Molecular and epigenetic pathogenesis of germ cell tumors

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.

Keywords: BMP signaling; Epigenetic reprogramming; Germ cell tumor; Microenvironment; Plasticity; Primordial germ cell; SOX17; SOX2.

Figure 1

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.

Figure 2

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.