Sumario:
The International Journal of Developmental Biology
Linking Development, Stem Cells and Cancer Research
Euskal Herriko Unibertsitateko Argitalpen Zerbitzua / Servicio de la Universidad del País Vasco / University of the Basque Country Press
Volume 57 - Numbers 2/3/4 (2013) - Special Issue Editor-in-Chief: Juan Aréchaga
MORE INFORMATION [Abstract - FullText / FullText Open Access]
ISSN: 0214-6282 / ISSN-e: 1696-3547 www.intjdevbiol.com
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Special Issue: MALE GERM CELLS IN DEVELOPMENT & TUMORS
Guest Editor: Massimo De Felici and Susanna Dolci
CONTENTS + ABSTRACTS
Preface
Male germ cells and cancer: a connection among pluripotency, differentiation and stem cell biology
Massimo De Felici and Susanna Dolci
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 101-103
Primodial germ cells, male germ cells and germ cell tumors
A lifetime of migration
Peter Donovan and Christopher Wylie
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 105-113
From testis to teratomas: a brief history of male germ cells in mammals
Massimo De Felici and Susanna Dolci
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 115-121
Perceiving signals, building networks, reprogramming germ cell fate
Florencia Barrios, Naoko Irie and M. Azim Surani
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 123-132
Classification, epidemiology and therapies for testicular germ cell tumours
Nikhil Vasdev, Andrew Moon and Andrew C. Thorpe
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 133-139
Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults
Katherine A. Ewen, Inge A. Olesen, Sofia B. Winge, Ana R. Nielsen, John E. Nielsen, Niels Graem, Anders Juul and Ewa Rajpert-De Meyts
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 141-151
Patient with two secondary somatic-type malignancies in a late recurrence of a testicular non-seminoma: illustration of potential and flaw of the cancer stem cell therapy concept
J.Wolter Oosterhuis, Suzanne H.P. Peeters, Vincent T.H.B.M. Smit, Hans Stoop, Leendert H.J. Looijenga, Henk W. Elzevier, Suzanne Osanto
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 153-157
The control of male germ cell cycle and the spermatogonia stem cell “niche”
Role of cyclins in controlling progression of mammalian spermatogenesis
Debra J. Wolgemuth, Marcia Manterola and Ana Vasileva
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 159-168
Cycling to and from a stem cell niche: the temporal and spatial odyssey of mitotic male germ cells
Christopher J. Payne
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 169-177
Transcriptional control of KIT gene expression during germ cell development
Pellegrino Rossi
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 179-184
The spermatogonial stem cell niche in testicular germ cell tumors
Unai Silván, Alejandro Díez-Torre, Pablo Moreno, Jon Arluzea, Ricardo Andrade, Margarita Silió and Juan Aréchaga
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 185-195
Testicular teratomas and teratocarcinomas
Testicular germ cell tumors and related research from a historical point of view
Ivan Damjanov and Nicolai Wewer-Albrechtsen
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 197-200
Testicular teratomas: an intersection of pluripotency, differentiation and cancer biology
Ximena Bustamante-Marín, Jason A. Garness and Blanche Capel
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 201-210
Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors
Cassy M. Spiller, Josephine Bowles and Peter Koopman
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 211-219
Environmental endocrine disruptors and germ cell tumors
Carcinoma in situ -from clinical observation to a paradigm shift for testicular carcinogenesis
Jorma Toppari
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 221-223
Endocrine disruptors, gene deregulation and male germ cell tumors
Jesús Del Mazo, Miguel A. Brieño-Enríquez, Jesús García-López, Luis A. López-Fernández and Massimo De Felici
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 225-239
Development of malignant germ cells - the genvironmental hypothesis
Leendert H.J. Looijenga, Ton Van Agthoven and Katharina Biermann
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 241-253
Effect of endogenous and exogenous hormones on testicular cancer: the epidemiological evidence
Fabrizio Giannandrea, Donatella Paoli, Irene Figà-Talamanca, Francesco Lombardo, Andrea Lenzi and Loredana Gandini
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 255-263
Male germ cell apoptosis and DNA damage
Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development
R. John Aitken and Mark A. Baker
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 265-272
Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors
Francesca Cavallo, Darren R. Feldman and Marco Barchi
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 273-280
UV and genotoxic stress induce ATR relocalization in mouse spermatocytes
Sara Di Siena, Federica Campolo, Pellegrino Rossi, Emmanuele A. Jannini, Susanna Dolci and Manuela Pellegrini
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 281-287
New insights into the molecular mechanisms of germ cell tumors: pluripotency genes, epigenetics and micrornas
Pathobiology of germ cell tumors - applying the gossip test!
