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Molecular and epigenetic pathogenesis of germ cell tumors
Open accessAbstract
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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![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.](/paper-figures/be652bd315284e418846ea65943685f9/molecular-and-epigenetic-pathogenesis-of-germ-cell-tumors-figure-1.jpg)
![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.](/paper-figures/e437b4174fb2445bb274139ec97796d9/molecular-and-epigenetic-pathogenesis-of-germ-cell-tumors-figure-2.jpg)
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“In TGCTs, the relationship between malignant cells and the surrounding tumor microenvironment (TME) seems to play an important role in the disruption of this balance [16,17,18,19].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [19]
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Cites
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G-protein-coupled receptors and cancer
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Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells
Hayashi, K., Ohta, H., Kurimoto, K., Aramaki, S., & Saitou, M. (2011) · Cell · doi:10.1016/j.cell.2011.06.052 · Cited by 1,379
N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells
Wang, Y., Li, Y., Toth, J. I., Petroski, M. D., Zhang, Z., & Zhao, J. C. (2014) · Nature Cell Biology · doi:10.1038/ncb2902 · Cited by 1,290
Schwartz, S., Mumbach, M. R., Jovanovic, M., Wang, T., Maciag, K., Bushkin, G. G., Mertins, P., Ter-Ovanesyan, D., Habib, N., Cacchiarelli, D., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.048 · Cited by 1,216
m6A RNA Modification Controls Cell Fate Transition in Mammalian Embryonic Stem Cells
Batista, P. J., Molinie, B., Wang, J., Qu, K., Zhang, J., Li, L., Bouley, D. M., Lujan, E., Haddad, B., Daneshvar, K., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.09.019 · Cited by 1,203
Testicular germ-cell tumours in a broader perspective
Oosterhuis, J. W., & Looijenga, L. H. J. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1568 · Cited by 916
Epigenetic events in mammalian germ-cell development: reprogramming and beyond
Sasaki, H., & Matsui, Y. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2295 · Cited by 871
SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate
Irie, N., Weinberger, L., Tang, W. W. C., Kobayashi, T., Viukov, S. V., Manor, Y. S., Dietmann, S., Hanna, J. H., & Surani, M. A. (2014) · Cell · doi:10.1016/j.cell.2014.12.013 · Cited by 864
Cited by
Skowron, M. A., Eul, K., Stephan, A., Ludwig, G. F., Wakileh, G. A., Bister, A., Söhngen, C., Raba, K., Petzsch, P., Poschmann, G., et al. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13282 · Cited by 20
Self-citationEvmorfopoulos, K., Marsitopoulos, K., Karachalios, R., Karathanasis, A., Dimitropoulos, K., Tzortzis, V., Zachos, I., & Vlachostergios, P. J. (2024) · Cancers · doi:10.3390/cancers16020428 · Cited by 11
“In TGCTs, the relationship between malignant cells and the surrounding tumor microenvironment (TME) seems to play an important role in the disruption of this balance [16–19].”
Background
Metadata
- Authors
- Müller, M. R., Skowron, M. A., Albers, P., & Nettersheim, D.
- Affiliations
- Düsseldorf University Hospital (DE)
- Corresponding author
- Nettersheim, Daniel
- Venue
- Asian Journal of Urology
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 8
- Issue
- 2
- Pages
- 144-154
- ISSN
- 2214-3882 (ISSN-L)
- PMC
- PMC8099689
- OpenAlex
- W3030743858
- Cited by
- 50
- References
- 77
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 11 · 2023: 10 · 2022: 7 · 2021: 3
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
- Locations
- Asian journal of urology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Surgery › Testicular diseases and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- germ cell tumors, primordial germ cells, epigenetic modifications, SOX2, SOX17, embryonal carcinoma, seminoma, germ cell neoplasia in situ, BMP signaling, tumor microenvironment, pluripotency regulation, germ cell migration, tumor plasticity
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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