Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells

Abstract

Several proteins, such as the placental/germ cell alkaline phosphatases (PLAPs), the stem cell factor receptor c-KIT, and the transcriptional regulator and marker of pluripotency OCT3/4, have been found in both normal immature and malignant germ cells, known as carcinoma in situ/intratubular germ cell neoplasia unclassified (CIS/ITGCNU). In the present study, immunohistochemical methods were used to evaluate the expression of these markers in a series of male gonads from fetuses from the second and third trimesters, and neonates. In addition to these markers, the presence of VASA (a protein specific for the germ cell lineage), TSPY (the testis-specific protein, Y-encoded), and the proliferation index (Ki-67 antigen) was analysed. All these proteins are reported to be present both during spermatogenesis and in CIS/ITGCNU. Positive staining for VASA with varying intensity was found in all germ cells, while TSPY was predominantly located in the prespermatogonial cells at all developmental ages. In contrast, the markers PLAP, c-KIT, OCT3/4, and Ki-67 were more frequent at earlier developmental stages and decreased gradually with time, although they could occasionally be detected in germ cells of neonates. These findings are in line with a declining number of gonocytes during fetal development, concomitant with an increase in the number of prespermatogonia. The latter have lost the immature germ cell phenotype. These findings are compatible with the hypothesis that CIS/ITGCNU arises from developmentally arrested germ cells, most likely primordial germ cells/gonocytes, at an early time point during intrauterine development.

Germ cell neoplasia in situ: The precursor cell for invasive germ cell tumors of the testis

“…Indeed, the gene expression profile of GCNIS and fetal germ cells differed for only 5 genes in one gene expression study (Sonne et al, 2009). In particular, PLAP, KIT, OCT3/4 and Ki-67 are expressed in GCNIS, lending support to the hypothesis that it arises from a fetal gonocyte (Honecker et al, 2004). Further, the low level of DNA methylation in GCNIS is thought to reflect the stage at which the germ cell became developmentally blocked i.e.…”

TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

“…The number of TSPY repeats varies from B23 to 64 among phenotypically normal individual males (Repping et al, 2006), but could change under certain disease conditions (Vijayakumar et al, 2006), suggesting the possibility of genomic instability in this region of the chromosome. TSPY is normally expressed in early gonocytes and prespermatogonia in fetal testis and in spermatogonia, spermatocytes and round spermatids in adult testis (Honecker et al, 2004;Kido and Lau, 2005), and has been postulated to serve normal functions in stem germ cell proliferation and meiotic division (Schnieders et al, 1996;Lau, 1999). TSPY is ectopically expressed in tumor cells in various types of germ cell tumors, including gonadoblastoma, testicular germ cell tumors and male intracranial germ cell tumors, and has been considered as a key marker that is important in the pathogenesis of these types of human tumors Kersemaekers et al, 2005;Hoei-Hansen et al, 2006;Oram et al, 2006;Li et al, 2007b).…”

Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization

“…Furthermore, it has been demonstrated that certain histologic types express markers associated with distinct maturational stages of germ cell development, which presumably are dependent on a specific gonadal environment. 7,[43][44][45] Lastly, there are some data suggesting that the chromosomal marker characteristic of testicular germ cell tumors, the isochromosome 12p, plays only a minor role in CNS-GCTs. 18,22 As a consequence, it must be debated whether the information generated in the more frequent (and more easily assessable) testicular germ cell tumors can indeed be transferred to CNS-GCTs without scrutiny.…”