Leendert H. J. Looijenga and J. Wolter Oosterhuis
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 289-298
Role of epigenetics in the etiology of germ cell cancer
Yvonne G. Van Der Zwan, Hans Stoop, Fernando Rossello,Stefan J. White and Leendert H.J. Looijenga
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 299-308
Epigenetic features of testicular germ cell tumours in relation to epigenetic characteristics of foetal germ cells
Dina G. Kristensen, Niels E. Skakkebæk, Ewa Rajpert-De Meyts and Kristian Almstrup
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 309-317
Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer
Ronak Eini, Lambert C. J. Dorssers and Leendert H. J. Looijenga
EHU/UPV/UBC - The International Journal of Developmental Biology (2013) 57: 319-332
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ABSTRACTS:
Preface
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 101-103 (2013)
doi: 10.1387/ijdb.130167md / © UBC Press (www.a360grados.net)
Male germ cells and cancer: a connection among pluripotency, differentiation and stem cell biology
Massimo De Felici and Susanna Dolci
Abstract: The development of male germ cells begins with the formation of the primordial germ cells (PGCs) and ends with that of sperm. During this process, spanning from the embryo to the adult age, there are points in which abnormalities in the corresponding processes can produce defective germ cells prone to tumour transformation.
Primodial germ cells, male germ cells and germ cell tumors
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 105-113 (2013)
doi: 10.1387/ijdb.130059 / © UBC Press (www.a360grados.net)
A lifetime of migration
Peter Donovan 1 and Christopher Wylie 2
1 Sue and Bill Gross Stem Cell Research Center, Gross Hall, A CIRM Institute, UC Irvine, CA, USA
2 Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA
Abstract: Careers in any profession can take a curious path. One small choice can seemingly change a career path and chance encounters open doors to new opportunities that take a person in new, unforeseen directions. For Chris Wylie this has certainly been the case. This interview highlights how someone can build a successful career in science, how that career can be fulfilling and fun and at the same time, it’s possible to have a family and a life outside of science. Chris has certainly had success in science, having built very successful labs at many institutions and helped found and grow world-renowned research centers. He gives great credit for his success to his longtime collaborator and wife, Janet Heasman. Although they have indeed made major contributions to their chosen fields of study, what is remarkable is the number of trainees that they have had pass through their labs. Ultimately for any scientist that might be their greatest legacy and it is obvious the impact that great mentors such as J.Z. Young and Ruth Bellairs had on how Chris ran his own lab. As Chris moves on to the next stage of his career, it seems likely that he will pursue it with as much vigor and passion as he pursued his love of scientific research and have a lot of fun. I can’t wait for the next interview!
Keywords: primordial germ cell, embryo, Xenopus, chick, teaching, mentorship
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: (2013)
doi: 10.1387/ijdb.130069md / © UBC Press (www.a360grados.net)
From testis to teratomas: a brief history of male germ cells in mammals
Massimo De Felici and Susanna Dolci
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Abstract: In antiquity, many theories were advanced on reproduction and the functions of the gonads. The male genitalia were called “testes” probably from the Latin word “testis “ that originally meant “witnesses”, because they provide evidence of virility. Through the first dissection of the seminipherous tubules by Renier de Graaf (1668), the discovery of spermatozoa by Antonj van Leeuwenhoek (1677) and in vitro fertilization by Spallanzani (1780) and later by George Newport and George Vines Ellis (1854), it was only in the early part of the XIX century when it was realized that testes produce spermatozoa and that they are essential for egg fertilization and subsequent embryo development. In the period between the end of the XIX and the beginning of the XX century, scientists such as Albert von Kölliker, Franz von Leydig, Enrico Sertoli and Gustaf Retzius (1842-1919) did microscopic observations of testis that marked the history of male germ cells and established the bases for the development of contemporary in vitro culture and molecular studies that are revealing the deeper secrets of male germ cells. Among these, those by Leroy Stevens on embryonal carcinoma cells in the early 1950s led to the present concepts that germ cells and cancer cells share several characteristics and that a close relationship exists between germ cells and stem cells, these being two pillars of modern developmental biology.
Keywords: germ cell, teratoma, teratocarcinoma, testis, stem cell
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 123-132 (2013)
doi: 10.1387/ijdb.130132fb / © UBC Press (www.a360grados.net)
Perceiving signals, building networks, reprogramming germ cell fate
Florencia Barrios, Naoko Irie and M. Azim Surani
Wellcome Trust / Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom
Abstract: Germ cell development is a step-wise process that ensures the progression of the life cycle due to their unique ability to transmit their genome from one generation to the next. In the mouse, the precursors of germ cells, the Primordial Germ Cells (PGCs), arise at the onset of gastrulation. Here we discuss how PGCs acquire their fate in the epiblast and outline their development until their arrival into the gonads. Male germ cell tumors (GCTs) have a similar gene expression pattern to that of fetal germ cells and to pluripotent cells, suggesting that GCT originate from an alteration of gonocyte normal development. We evaluate coincidences and differences in germ cell development in mouse and humans and on this basis, we speculate future research perspectives.
Keywords: primordial germ cell, male germ cell tumor, signalling, reprogramming, cell fate
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 133-139 (2013)
doi: 10.1387/ijdb.130031nv / © UBC Press (www.a360grados.net)
Classification, epidemiology and therapies for testicular germ cell tumours
Nikhil Vasdev, Andrew Moon and Andrew C. Thorpe
Department of Urology, Freeman Hospital, Newcastle upon Tyne, United Kingdom
Abstract: Testicular germ cell tumours (TGCT) account for between 1% and 1.5% of male neoplasms and 5% of urological tumours in general. They are classified broadly into Seminoma, which resemble primordial germ cells (PGCs), and Non-Seminoma, which are either undifferentiated (embryonal carcinoma) or differentiated (exhibiting a degree of embryonic (teratoma) or extra-embryonic (yolk sac choriocarcinoma) patterning). We present the current details of the latest classification, epidemiology and treatment aspects of TGCT in the UK in our review.
