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| Molecular and epigenetic pathogenesis of germ cell tumors |
Melanie R. Müllera,Margaretha A.Skowrona,Peter Albersb,Daniel Nettersheima,*( )
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a Department of Urology, Urological Research Lab, Translational UroOncology, University Hospital Düsseldorf, Düsseldorf, Germany
b Department of Urology, University Hospital Düsseldorf, Düsseldorf, Germany |
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Abstract The development of germ cell tumors (GCTs) is a unique pathogenesis occurring at an early developmental stage during specification, migration or colonization of primordial germ cells (PGCs) in the genital ridge. Since driver mutations could not be identified so far, the involvement of the epigenetic machinery during the pathogenesis seems to play a crucial role. Currently, it is investigated whether epigenetic modifications occurring between the omnipotent two-cell stage and the pluripotent implanting PGCs might result in disturbances eventually leading to GCTs. Although progress in understanding epigenetic mechanisms during PGC development is ongoing, little is known about the complete picture of its involvement during GCT development and eventual classification into clinical subtypes. This review will shed light into the current knowledge of the complex epigenetic and molecular contribution during pathogenesis of GCTs by emphasizing on early developmental stages until arrival of late PGCs in the gonads. We questioned how misguided migrating and/or colonizing PGCs develop to either type I or type II GCTs. Additionally, we asked how pluripotency can be regulated during PGC development and which epigenetic changes contribute to GCT pathogenesis. We propose that SOX2 and SOX17 determine either embryonic stem cell-like (embryonal carcinoma) or PGC-like cell fate (seminoma). Finally, we suggest that factors secreted by the microenvironment, i.e. BMPs and BMP inhibiting molecules, dictate the fate decision of germ cell neoplasia in situ (into seminoma and embryonal carcinoma) and seminomas (into embryonal carcinoma or extraembryonic lineage), indicating an important role of the microenvironment on GCT plasticity.
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Received: 01 November 2019
Available online: 30 May 2020
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Corresponding Authors:
Daniel Nettersheim
E-mail: Daniel.Nettersheim@med.uni-duesseldorf.de
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Development of GCs and pathogenesis of TGCTs. Upper panel: Development of the human embryo from the zygote (0 day post fertilization [dpf]) until Week 6 post fertilization when the PGC reach the gonads. Lower panel: DNA methylation events during PGC migration and arrival at the genital ridge and where different types pf TGCTs are thought to originate from. The table summarizes molecular and epigenetic findings from this review. Data from Refs. [1,48,49,52,58,74]. PGC, primordial germ cell; ICM, inner cell mass; SE, seminoma; EC, embryonal carcinoma; CC, choriocarcinoma; TE, teratoma; YST, yolk sac tumor; NS, non-seminoma; GCNIS, germ cell neoplasia in situ; GC, germ cell; TGCTs, testicular germ cell tumors.
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| Chapter | References | | Comparability of murine and human (primordial) GC development | | The Phenotype differs: Egg cylinder in mice and bilaminar disc in human | [4,19] | | Commonly expressed genes between the species: PRDM1/Prdm1, TFAP2C/Tfap2c, NANOS3/Nanos3, DND1/Dnd1, DDX4/Ddx4, DAZL/Dazl, OCT4/Oct4, NANOG/Nanog | [19] | | Mouse specific genes: Prdm14, Sox2 | [21,22] | | Human specific genes: SOX17, SOX15 | [21,24] | | Development of type I GCTs | | PGC specification depends on WNT and BMP pathways | [27,28] | | The surrounding tissue and extracellular matrix might influence BMP and WNT signaling pathways | this review | | Misrouting of PGCs and failures in downregulating the pluripotency program could lead to type I GCTs | [7] | | Development of type I GCT from PGCs in a short time-frame | [7] | | The testicular dysgenesis syndrome and formation of GCNIS | | TDS results from disturbed hormonal microenvironmental factors during fetal development | [31,32] | | TDS is related to TGCT development | [33] | | Impaired Sertoli and Leydig cell function are not the only triggers leading to GCNIS formation | [33] | | The PGC gene expression program in type II GCTs | | TFAP2C expression is associated with a PGC-like cell fate | [39] | | TFAP2C in GCTs allows maintenance of a latent pluripotent state | this review | | DAZL, DDX4, MAEL and TDRD12 are gonad-specifically activated in PGCs upon arrival at the genital ridge | [40] | | DAZL deficiency leads to an increase in TE formation | [40] | | SOX2 and SOX17 regulating GCT fate | | SOX2 and SOX17 share a common set of overlapping target genes, such as NANOG, OTX2, PIM1/2, PRDM14, DPP4, TDGF1, LIN28A, and TRIM71 | [45] | | Epigenetic re-arrangements might contribute to SOX17 target gene accessibility including GC-fate and pluripotency genes in PGCs | this review | | DNA-Methylation in GCTs | | Compared to SE and GCNIS, NS shows high de novo DNA methylation levels (high expression of DNMT3A and DNMT3L) | [[47], [48], [49]] | | Active 5mC demethylation in TGCTs | [49] | | The influence of microenvironment on TGCT pathogenesis | | Important interactions between SDF1/CXCL12 and CXCR4 as well as functioning Msx genes are involved in a correct migration during PGC development | [[62], [63], [64], [65],67,69] | | A pro-inflammatory micromilieu (IL-1β, IL-6, TNF-α, CCL5, SDF-1/CXCL12, CXCL-13) might favor TGCT development | [68] | | FOXA2 is identified as a key factor of differentiation of SE to NS (not EC) | [44,73] | | Microenvironmental components and BMP-inhibiting factors could directly differentiate SE into EC | [22,44] | | Colonization of the genital ridge is influenced by factors secreted by surrounding Sertoli-, Leydig-, and immune cells, such as chemokines and cytokines | this review |
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Main findings of this review.
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Plasticity of SE cells—Transformation into EC and CC/YST. Depending on BMP activity GCNIS either develop into SE (BMP active) or EC (BMP inhibited) which further differentiates into TE, CC and YST. Additionally, to the commonly accepted TGCT developmental theory (Fig. 1), in vitro experiments indicated reprogramming of SE to EC [22] as well as directly into extraembryonal tumors without EC intermediate (SOX2) [44,75]. SE to EC transformation is initiated in vitro by BMP inhibition through the microenvironment. SOX2 upregulation and establishment of NODAL signaling give rise to mixed SE/EC. These can further differentiate into mixed SE/NS, eventually leading to mixed tumors with SE components while also containing extraembryonal proportions. Direct SE differentiation into extraembryonal-like tissue has been demonstrated in vitro and in vivo although the factors involved in the latter still remain unknown and have yet to be determined. GCNIS, germ cell neoplasia in situ; EC, embryonal carcinoma; SE, seminoma; NS, non-seminoma; CC, choriocarcinoma; TE, teratoma; YST, yolk sac tumor; NS, non-seminoma; GC, germ cell; TGCT, testicular germ cell tumor.
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