Carcinoma‐in‐situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma

Skakkebæk, N. E.; Berthelsen, Jens; Giwercman, Aleksander; Müller, Jørn

doi:10.1111/j.1365-2605.1987.tb00161.x

Cited by 718 publications

(470 citation statements)

References 35 publications

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“…Therefore, our data support the common hypothesis of a different cell origin concerning spermatocytic seminoma and classic seminoma. 1,35 Although intratubular germ cell neoplasia unclassified is considered to be derived from developmentally arrested gonocytes, 2,[36][37][38] there is some controversy about the progenitor 39 Previous studies suspected primary spermatocytes 40 or spermatogonia 35,41 as progenitor cells. In our study, we found a strong expression of cancer testis antigens in spermatogonia and in spermatocytic seminoma, which is consistent with an origin of spermatocytic seminoma from spermatogonia, too.…”

Section: Discussionmentioning

confidence: 99%

Cancer testis antigen expression in testicular germ cell tumorigenesis

et al. 2014

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Cancer testis antigens are encoded by germ line-associated genes that are present in normal germ cells of testis and ovary but not in differentiated tissues. Their expression in various human cancer types has been interpreted as 're-expression' or as intratumoral progenitor cell signature. Cancer testis antigen expression patterns have not yet been studied in germ cell tumorigenesis with specific emphasis on intratubular germ cell neoplasia unclassified as a precursor lesion for testicular germ cell tumors. Immunohistochemistry was used to study MAGEA3, MAGEA4, MAGEC1, GAGE1 and CTAG1B expression in 325 primary testicular germ cell tumors, including 94 mixed germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. Spermatogonia in the normal testis were positive, whereas intratubular germ cell neoplasia unclassified was negative for all five CT antigens. Cancer testis antigen expression was only found in 3% (CTAG1B), 10% (GAGE1, MAGEA4), 33% (MAGEA3) and 40% (MAGEC1) of classic seminoma but not in nonseminomatous testicular germ cell tumors. In contrast, all spermatocytic seminomas were positive for cancer testis antigens. These data are consistent with a different cell origin in spermatocytic seminoma compared with classic seminoma and support a progression model with loss of cancer testis antigens in early tumorigenesis of testicular germ cell tumors and later re-expression in a subset of seminomas.

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Section: Discussionmentioning

confidence: 99%

Cancer testis antigen expression in testicular germ cell tumorigenesis

et al. 2014

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“…Because CIS is found at sites normally occupied by spermatogonia (Skakkebak et al, 1987), these sites are likely to provide the specialized conditions required for their survival and proliferation. Based upon our results, we hypothesize that activin synthesis provides autocrine/paracrine conditions for tumour progression, making the germ cell neoplasms independent from Sertoli cell-secreted factors.…”

Section: Inhibin Subunits and Follistatinmentioning

confidence: 99%

Human testicular germ cell tumours express inhibin subunits, activin receptors and follistatin mRNAs

Schaik

Wierikx²,

Looijenga³

et al. 1997

Br J Cancer

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Summary Germ cell development is influenced by activin and inhibin, which are produced by Sertoli cells. Activin also affects differentiation of mouse embryonal carcinoma cells, which, to a certain extent, resemble the embryonal carcinoma component of germ cell tumours. Therefore, the expression of inhibin/activin subunits, of activin receptors and of the activin-binding protein follistatin was studied in testicular germ cell tumours, using RNAase protection assays. Testicular germ cell tumours of adolescents and adults (TGCTs) and spermatocytic seminomas expressed activin type and type 11 receptors (ActRi and ActRII respectively). Seminomas expressed significantly lower levels of ActRIIA (P<0.05, Mann-Whitney U-test) and higher levels of ActRIA (P<0.05) and ActRIB (P<0.05) compared with non-seminomas. All tumours expressed inhibin n-subunit transcripts, which are a prerequisite for activin synthesis. Non-seminomas contained significantly higher levels of the inhibin PA subunit (P<0.001) compared with seminomas. No activin PC subunit transcripts could be demonstrated by RNAase protection. Inhibin a-subunit expression was absent in the spermatocytic seminomas, in six out of nine seminomas and in 10 out of 11 nonseminomas. Follistatin was expressed predominantly in non-seminomas and spermatocytic seminomas. This expression of activin type and type 11 receptors in combination with expression of inhibin 5-subunits indicates that activin may act as a para-or autocrine factor in the regulation of growth and differentiation of tumours of human germ cells.

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“…Epidemiological (Moller, 1989), morphological (Skakkebaek et al, 1987;Holstein, 1993) and immunohistochemical data (Jorgensen et al, 1995) suggest that TGCTs arise from fetal germ cells, probably primordial germ cells (PGCs). In particular, seminoma cells mimic early germ cells, probably PGCs or gonocytes (Skakkebaek et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, seminoma cells mimic early germ cells, probably PGCs or gonocytes (Skakkebaek et al, 1987). Recent immunohistochemical data demonstrated that seminoma and embryonal carcinoma cells are positive for OCT3/4, suggesting TGCTs derive from PGCs (Looijenga et al, 2003;Rajpert-De Meyts et al, 2004;Oosterhuis and Looijenga, 2005).…”

Section: Introductionmentioning

confidence: 99%

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

et al. 2006

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Genome-wide epigenetic modification plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and nonseminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/ IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and nonseminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.

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Carcinoma‐in‐situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma

Cited by 718 publications

References 35 publications

Cancer testis antigen expression in testicular germ cell tumorigenesis

Cancer testis antigen expression in testicular germ cell tumorigenesis

Human testicular germ cell tumours express inhibin subunits, activin receptors and follistatin mRNAs

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

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