Keywords: classification, epidemiology, therapy, testicular germ cell tumor, prognosis
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 141-151 (2013)
doi: 10.1387/ijdb.130022er / © UBC Press (www.a360grados.net)
Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults
Katherine A. Ewen 1, Inge A. Olesen 1, Sofia B. Winge 1, Ana R. Nielsen 1, John E. Nielsen 1, Niels Graem 2, Anders Juul 1 and Ewa Rajpert-De Meyts 1
1 Department of Growth & Reproduction
2 Department of Pathology, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Abstract: Observations in patients with an activating mutation of fibroblast growth factor receptor 3 (FGFR3) suggest a role for FGFR3 signalling in promoting proliferation or survival of germ cells. In this study, we aimed to identify the FGFR3 subtype and the ontogeny of expression during human testis development and to ascertain whether FGFR3 signalling is linked to germ cell proliferation and the pathogenesis of testicular germ cell tumours (TGCTs) of young adult men. Using RT-PCR, immunohistochemistry and Western blotting, we examined 58 specimens of human testes throughout development for FGFR3 expression, and then compared expression of FGFR3 with proliferation markers (PCNA or Ki67). We also analysed for FGFR3 expression 30 TGCTs and 28 testes containing the tumour precursor cell, carcinoma in situ (CIS). Fetal and adult testes expressed exclusively the FGFR3IIIc isoform. FGFR3 protein expression was restricted to the cytoplasm/plasma membrane of spermatogonia and was most prevalent at mid-gestation, infancy and from puberty onwards. Phosphorylated (p)FGFR was detected in pre-spermatogonia at mid-gestation and in spermatogonia during puberty and in the adult testis. Throughout normal human testis development, expression of FGFR3 did not directly correlate with proliferation markers. In preinvasive CIS cells and in TGCTs, including classical seminoma and embryonal carcinoma, FGFR3IIIc was detected only in a small number of cells, with a heterogeneous expression pattern. FGFR3 is an excellent marker for human pre-/spermatogonia throughout development. Signalling through this receptor is likely associated with spermatogonial survival rather than proliferation. FGFR3 is not expressed in gonocytes and may not be essential to the aetiology of TGCTs stemming from CIS.
Keywords: FGFR3, testis, carcinoma in situ, testicular neoplasm, germ cell
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 153-157 (2013)
doi: 10.1387/ijdb.130141jo / © UBC Press (www.a360grados.net)
Patient with two secondary somatic-type malignancies in a late recurrence of a testicular non-seminoma: illustration of potential and flaw of the cancer stem cell therapy concept
J. Wolter Oosterhuis 1, Suzanne H.P. Peeters 2, Vincent T.H.B.M. Smit 3, Hans Stoop 1, Leendert H.J. Looijenga 1, Henk W. Elzevier 2, Suzanne Osanto 4.
1 Department of Pathology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
2 Department of Urology, 3 Department of Pathology and 4 Department of Clinical Oncology, Leiden University Medical Center, The Netherlands
Abstract: Here, we report the case of a patient with a non-seminoma of the left testicle, with an intestinal-type adenocarcinoma and a low grade leiomyosarcoma in a late recurrence 19 years after initial diagnosis. The history of the patient, alive with disease 21 years after initial treatment, illustrates the potential and flaw of the cancer stem cell therapy concept. In addition, it is proposed that residual mature teratoma can be regarded as normalization of cancer due to embryonic patterning, and the development of a secondary somatic-type malignancy as failure of normalization.
Keywords: case report, residual mature teratora, secondary non-germ cell malignancy, cisplatin, chemotherapy
The control of male germ cell cycle and the spermatogonia stem cell “niche”
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 159-168 (2013)
doi: 10.1387/ijdb.130047av / © UBC Press (www.a360grados.net)
Role of cyclins in controlling progression of mammalian spermatogenesis
Debra J. Wolgemuth 1,2,3,4, Marcia Manterola 1 and Ana Vasileva 1,5
1 Departments of Genetics & Development and 2 Obstetrics & Gynecology
3 Institute of Human Nutrition
4 Herbert Irving Comprehensive Cancer Center
5 Center for Radiological Research, Columbia University Medical Center, New York, USA
Abstract: Cyclins are key regulators of the mammalian cell cycle, functioning primarily in concert with their catalytic partners, the cyclin-dependent kinases (Cdks). While their function during mitosis in somatic cells has been extensively documented, their function during both mitosis and meiosis in the germ line is poorly understood. From the perspective of cell cycle regulation there are several aspects of mammalian spermatogenesis that suggest unique modes of regulation and hence, possible unique functions for the cyclins. This review will summarize our current understanding of cyclin expression and function in the male germ line, with particular focus on the A and E type cyclins in the mouse model. While the focus is on mammalian spermatogenesis, we note contrasts with similar functions in the female germ line when relevant and also draw upon observations in other model systems to provide further insight.
