteins from their cognate mRNAs. High levels of DND1 are found in the progenitor cells that develop into the egg and sperm. Here we review how and why defects in DND1 cause tumors in the testes and ovaries of vertebrates. Unexpectedly, some recent reports indicate that DND1 may also participate in human cancer development in cells other than those of the testes and ovaries. The goal of this review is to summarize the literature on the role of DND1 in cancers to obtain perspective regarding future scientific endeavors on DND1 function. The Ter mutation in Dead-End 1 (Dnd1), Dnd1
Ter , which leads to a premature stop codon, has been determined to be the cause for primordial germ cell deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas in the 129/Sv-Ter mice. As an RNA-binding protein, DND1 can bind the 3′-untranslated region (3′-UTR) of mRNAs and function in translational regulation. DND1 can block microRNA (miRNA) access to the 3′-UTR of target mRNAs, thus inhibiting miRNA-mediated mRNA degradation and up-regulating translation or can also function to degrade or repress mRNAs. Other mechanisms of DND1 activity include promoting translation initiation and modifying target protein activity. Although Dnd1Ter mutation causes spontaneous TGCT only in male 129 mice, it can also cause ovarian teratomas in mice when combined with other genetic defects or cause germ cell teratomas in both genders in the WKY/Ztm rat strain. Furthermore, studies on human cell lines, patient cancer tissues, and the use of human cancer genome analysis indicate that DND1 may possess either tumor-suppressive or -promoting functions in a variety of somatic cancers. Here we review the involvement of DND1 in cancers, including what appears to be its emerging role in somatic cancers. [ABSTRACT FROM AUTHOR]- Published
- 2021
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144. Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors.
- Author
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Singh, Ratnakar, Fazal, Zeeshan, Freemantle, Sarah J., Spinella, Michael J., Köberle, Beate, and Di Lorenzo, Giuseppe
- Subjects
CANCER chemotherapy ,GERM cells ,DNA methylation ,TESTIS tumors ,EPIGENOMICS - Abstract
Simple Summary: This minireview focuses on the role of epigenetics in testicular cancer. A working model is developed that postulates that epigenetic features that drive testicular cancer malignancy also enable these tumors to be cured at a high rate with chemotherapy. Chemoresistance may occur by epigenetic uncoupling of malignancy and chemosensitivity, a scenario that may be amenable to epigenetic-based therapies. Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. Decades of focus on genomic alterations in TGCTs including awareness of a near universal increase in copies of chromosome 12p have failed to uncover exceptional driver genes, especially in genes that can be targeted therapeutically. Thus far, TGCT patients have missed out on the benefits of targeted therapies available to treat most other malignancies. In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. While genetics undoubtedly plays a role in TGCT biology, this mini-review will focus on the epigenetic "states" or features of testicular cancer, with an emphasis on DNA methylation, histone modifications, and miRNAs associated with TGCT susceptibility, initiation, progression, and response to chemotherapy. In addition, we comment on the current status of epigenetic-based therapy and epigenetic biomarker development for TGCTs. Finally, we suggest a unifying "rock and a hard place" or "differentiate or die" model where the tumorigenicity and curability of TGCTs are both dependent on common but still ill-defined epigenetic states. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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145. Role of the Glycosylphosphatidylinositol-Anchored Protein TEX101 and Its Related Molecules in Spermatogenesis.
- Author
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Yoshitake, Hiroshi and Araki, Yoshihiko
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GERM cells ,MONOCLONAL antibodies ,PLASMINOGEN activators ,MOLECULES ,ION channels ,SPERMATOGENESIS ,PROTEINS ,PLASMINOGEN - Abstract
Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) on the plasma membrane are involved in several cellular processes, including sperm functions. Thus far, several GPI-APs have been identified in the testicular germ cells, and there is increasing evidence of their biological significance during fertilization. Among GPI-APs identified in the testis, this review focuses on TEX101, a germ cell-specific GPI-AP that belongs to the lymphocyte antigen 6/urokinase-type plasminogen activator receptor superfamily. This molecule was originally identified as a glycoprotein that contained the antigen epitope for a specific monoclonal antibody; it was produced by immunizing female mice with an allogenic testicular homogenate. This review mainly describes the current understanding of the biochemical, morphological, and physiological characteristics of TEX101. Furthermore, future avenues for the investigation of testicular GPI-Aps, including their potential role as regulators of ion channels, are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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146. CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males.
- Author
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Spiller, Cassy M., Lobo, João, Boellaard, Willem P. A., Gillis, Ad J. M., Bowles, Josephine, and Looijenga, Leendert H. J.
