Müller Melanie R, Skowron Margaretha A, Albers Peter, Nettersheim Daniel
Department of Urology, Urological Research Lab, Translational UroOncology, University Hospital Düsseldorf, Düsseldorf, Germany.
Department of Urology, University Hospital Düsseldorf, Düsseldorf, Germany.
Asian J Urol. 2021 Apr;8(2):144-154. doi: 10.1016/j.ajur.2020.05.009. Epub 2020 May 30.
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, BMPs and BMP inhibiting molecules, dictate the fate decision of germ cell neoplasia (into seminoma and embryonal carcinoma) and seminomas (into embryonal carcinoma or extraembryonic lineage), indicating an important role of the microenvironment on GCT plasticity.
生殖细胞肿瘤（GCTs）的发生是一种独特的发病机制，发生在原始生殖细胞（PGCs）在生殖嵴中特化、迁移或定植的早期发育阶段。由于目前尚未发现驱动突变，发病机制中表观遗传机制的参与似乎起着关键作用。目前，正在研究全能双细胞阶段和多能植入PGCs之间发生的表观遗传修饰是否可能导致最终引发GCTs的紊乱。尽管在理解PGC发育过程中的表观遗传机制方面正在取得进展，但对于其在GCT发育过程中的参与全貌以及最终分类为临床亚型的了解却很少。本综述将通过强调早期发育阶段直至晚期PGCs到达性腺，来阐明GCTs发病机制中复杂的表观遗传和分子贡献的当前知识。我们质疑迁移和/或定植错误的PGCs如何发展为I型或II型GCTs。此外，我们还询问了在PGC发育过程中多能性如何受到调控，以及哪些表观遗传变化导致了GCT发病机制。我们提出，SOX2和SOX17决定了胚胎干细胞样（胚胎癌）或PGC样细胞命运（精原细胞瘤）。最后，我们认为微环境分泌的因子，即骨形态发生蛋白（BMPs）和BMP抑制分子，决定了生殖细胞肿瘤的命运决定（分化为精原细胞瘤和胚胎癌）以及精原细胞瘤的命运决定（分化为胚胎癌或胚外谱系），这表明微环境对GCT可塑性具有重要作用。