Keywords: cyclin, cell cycle, meiosis, spermatogenesis
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 169-177 (2013)
doi: 10.1387/ijdb.130006cp / © UBC Press (www.a360grados.net)
Cycling to and from a stem cell niche: the temporal and spatial odyssey of mitotic male germ cells
Christopher J. Payne
Children’s Hospital of Chicago Research Center, Human Molecular Genetics Program, Departments of Pediatrics and Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Abstract: The development of male germ cells within the prenatal and prepubertal periods in mammals combines multiple biological events that integrate cell cycle regulation, epigenetic reprogramming, and cell migration along temporally and spatially dynamic lines. Germ cells arise from their precursor primordial germ cells in the mid-gestation embryo, forming gonocytes that enter G0 phase cell cycle arrest within the fetal testis. Cyclin-dependent kinase inhibitors, activated retinoblastoma 1 protein, and increased levels of transforming growth factor beta 2 collectively influence this cell cycle arrest. Gonocyte quiescence persists until shortly after birth, whereupon the cells concomitantly re-enter the cell cycle and migrate towards a niche that establishes and maintains self-renewing spermatogonial stem cells and balances them with differentiating spermatogonia. Platelet-derived growth factor signaling is one of the mechanisms that regulates both mitotic activation and migration in neonatal gonocytes, along with mitogens, 17β-estradiol and retinoic acid, and chemoattractants C-C-motif ligand 9 and members of the ADAM, integrin, and tetraspanin families. Numerous germ cell-intrinsic proteins have been identified that ensure the retention of germ cells within the spermatogonial stem cell niche. Sertoli cells are a significant component of this niche, contributing essential growth factors and chemokines to spermatogonia. This review focuses on the dynamic events that occur to mitotic male germ cells before and during their arrival at this niche, with an emphasis on the cell cycle and directed migration.
Keywords: spermatogonia, cell cycle, germ cell, testis, gonocyte, stem cell niche
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 179-184 (2013)
doi: 10.1387/ijdb.130014pr / © UBC Press (www.a360grados.net)
Transcriptional control of KIT gene expression during germ cell development
Pellegrino Rossi
Dipartimento di Biomedicina e Prevenzione, Universita’ di Roma Tor Vergata, Rome, Italy
Abstract: The characterization of the mechanisms that regulate KIT expression in germ cells at different times of their development is important not only in the field of reproduction, but also for a better understanding of the biology of testicular germ cell tumors (TGCTs). Indeed this tyrosine kinase receptor, besides being essential for the survival and proliferation of primordial germ cells (PGCs) and for postnatal spermatogenesis and oogenesis, is also frequently overexpressed or constitutively active due to activating mutations in carcinoma in situ of the testis and in seminomas. In this review, I will summarize available data about the transcriptional mechanisms involved in the control of Kit expression in the germline. Variable mechanisms, involving different germ cell-specific transcription factors, are operating in the various developmental stages: SOX2 and SOHLH1/2 act as direct positive regulators in PGCs and in postnatal spermatogonia, respectively, whereas PLZF suppresses KIT expression in spermatogonial stem cells. DMRT1, acting through indirect mechanisms, suppresses KIT transcription in fetal gonocytes, while activating it in differentiating spermatogonia.
Keywords: KIT tyrosine kinase,primordial germ cell, spermatogenesis, testicular germ cell tumor
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 185-195 (2013)
doi: 10.1387/ijdb.130068ja / © UBC Press (www.a360grados.net)
The spermatogonial stem cell niche in testicular germ cell tumors
Unai Silván 1, Alejandro Díez-Torre 2, Pablo Moreno 1, Jon Arluzea 1,2, Ricardo Andrade 2, Margarita Silió 1 and Juan Aréchaga 1,2
1 Laboratory of Stem Cells, Development and Cancer, Department of Cell Biology and Histology
2 Analytical and High Resolution Biomedical Microscopy Core Facility, University of the Basque Country, Vizcaya, Spain
Abstract: Spermatogonial stem cells (SSCs) are pluripotent elements found in the adult seminiferous epithelium between Sertoli cells and a basal lamina which covers the multilayered external wall of peritubular myoid cells. The microenvironment of this pluripotent stem cell niche creates the complex and dynamic system that is necessary for the initiation of spermatogenesis, but this system also contains factors which can potentially collaborate in the progression of testicular germ cell tumors (TGCTs). In this review, we summarize our current knowledge about some important structural and molecular features related to the SSC niche, including growth factors, adhesion molecules, extracellular matrix, mechanical stress and vascularization. We discuss their possible collaborative effects on the generation and progression of TGCTs, which are a type of cancer representing the most frequent neoplasia among young men and whose incidence has grown very quickly during the past decades in North America and Europe. In this regard, a better understanding of the pluripotent stem cell niche where these malignancies arise will provide further insights into the origin of TGCTs and the mechanisms underlying their growth and invasion of adjacent and distant tissues.
