Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors

Spiller, Cassy M.; Bowles, Josephine; Koopman, Peter

doi:10.1387/ijdb.130028pk

Cited by 28 publications

(22 citation statements)

References 107 publications

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“…The NODAL/CRIPTO signaling pathway is believed to regulate the delicate balance between the proliferation of germ cells and fate commitment, meaning that disturbance of this signaling cascade may lead both to infertility (due to insufficient spermatogonial stem cells) or to prolonged pluripotency, resulting in the development of TGCTs [14]. This is in line with the finding of ectopic NODAL/CRIPTO signaling activation in NS [15]. CRIPTO was also found to be at least partially regulated by promoter methylation [16,17].…”

Section: Introductionsupporting

confidence: 78%

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

Spiller

Lobo

Boellaard

et al. 2020

Cancers

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miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker of testicular GCTs (TGCTs) and also to assess its presence in seminal plasma samples, compared with miR-371a-3p. In total, 217 and 94 serum/seminal plasma samples were analyzed. CRIPTO was quantified using ELISA and miR-371a-3p using bead-based isolation followed by RT-qPCR. Methylation profiling (EPIC array) for the CRIPTO promoter region was undertaken in 35 TGCT tissues plus four (T)GCT cell lines. Significantly higher CRIPTO concentration was found in sera of non-seminomas compared to controls (p = 0.0297), and in stage II/III disease compared to stage I (p = 0.0052, p = 0.0097). CRIPTO concentration was significantly positively correlated with miR-371a-3p levels in serum (r = 0.16) and seminal plasma (r = 0.40). CRIPTO/miR-371a-3p levels were significantly higher in seminal plasma controls when compared to serum controls (p = 0.0001, p < 0.0001). CRIPTO/miR-371a-3p were detected both in normospermic and azoospermic males, and levels were higher in TGCTs compared to GCNIS-only. We have provided the largest dataset of evaluation of CRIPTO in serum and seminal plasma of GCTs, showing its potential value as a biomarker of the disease.

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Section: Introductionsupporting

confidence: 78%

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

Spiller

Lobo

Boellaard

et al. 2020

Cancers

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“…We recently discovered that the TGFβ signaling molecule Nodal and its obligate receptor Cripto are expressed at a critical point during fetal XY germ cell development in mice and that Nodal/Cripto signaling is active, apparently acting to maintain pluripotency and oppose differentiation (Spiller et al., 2012). We also found that Nodal/Cripto signaling is ectopically activated in NS and we therefore hypothesize that ectopic activation of Nodal signaling, or failure to silence it, contributes to GCC formation (Spiller et al., 2013).…”

Section: Introductionmentioning

confidence: 87%

Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors

et al. 2015

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Type II germ cell tumors arise after puberty from a germ cell that was incorrectly programmed during fetal life. Failure of testicular germ cells to properly differentiate can lead to the formation of germ cell neoplasia in situ of the testis; this precursor cell invariably gives rise to germ cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal germ cell development and is ectopically expressed in non-seminomas that arise from germ cell neoplasia in situ, suggesting that its aberrant expression may underlie germ cell dysregulation and hence germ cell cancer. Here we investigated methylation of the Cripto promoter in mouse germ cells and human germ cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal germ cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in germ cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of germ cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with germ cell neoplasia in situ cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during germ cell cancer management.

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“…Type II TGCC are divided into two categories: seminomas which resemble a less aggressive carcinoma in-situ, and non-seminomas which display a high degree of pluripotency factors [106]. Non-seminomas form highly heterogeneous tumors with both differentiated and undifferentiated cells forming teratomas and choriocarcinomas and display more embryonal-like features.…”

Section: Nodal and Cancermentioning

confidence: 99%

Plasticity underlies tumor progression: role of Nodal signaling

Bodenstine

Chandler

Seftor

et al. 2016

Cancer Metastasis Rev

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The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its re-expression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.

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Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors

Cited by 28 publications

References 107 publications

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors

Plasticity underlies tumor progression: role of Nodal signaling

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