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

Schaik, Ron van; Wierikx, C. D. J.; Looijenga, Leendert H. J.; Oosterhuis, J. Wolter; Jong, Frank H. de

doi:10.1038/bjc.1997.532

Cited by 21 publications

(13 citation statements)

References 57 publications

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“…INHA and b-glycan are normally produced by somatic cells in the adult testis; their synthesis in a subset of germ cellderived seminomas may allow selected tumors to gain independence from Sertoli cell-derived factors as they gain the capacity to antagonize activin signaling in an autocrine manner and thereby limit activin bioactivity. Our data illustrating a differential expression of the INHA subunit between individual seminoma specimens (6 out of 28) is consistent with a previous report documenting the presence of INHA mRNA in a subset of seminomas (three out of nine) using RNAase protection assays (van Schaik et al 1997). In the normal testis, production of the INHA subunit is confined to Sertoli and Leydig cells in species, including the human and mouse (Roberts 1997, Majdic et al 1997, Barakat et al 2008.…”

Section: Discussionsupporting

confidence: 91%

“…Both INHA and b-glycan are produced by Leydig cells in the fetal testis (Vliegen et al 1993, Majdic et al 1997, Roberts 1997, Andersson et al 1998, Anderson et al 2002, Marchetti et al 2003, indicating regulated TGFB superfamily signaling features during normal human fetal testis development and that gonocytes do not make these proteins. In addition, RNAse protection assays and immunohistochemical analysis have identified the INHA subunit mRNA and protein in a subset of testicular germ cell tumors (TGCTs), indicating that individual tumors differ in their responses to activin and TGFB signaling (van Schaik et al 1997, Cobellis et al 2001.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

et al. 2009

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Activin is a pleiotropic growth factor belonging to the transforming growth factor-b (TGFB) superfamily of signaling molecules. Regulated activin signaling is known to influence several steps in rodent male gamete differentiation. TGFB ligand isoforms, TGFB1-B3, also influence germ cell survival in the rodent testis at the onset of spermatogenesis and around the time of puberty. Given the importance of regulated activin and TGFB signaling in testis development and function, we sought to investigate the cellular production sites of activin/TGFB-signaling modulators in normal and dysfunctional adult human testes samples. Signaling transducers phosphorylated SMAD2/3, and signaling modulators SMAD6, MAN-1, inhibin a (INHA), and b-glycan were detected in Bouins fixed, paraffin-embedded adult human testis sections using immunohistochemistry. Additional samples examined were from testicular cancer patients and from normal men subjected to gonadotropin suppression with androgen-based contraceptives. Our findings identify distinct differences between normal and gonadotropin-deprived human testis in the expression and cellular localization of activin/TGFB-signaling modulators. The presence of a nuclear phosphorylated SMAD2/3 signal in all analyzed seminoma specimens indicated active activin/TGFB signaling. Moreover, a subset of seminoma specimens exhibited selective enhanced expression of b-glycan (4 out of 28 seminoma tumors), INHA (6 out of 28), and MAN-1 (6 out of 28), highlighting potential functional differences between individual tumors in their capacity to regulate activin/TGFB signaling. Within the heterogenous nonseminomas, expression of signaling modulators was variable and reflected the degree of somatic differentiation. Thus, synthesis of activin and TGFB-signaling modulators may be affected by spermatogenic disruption and altered hormone levels in the testis. Reproduction (2009) 138 801-811

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

et al. 2009

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“…These data correlate well with analyses that indicate the presence of only very low levels of the INHIBIN and ACTIVIN subunits in seminoma (Cobellis et al. , 2001), or expression of these subunits in only some seminomas (van Schaik et al. , 1997).…”

Section: Discussionsupporting

confidence: 85%

TCam‐2 seminoma cell line exhibits characteristic foetal germ cell responses to TGF‐beta ligands and retinoic acid

et al. 2011

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Germ cell testicular cancer is understood to arise during embryogenesis, based on the persistence of embryonic germ cell markers in carcinoma in situ and seminoma. In this study, we examine the potential of the seminoma-derived TCam-2 cell line to be used as representative in functional analyses of seminoma. We demonstrate expression of several early germ cell markers, including BLIMP1, OCT3/4, AP2γ, NANOG and KIT. Many TGF-beta superfamily receptors and downstream transcription factors are also present in these cells including the normally foetal ACTRIIA receptor, indicating potential responsiveness to TGF-beta superfamily ligands. Treatment with BMP4 or RA induces a significant increase in ACTRIA, ACTRIIA and ACTRIIB transcripts, whereas activin A decreases ACTRIB. BMP4 and RA each support TCam-2 survival and/or proliferation. In addition, despite increased KIT mRNA levels induced by BMP4, RA and activin A, activin A does not improve survival or proliferation. The capacity for BMP4 and retinoic acid to enhance foetal germ cell survival and proliferation/self-renewal has been demonstrated in mice, but not previously tested in humans. This study is the first to demonstrate a functional response in seminoma cells, using a well-characterized cell line, consistent with their foetal germ cell-like identity.

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“…Moreover, activin receptors are expressed by testicular germ cells (37,38), and are able to bind activin and inhibin (39). Testicular germ cell tumors express activin type I and type II receptors, and the presence of inhibin/activin bA and bB mRNAs in these tumors but not in normal germ cells suggests that testicular germ cell tumor development may, in part, be regulated and modulated by the inhibin/activin system (40).…”

Section: Discussionmentioning

confidence: 99%

Gonadal malignant germ cell tumors express immunoreactive inhibin/activin subunits

Cobellis

Cataldi

Reis

et al. 2001

European Journal of Endocrinology

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Objective: Inhibin and activin are proteins produced by ovarian granulosa cells and testicular Sertoli cells and are members of the transforming growth factor-b superfamily. Since increased circulating levels of immunoreactive inhibin were detected in women with malignant ovarian tumors, they were proposed as tumor markers for ovarian carcinoma. Immunohistochemical studies later confirmed the presence of inhibin and activin subunits in granulosa cell tumors and epithelial ovarian cancer, as well as in Sertoli and Leydig cell testicular cancer. However, there is discrepant information on the detection of inhibin and activin in malignant germ cell tumors (MGCT). The aim of the present study was to evaluate the immunohistochemical expression of the inhibin/activin a, bA and bB subunits in ovarian and testicular MGCT specimens using polyclonal antisera. Methods: The ovarian tissue samples were composed of 19 MGCT, including dysgerminoma ðn ¼ 18Þ and yolk sac tumor ðn ¼ 1Þ. The testis specimens included classic seminomas ðn ¼ 20Þ; embryonal carcinomas ðn ¼ 7Þ; choriocarcinomas ðn ¼ 2Þ; and yolk sac tumor ðn ¼ 1Þ. Results: Ovarian and testicular malignant germ cell tumors expressed positive staining for inhibin/ activin a, bA and bB subunits, with some variations between and within individual tumors: while ovarian dysgerminomas were diffusely positive for a, bA and bB, testicular tumors expressed a and bB subunits, whereas bA staining was weak. Conclusions:The present results show positive staining for inhibin/activin subunits in ovarian and testicular MGCT, suggesting a possible role in tumorigenesis with the resultant clinical implication.

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

Cited by 21 publications

References 57 publications

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

TCam‐2 seminoma cell line exhibits characteristic foetal germ cell responses to TGF‐beta ligands and retinoic acid

Gonadal malignant germ cell tumors express immunoreactive inhibin/activin subunits

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