Keywords: testis, spermatogonia, germ cell tumor, embryonal carcinoma, teratocarcinoma, cancer stem cell
Testicular teratomas and teratocarcinomas
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 197-200 (2013)
doi: 10.1387/ijdb.130143id / © UBC Press (www.a360grados.net)
Testicular germ cell tumors and related research from a historical point of view
Ivan Damjanov 1 and Nicolai Wewer-Albrechtsen 2
1 Department of Pathology and Laboratory Medicine, The University of Kansas School of Medicine, Kansas City, KS, USA
2 Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Denmark
Abstract: In this brief overview of the history of testicular germ cell tumors, we touch upon the key events and personalities that have contributed to our current understanding of germ cell tumors in general, and those of the testis in particular. The intricacies of human germ cell tumor pathology and histogenesis have been elucidated in part by contributions in the field of experimental pathology and developmental biology. Correlation between clinical oncologic findings, pathology and experimental studies of germ cell tumors and related topics ushered the era of cellular and genetic engineering that have revolutionized contemporary cell and molecular biology.
Keywords: history, testis, germ cell tumor, teratoma, teratocarcinoma, embryonal carcinoma, embryonic stem cell
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 201-210 (2013)
doi: 10.1387/ijdb.130136bc / © UBC Press (www.a360grados.net)
Testicular teratomas: an intersection of pluripotency, differentiation and cancer biology
Ximena Bustamante-Marín 1,2, Jason A. Garness 1 and Blanche Capel 1
1 Department of Cell Biology, Duke University Medical Center, Durham, N.C., USA
2 Facultad de Ciencias de la Salud, Departamento Biomédico Universidad de Antofagasta, Antofagasta, Chile
Abstract: Teratomas represent a critical interface between stem cells, differentiation and tumorigenesis. These tumors are composed of cell types representing all three germ layers reflecting the pluripotent nature of their cell of origin. The study of these curious tumors became possible when Leroy Stevens identified the 129 mouse strain as a model of spontaneous testicular teratoma and later isolated a substrain carrying the Ter mutation, a potent modifier of tumor incidence. Early studies with 129 mice lead to the discovery of embryonal carcinoma (EC) cells which played a foundational role in the embryonic stem (ES) cell field and the study of pluripotency. The cells of origin of testicular teratomas are germ cells. During early development, primordial germ cells diverge from somatic differentiation and establish their pluripotent nature, maintaining or re-expressing core pluripotency genes; Oct4, Sox2 and Nanog. It is believed that a misregulation of male germ cell pluripotency plays a critical role in teratoma development. Several mouse models of teratoma development have now been identified, including a chromosome substitution strain, 129-Chr19MOLF, conditional Dmrt1 and Pten alleles and the Ter mutation in the Dnd1 gene. However, it is still unknown what role somatic cells and/or physiology play in the sensitivity to teratoma development. These unusual tumors may hold the key to understanding how pluripotency is regulated in vivo.
Keywords: testicular teratoma, germ cell, Dnd1, stem cell
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 211-219 (2013)
doi: 10.1387/ijdb.130028pk / © UBC Press (www.a360grados.net)
Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors
Cassy M. Spiller, Josephine Bowles and Peter Koopman
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
Abstract: Testicular cancer is the most frequent cancer in young men aged 15-40 years and accounts for 1% of all cancer diagnosed in males. Testicular germ cell tumors (TGCT) encompass a broad group of cancers, each displaying different levels of pluripotency and differentiation as well as malignancy potential. The TGCT cell of origin is thought to be a fetal germ cell that failed to correctly differentiate during development: this is known as the ‘fetal origins hypothesis’. This theory predicts that developmental pathways that control germ cell pluripotency or differentiation may be involved in the malignant transformation of these cells. Recently the Nodal/Cripto signaling pathway, known to control pluripotency and differentiation in embryonic stem (ES) cells, was implicated in regulating normal male fetal germ cell pluripotency. Although genes of this pathway are not normally expressed in germ cells during adult life, ectopic expression of this pathway was detected in several sub-groups of TGCTs. In this review, we consider the evidence for the fetal origins of TGCT and discuss the implications of Nodal/Cripto signaling in various aspects of germ cell development and cancer progression.
Keywords: germ cell, nodal, cripto, testicular germ cell tumor
Environmental endocrine disruptors and germ cell tumors
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 221-223 (2013)
doi: 10.1387/ijdb.130145jt / © UBC Press (www.a360grados.net)
Carcinoma in situ -from clinical observation to a paradigm shift for testicular carcinogenesis
Jorma Toppari
Departments of Physiology and Paediatrics, University of Turku, Turku, Finland and Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark
Abstract: Carcinoma in situ in the testis has its origin in the fetal gonad and leads to testicular cancer in young adulthood. It can be detected in a testicular biopsy and treated with irradiation, which can preserve testosterone production of the man. These are the key findings of Niels E. Skakkebaek that changed our view of testicular tumourigenesis during the last fifty years. These and other findings are discussed in this interview-based review of testicular germ cell cancer.
