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.

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility

“…Since TRIM71 is known to regulate proliferation in several cell lines ( Chen et al, 2013 ; Ren et al, 2018 ; Hu et al, 2019 ; Torres-Fernández et al, 2019 ), we next wanted to investigate whether TRIM71 may control proliferation also in PGCs. Because the isolation of sufficient PGCs from genital ridges for its absolute reliable quantification is technically very challenging, we used the human GCT-derived seminoma cell line TCam-2, which is a widely accepted in vitro PGC model ( Irie et al, 2015 ; Sugawa et al, 2015 ; Nettersheim et al, 2016a , b , c ; Mitsunaga et al, 2017 ; Müller et al, 2020 ) and expresses high TRIM71 levels, similar to other GCT-derived cell lines ( Supplementary Figure 8A ). To this end, we knocked down (KD) TRIM71 with two different siRNAs ( Figure 4A ), and monitored the increase in cell numbers over time ( Figure 4B ).…”

“…While we excluded in vivo PGC migration defects upon TRIM71 depletion, in vitro proliferation assays with TCam-2 and NCCIT cells showed that TRIM71 actively promotes proliferation of these GCT-derived cell lines. Given the similarities of TCam-2 cells -and to a lesser extent of NCCIT cells -with PGCs (Irie et al, 2015;Sugawa et al, 2015;Nettersheim et al, 2016a,b,c;Mitsunaga et al, 2017;Müller et al, 2020), our results suggest that TRIM71 may be involved in the control of PGC proliferation after they reach the genital ridges, when a significant expansion of the PGC pool occurs (Tam and Snow, 1981;Anderson et al, 2000;Bowles and Koopman, 2010;Ewen and Koopman, 2010). To strengthen this notion, future experiments should investigate the role of TRIM71 in the proliferation of post-migratory PGCs in vivo.…”

Female Germ Cell Development, Functioning and Associated Adversities under Unfavorable Circumstances

“…Female germ cell tumors may be derived from various types of cells including surface epithelium, stroma, or follicular cell elements. Ovarian germ cell tumors (OGCTs) are mostly associated with early developmental stages of primitive germ cells of the embryonic gonad and are developed during specification, migration, and colonization of the primordial germ cells in the genital ridges [ 79 , 80 ].…”

Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights

“…Compared to most other cancer types, GCTs harbor a very low mutational burden [ 7 , 8 ]. Hence, it is postulated that epigenetic aberrations could be the driver of tumorigenesis in GCTs [ 3 , 9 ]. It has been shown that the GCT subtypes vary greatly in their DNA methylation status, i.e.…”