Abstract
Human germ cell development is regulated in a spatio-temporal manner by complex regulatory networks. Here, we summarize results obtained in germ cell tumors and respective cell lines and try to pinpoint similarities to normal germ cell development. This comparison allows speculating about the critical and error-prone mechanisms, which when disturbed, lead to the development of germ cell tumors. Short after specification, primordial germ cells express markers of pluripotency, which, in humans, persists up to the stage of fetal/infantile spermatogonia. Aside from the rare spermatocytic tumors, virtually all seminomas and embryonal carcinomas express markers of pluripotency and show signs of pluripotency or totipotency. Therefore, it appears that proper handling of the pluripotency program appears to be the most critical step in germ cell development in terms of tumor biology. Furthermore, data from mice reveal that germline cells display an epigenetic signature, which is highly similar to pluripotent cells. This signature (poised histone code, DNA hypomethylation) is required for the rapid induction of toti- and pluripotency upon fertilization. We propose that adult spermatogonial cells, when exposed to endocrine disruptors or epigenetic active substances, are prone to reinitiate the pluripotency program, giving rise to a germ cell tumor. The fact that pluripotent cells can be derived from adult murine and human testicular cells further corroborates this idea.
Highlights
Germ cells (GCs) are the progenitor cells of sperm and oocytes, which are a prerequisite for the development of new life
Human primordial germ cell (PGC) lack the expression of the pluripotency marker SOX2, which is expressed in murine PGCs aside with OCT3/4 and NANOG (Perrett et al 2008)
Cultivation of TCam-2 under culture conditions mimicking a somatic environment, forces differentiation into a mixed non-seminoma (Nettersheim et al 2011b) (Fig. 1A). This transition of seminoma to an EC-like phenotype is accompanied by a number of epigenetic and molecular changes: the initial step in this process is the inhibition of BMP signaling by the microenvironment, resulting in de-repression of NODAL signaling (Nettersheim et al 2015)
Summary
Germ cells (GCs) are the progenitor cells of sperm and oocytes, which are a prerequisite for the development of new life. The PGCs migrate along the developing hindgut to the genital ridges, which eventually differentiate into testes or ovaries During this migration, PGCs undergo crucial changes, like a G2-arrest, global DNA demethylation and erasure of imprinted genes as shown in mice and partially for humans (Saitou & Yamaji 2012, Meyenn & Reik 2015). In human males, undifferentiated GCs (Adarkspermatogonia), which are discussed to be the testicular stem cells, settle down at the basement membrane of the developing seminiferous tubules (Clermont 1966) They give rise to Apale-spermatogonia, which divide mitotically and differentiate into B-spermatogonia (de Rooij 2001). Development of the flagellum and the acrosome gives sperm cells their characteristic morphology, necessary for full functionality, i.e. motility and penetration of the egg respectively
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