Keywords: testis, cancer, fertility, CIS, germ cell
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 225-239 (2013)
doi: 10.1387/ijdb.130042jd / © UBC Press (www.a360grados.net)
Endocrine disruptors, gene deregulation and male germ cell tumors
Jesús Del Mazo 1, Miguel A. Brieño-Enríquez 1, Jesús García-López 1, Luis A. López-Fernández 2 and Massimo De Felici 3
1 Department of Cellular and Molecular Biology. Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
2 Hospital General Universitario Gregorio Marañón, Madrid, Spain
3 Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
Abstract: Endocrine disruptors (EDs) belong to a large group of compounds, usually present as environmental pollutants, which can alter the homeostasis of living organisms by modifying hormonal balance and changing the normal patterns of gene regulation during development and cell differentiation. Hence, the development of male gonads and their functionality may be affected by exposure to specific EDs or their mixtures. The molecular mechanisms of action of these reprotoxicants leading to pathologies of the reproductive system such as testicular cancer, are complex and not well characterized. It is likely, however, that these compounds alter the interaction between the mechanisms of gene regulation and functional gene networks in windows of risk, mainly during embryonic development. Moreover, such changes could be transmitted through generations by epigenetic mechanisms. There are examples of the action of EDs on the expression of mRNAs, small non-coding RNAs and epigenetic marks in the developing testis associated with cellular and molecular alterations found in germ cell tumors. In the present review, we will discuss various aspects of genetic, transcriptomic and epigenetic changes related to testicular development, exposure to EDs and the occurrence of germ cell tumors.
Keywords: testis, tumor, primordial germ cell, miRNA, piRNA, epigenetic, DNA methylation, histone modification
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 241-253 (2013)
doi: 10.1387/ijdb.130026ll / © UBC Press (www.a360grados.net)
Development of malignant germ cells - the genvironmental hypothesis
Leendert H.J. Looijenga, Ton Van Agthoven and Katharina Biermann
Department of Pathology, Erasmus MC – University Medical Center Rotterdam, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
Abstract: Human germ cell tumors are of interest because of their epidemiology, clinic and patho-biology. Histologically, they are subdivided into various elements, with similarities to embryogenesis. Recent insight triggered development of a higher order division into five types of human germ cell tumors. In the context of male germ cells, only three are relevant; Type I: teratomas and yolk sac tumors of neonates and infants; Type II: seminomas and nonseminomas of (predominantly) adolescents and adults; and Type III: spermatocytic seminomas of the elderly. Various animal models, both occurring spontaneous or induced, are reported, of which their relevance is still a matter of debate. Recent multidisciplinary studies have led to a significant increase in our understanding of the parameters involved in the earliest pathogenetic steps of human germ cells tumors, particularly the seminomas and nonseminomas (Type II). This paper will discuss a number of interesting insights into the normal and aberrant regulation of germ cell development, resulting in the so-called genvironmental hypothesis. This assumes a subtle interaction between environmental- and (epi)genetic parameters, resulting in clinical/phenotypical characteristics. These influence signaling pathways and thereby developmental processes, including gonadal development, germ cell proliferation, maturation and apoptosis. In the case of a disturbed physiology, either due to the germ cell itself, or the micro-environment, embryonic germ cells, during a specific window of sensitization, might be blocked in their maturation, resulting in carcinoma in situ or gonadoblastoma, the precursors of seminomas and nonseminomas. The level of testicularization of the gonad determines the histological composition of the precursor. These insights will allow a better definition of individuals at risk of developing a germ cell malignancy, and allow a better selection of scientific approaches to elucidate the corresponding pathogenesis.
Keywords: testis, gonad, germ cell tumor, environment
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 255-263 (2013)
doi: 10.1387/ijdb.130015fg / © UBC Press (www.a360grados.net)
Effect of endogenous and exogenous hormones on testicular cancer: the epidemiological evidence
Fabrizio Giannandrea 1, Donatella Paoli 1, Irene Figà-Talamanca 2, Francesco Lombardo 1, Andrea Lenzi 1 and Loredana Gandini 1
1 Department of Experimental Medicine, Laboratory of Seminology - Semen Bank, University of Rome "La Sapienza", Rome, Italy
2 Department of Public Health and Infectious Diseases, University of Rome "La Sapienza", Rome, Italy
Abstract: Testicular cancer is the most common type of malignancy in men aged 15–40 years. Although its incidence has increased over the past 40 years in most countries, the reasons for this rise are unclear. It has been suggested that a relative excess of endogenous estrogens during prenatal life and/or later exposures to various occupational and environmental estrogenic chemicals such as organochlorine compounds may play a causal role in the etiology of testicular cancer, but the issue is still open to further research. The purpose for this review is to summarize the epidemiologic literature about hormonal factors, endogenous hormones and environmental xenoestrogens, and testicular carcinogenesis. Future studies need to (a) consider the possible synergistic effect of exposure to environmental xenoestrogens and sex hormones, (b) focus on the most vulnerable life stages of exposure to endocrine disruptors and testicular cancer risk, (c) assess the possible additive role of androgen secretion occurring during puberty in tumor progression, and (d) consider more systematically gene–environment interactions.
