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.non-seminoma | SMAD | teleost | haplotype
Summary
Germ cell tumors (GCTs) are cancers of the testis, ovary or extragonadal sites that occur in infants, children and adults. Testicular GCT is the most common cancer in young men aged 15–40. Abnormalities in developmental signaling pathways such as wnt/β-catenin, TGF-β/BMP and Hedgehog have been described in many childhood tumors. To date, however, the status of BMP signaling in germ cell tumors has not been described. Here, we examine BMP-SMAD signaling in a set of clinically-annotated pediatric germ cell tumors. We find that BMP signaling activity is absent in undifferentiated tumors such as seminomas and dysgerminomas, but robustly present in most yolk sac tumors, a differentiated tumor type. Gene expression profiling of TGF-β/BMP pathway genes in germinomas and yolk sac tumors reveals a set of genes that distinguish the two tumor types. There is significant intertumoral heterogeneity between tumors of the same histologic subclass, implying that the BMP pathway can be differentially regulated in individual tumors. Finally, through miRNA expression profiling, we identify differential regulation of a set of miRNAs predicted to target the TGF-β/BMP pathway at multiple sites. Taken together, these results suggest that the BMP signaling pathway may represent a new therapeutic target for childhood germ cell tumors.
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 germ cell tumors has been hampered by a lack of suitable animal models. Here we report the identification of a zebrafish model of highly penetrant, heritable testicular germ cell tumor 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 germ cell tumor 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 germ cell tumor-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 germ cell tumors.
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