- Subjects
CELL lines ,COMPARATIVE studies ,ENZYME-linked immunosorbent assay ,INFERTILITY ,METHYLATION ,POLYMERASE chain reaction ,SEMEN ,TESTIS tumors ,TUMOR markers ,TUMOR classification ,PREDICTIVE tests ,REVERSE transcriptase polymerase chain reaction ,DESCRIPTIVE statistics ,GERMINOMA - Abstract
miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker of testicular GCTs (TGCTs) and also to assess its presence in seminal plasma samples, compared with miR-371a-3p. In total, 217 and 94 serum/seminal plasma samples were analyzed. CRIPTO was quantified using ELISA and miR-371a-3p using bead-based isolation followed by RT-qPCR. Methylation profiling (EPIC array) for the CRIPTO promoter region was undertaken in 35 TGCT tissues plus four (T)GCT cell lines. Significantly higher CRIPTO concentration was found in sera of non-seminomas compared to controls (p = 0.0297), and in stage II/III disease compared to stage I (p = 0.0052, p = 0.0097). CRIPTO concentration was significantly positively correlated with miR-371a-3p levels in serum (r = 0.16) and seminal plasma (r = 0.40). CRIPTO/miR-371a-3p levels were significantly higher in seminal plasma controls when compared to serum controls (p = 0.0001, p < 0.0001). CRIPTO/miR-371a-3p were detected both in normospermic and azoospermic males, and levels were higher in TGCTs compared to GCNIS-only. We have provided the largest dataset of evaluation of CRIPTO in serum and seminal plasma of GCTs, showing its potential value as a biomarker of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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147. Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription.
- Author
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Bajusz, Izabella, Henry, Surya, Sutus, Enikő, Kovács, Gergő, and Pirity, Melinda K.
- Subjects
GERM cell differentiation ,RETINOIC acid receptors ,CELL receptors ,BINDING sites ,GERM cells ,TRANSCRIPTION factors ,GENE regulatory networks - Abstract
Separation of germline cells from somatic lineages is one of the earliest decisions of embryogenesis. Genes expressed in germline cells include apoptotic and meiotic factors, which are not transcribed in the soma normally, but a number of testis-specific genes are active in numerous cancer types. During germ cell development, germ-cell-specific genes can be regulated by specific transcription factors, retinoic acid signaling and multimeric protein complexes. Non-canonical polycomb repressive complexes, like ncPRC1.6, play a critical role in the regulation of the activity of germ-cell-specific genes. RING1 and YY1 binding protein (RYBP) is one of the core members of the ncPRC1.6. Surprisingly, the role of Rybp in germ cell differentiation has not been defined yet. This review is focusing on the possible role of Rybp in this process. By analyzing whole-genome transcriptome alterations of the Rybp
-/- embryonic stem (ES) cells and correlating this data with experimentally identified binding sites of ncPRC1.6 subunits and retinoic acid receptors in ES cells, we propose a model how germ-cell-specific transcription can be governed by an RYBP centered regulatory network, underlining the possible role of RYBP in germ cell differentiation and tumorigenesis. [ABSTRACT FROM AUTHOR]- Published
- 2019
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148. Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology.
- Author
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Looijenga, Leendert H. J., Kao, Chia-Sui, and Idrees, Muhammad T.
- Subjects
GERM cells ,SEX differentiation disorders ,DEVELOPMENTAL biology ,Y chromosome ,CANCER cells ,EMBRYOLOGY - Abstract
The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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149. GCT-17 - Developmental origins of testicular germ cell tumours (TGCT).
- Author
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Rajpert-De Meyts, E., Jørgensen, A., Jørgensen, N., Almstrup, K., and Skakkebaek, N.E.
- Subjects
- *
GERM cells , *TUMORS - Published
- 2019
- Full Text
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150. Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic.
- Author
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Lobo, João, Gillis, Ad J. M., Jerónimo, Carmen, Henrique, Rui, and Looijenga, Leendert H. J.
- Subjects
GERM cells ,EPIGENETICS ,DNA methylation ,CANCER cells ,CHROMOSOMES - Abstract
Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility as well as environmental factors in the pathogenesis, referred to as 'genvironment'. Moreover, it could also explain various epidemiological findings, including the rising incidence of this type of cancer in Western societies. In addition, it allows for identification of clinically relevant and informative biomarkers both for diagnosis and follow-up of individual patients. The current status of these findings will be discussed, including the use of high throughput DNA methylation profiling for determination of differentially methylated regions (DMRs) as well as chromosomal copy number variation (CNV). Finally, the potential value of methylation-specific tumor DNA fragments (i.e., XIST promotor) as well as embryonic microRNAs as molecular biomarkers for cancer detection in liquid biopsies will be presented. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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