Keywords: testicular cancer, estrogen, androgen, xenoestrogen, organochlorine compound
Male germ cell apoptosis and DNA damage
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 265-272 (2013)
doi: 10.1387/ijdb.130146ja / © UBC Press (www.a360grados.net)
Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development
R. John Aitken and Mark A. Baker
Discipline of Biological Sciences and Priority Research Centre in Reproductive Science, Faculty of Science and IT, University of Newcastle, Australia
Abstract: During early development, apoptosis plays a major role in the ontogeny of the germ line as a means of regulating the germ cell:Sertoli cell ratio. In the adult, apoptosis fulfils another function in removing damaged germ cells from the seminiferous epithelium in response to a wide range of physiological and environmental triggers. These include various forms of electromagnetic radiation, chemotherapeutic agents and commonly encountered toxicants such as phthalate esters, bisphenol A and cadmium. This form of apoptosis can lead to spermatogenic arrest and is predominantly mediated by the Fas/FasL system. In addition, senescent mature spermatozoa can undergo a truncated form of apoptosis in order to ensure their efficient phagocytosis within the male and female reproductive tracts. This apoptotic cascade appears to be triggered by oxidative stress and lipid peroxidation, which leads to activation of mitochondrial reactive oxygen species (ROS) generation in a self-perpetuating redox cycle. The electrophilic aldehydes generated as a result of lipid peroxidation also lead to a rapid loss of sperm motility followed some hours later by caspase activation and phosphatidylserine exposure on the sperm surface. The nuclear DNA suffers oxidative damage during this process but there is no immediate DNA cleavage by endonucleases as there is in somatic cells. The reasons for this deviation from the normal pattern of apoptosis involve the unusual physical architecture of spermatozoa and the limited capacity these cells possess for base-excision repair. These findings have practical implications for the approaches that might be used to detect and prevent DNA damage in spermatozoa.
Keywords: spermatozoa, apoptosis, reactive oxygen species, mitochondria DNA damage
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 273-280 (2013)
doi: 10.1387/ijdb.130135mb / © UBC Press (www.a360grados.net)
Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors
Francesca Cavallo 1,2, Darren R. Feldman 3 and Marco Barchi 1
1 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy
2 Developmental Biology Program, 3Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Abstract: Testicular germ cell tumors (TGCTs), ie, seminomas and nonseminomas, account for 1% to 3% of all neoplasms in men. They are the most common cancer in young white males and are unique in their responsiveness to cisplatin-based chemotherapy. For this reason, TGCTs are considered a model for curative disease. However, up to now, the molecular mechanisms behind this exceptional responsiveness to DNA-damaging agents have remained unclear. A hypersensitive apoptotic response, as well as a reduction in the proficiency to repair cisplatin-induced DNA damage might account for this behavior. In this review, building on recent findings of p53-induced apoptosis and DNA-repair mechanisms in TGCTs, we will discuss the molecular bases that drive tumor sensitivity to cisplatin, emphasizing the new therapeutic approaches proposed to eventually constrain tumor recurrence, and target TGCTs which are unresponsive to standard therapies.
Keywords: p53, XPF, ERCC1, homologous recombination (HR), nutlin-3, MDM2
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 281-287 (2013)
doi: 10.1387/ijdb.130039sd / © UBC Press (www.a360grados.net)
UV and genotoxic stress induce ATR relocalization in mouse spermatocytes
Sara Di Siena 1, Federica Campolo 2, Pellegrino Rossi 2, Emmanuele A. Jannini 3, Susanna Dolci 2 and Manuela Pellegrini 4
1 Department of SAIMLAL, University of Rome “La Sapienza”, Rome
2 Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome
3 Department of Clinical and Applied Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy
4 Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
Abstract: During meiosis, phosphorylation of H2AX is one of the earliest cellular responses to the generation of DNA double-strand breaks (DSBs) by the SPO11 topoisomerase. ATM is the kinase which mediates the formation of phosphorylated H2AX (H2AX) meiotic foci, while ATR is the kinase which signals chromosome asynapsis at the level of the XY bivalent. To investigate the possible role of ATR also in DNA damage signalling in meiotic cells, we studied the effect of UV radiation and chemotherapy drugs on H2AX phosphorylation and ATR relocalization in mouse pachytene spermatocytes. Here, we report that UV, a single strand break DNA-damaging agent, induces ATR relocalization from the XY sex body to nuclear foci and intense H2AX phosphorylation. Other DNA damage proteins such as MDC1, NBS1 and 53BP1 showed a similar relocalization following UVA microirradiation of spermatocytes. We found that DNA damage induced by UV increased the intensity and the number of H2AX foci also in Atm null spermatocytes. Inhibition of RNA synthesis was found to induce the formation of H2AX foci, but it did not influence the DNA damage response to UV irradiation. Finally, exposure of spermatocytes to double strand break DNA-damaging agents such as cisplatin, bleomycin or etoposide also induced ATR relocalization and intense H2AX phosphorylation and led to anomalies in synaptonemal assembly. Our results demonstrate that DNA damage induced by genotoxic stress can activate ATR and influence meiotic chromatin remodelling through H2AX phosphorylation, likely as part of a response which normally ensures germ cell genomic integrity.
Keywords: DNA damage, ATR, pachytene spermatocyte
New insights into the molecular mechanisms of germ cell tumors: pluripotency genes, epigenetics and micrornas
EHU/UPV/UBC - The International Journal of Developmental Biology 57: 289-298 (2013)
doi: 10.1387/ijdb.130025ll / © UBC Press (www.a360grados.net)
Pathobiology of germ cell tumors - applying the gossip test!
