RESUMO
Germ cell tumors are neoplasms arising from pluripotent germ cells. In humans, these tumors occur in infants, children and young adults. The tumors display a wide range of histologic differentiation states which exhibit different clinical behaviors. Information about the molecular basis of germ cell tumors, and representative animal models of these neoplasms, are lacking. Germline development in zebrafish and humans is broadly conserved, making the fish a useful model to probe the connections between germ cell development and tumorigenesis. Here, we provide an overview of germline development and a brief review of germ cell tumor biology in humans and zebrafish. We also outline some methods for studying the zebrafish germline.
Assuntos
Transformação Celular Neoplásica/metabolismo , Citometria de Fluxo/métodos , Células Germinativas/metabolismo , Imuno-Histoquímica/métodos , Neoplasias Embrionárias de Células Germinativas/metabolismo , Espermatogênese/imunologia , Neoplasias Testiculares/metabolismo , Testículo/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Epigênese Genética , Células Germinativas/patologia , Histonas/análise , Humanos , Lactente , Masculino , Camundongos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Cultura Primária de Células , Espermatogênese/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Testículo/patologia , Adulto Jovem , Peixe-ZebraRESUMO
Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Diferenciação Celular/genética , Células Germinativas/patologia , Mutação/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Peixe-Zebra/genética , Alelos , Animais , Sequência de Bases , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Clonagem Molecular , Feminino , Loci Gênicos/genética , Células Germinativas/metabolismo , Humanos , Masculino , Meiose , Dados de Sequência Molecular , Ovário/metabolismo , Ovário/patologia , Transdução de Sinais , Espermatozoides/metabolismo , Espermatozoides/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Testículo/metabolismo , Testículo/patologiaRESUMO
Germ cell tumors (GCTs) affect infants, children, and adults and are the most common cancer type in young men. Progress in understanding the molecular basis of GCTs has been hampered by a lack of suitable animal models. Here we report the identification of a zebrafish model of highly penetrant, heritable testicular GCT isolated as part of a forward genetic screen for cancer susceptibility genes. The mutant line develops spontaneous testicular tumors at a median age of 7 months, and pedigree analysis indicates dominant inheritance of the GCT susceptibility trait. The zebrafish model exhibits disruption of testicular tissue architecture and the accumulation of primitive, spermatogonial-like cells with loss of spermatocytic differentiation. Radiation treatment leads to apoptosis of the tumor cells and tumor regression. The GCT-susceptible line can serve as a model for understanding the mechanisms regulating germ cells in normal development and disease and as a platform investigating new therapeutic approaches for GCTs.