Leendert H. J. Looijenga and J. Wolter Oosterhuis
Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
Abstract: Residual mature teratoma, a frequent finding in clinical pathology since the introduction of cisplatin-based chemotherapy, put Wolter Oosterhuis on the track of germ cell tumors (GCTs). These neoplasms in the borderland between developmental biology and oncology have fascinated him ever since. He tells the story on how GCTs brought him in contact with leading investigators in the field like Ivan Damjanov, Peter Andrews, and Niels Skakkebaek. His fruitful line of research was made possible through a longstanding collaboration with Bauke de Jong and, to this day, Leendert Looijenga who joined his group as a student in 1988. Probably their most important contribution to the field of GCTs is an integrated approach to GCTs, combining epidemiology, pathology, (cyto)genetics and molecular biology, that has resulted in a pathobiology-based classification of GCTs in five types. It has clinical relevance and stimulates further research on these intriguing neoplasms and their corresponding animal models.
Keywords: teratoma, teratocarcinoma, carcinoma in situ, gonadoblastoma, seminoma, dysgerminoma, germinoma, canine spermatocytic seminoma, dermoid cyst, hydatiform mole, cytogenetics, genomic imprinting, gonadal dysgenesis
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 299-308 (2013)
doi: 10.1387/ijdb.130017ll / © UBC Press (www.a360grados.net)
Role of epigenetics in the etiology of germ cell cancer
Yvonne G. Van Der Zwan 1, Hans Stoop 1, Fernando Rossello 2,Stefan J. White 2 and Leendert H.J. Looijenga 1
1 Department of Pathology, Erasmus MC – University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands
2 Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton
3 Centre for Reproduction and Development, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Abstract: Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed appropriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency. This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an interactive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methylation, histone modifications, epigenetic memory and inheritance, as well as environmental factors.
Keywords: germ cell cancer, epigenetics, methylation, histone modification, environment
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 309-317 (2013)
doi: 10.1387/ijdb.130142ka / © UBC Press (www.a360grados.net)
Epigenetic features of testicular germ cell tumours in relation to epigenetic characteristics of foetal germ cells
Dina G. Kristensen, Niels E. Skakkebæk, Ewa Rajpert-De Meyts and Kristian Almstrup
Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Abstract: Foetal development of germ cells is a unique biological process orchestrated by cellular specification, migration and niche development in concert with extensive epigenetic and transcriptional programs. Many of these processes take place early in foetal life and are hence very difficult to study in humans. However, the common precursor of testicular cancers – the carcinoma in situ (CIS) cell – is thought to be an arrested foetal germ cell. Therefore studies of CIS cells may leverage information on human foetal germ cell development and, in particular, when neoplastic transformation is initiated. In this review, we will focus on current knowledge of the epigenetics of CIS cells and relate it to the epigenetic changes occurring in early developing germ cells of mice during specification, migration and colonization. We will focus on DNA methylation and some of the best studied histone modifications like H3K9me2, H3K27me3 and H3K9ac. We also show that CIS cells contain high levels of H3K27ac, which is known to mark active enhancers. Proper epigenetic reprogramming seems to be a pre-requisite of normal foetal germ cell development and we propose that alterations in these programs may be a pathogenic event in the initiation of testicular germ cell cancer. Even though only sparse information is available on epigenetic cues in human foetal germ cells, these indicate that the developmental patterns differ from the findings in mice and emphasize the need for further studies of foetal germ cell development in humans.
Keywords: primordial germ cell, gonocyte, epigenetics, carcinoma in situ testis
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EHU/UPV/UBC - The International Journal of Developmental Biology 57: 319-332 (2013)
doi: 10.1387/ijdb.130020re / © UBC Press (www.a360grados.net)
Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer
Ronak Eini, Lambert C. J. Dorssers and Leendert H. J. Looijenga
Erasmus MC, University Medical Center Rotterdam, Department of Pathology, The Netherlands
Abstract: Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of the blastocyst. These cells can proliferate indefinitely and differentiate into all cell lineages. Germ cell cancers (GCC) mimic embryonic development to a certain extent. The origin of GCC trace back to primordial germ cells/gonocytes in the embryo, which determines their specific characteristics such as totipotency and overall (exceptional) sensitivity to DNA damaging agents. Thus GCC provide a useful model system for the study of gene regulation involved in oncogenesis as well as development. Several reports have demonstrated the role of specific proteins and microRNAs (miRs) in the control of pluripotency and thus early development. miRs are small non-coding RNA molecules that post-transcriptionally regulate gene expression by base-paring to protein encoding mRNAs. miRs are predicted to regulate up to 30% of the protein-encoding genes within the human genome. They are expressed in a tissue-specific and developmentally regulated manner. Aberrant miR expression and its correlation with development and progression of cancers is an emerging field. Important evidences have shown that knock-down by synthetic anti-sense oligonucleotides or re-expression of specific miRs by pre-miR can induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. In addition, miRs have been found in body fluids of patients with different types of diseases, including cancer. Therefore, investigation of miRs can shed light on the process of pathogenesis, and may provide biomarkers for diagnosis and prognosis. A subset of miRs is specifically expressed in ES cells and GCC, suggesting their critical role in early embryogenesis and development. In this review we discuss the current view of the biology of embryonic stem cell proteins and miRs in GCC, and their potential clinical impact.
Keywords: embryonic stem cell, embryogenesis, microRNA, germ cell cancer
The International Journal of Developmental Biology
ISSN 1696-3547 (online) and 0214-6282 (print)
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