The role of microenvironment in testicular germ cell tumors

Díez-Torre, Alejandro; Silván, Unai; Díaz-Núñez, María; Aréchaga, Juan

doi:10.4161/cbt.10.6.13227

Cited by 27 publications

(13 citation statements)

References 82 publications

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“…Aberrant growth factor signalling, essential for normal testis development, may underpin the formation and progression of testicular germ cell tumours given that the pre‐invasive lesion of both seminoma and non‐seminoma tumours arises from an ‘abnormal’ gonocyte (Sonne et al ., ). In the adult human testis, CXCR4 is expressed in the germ cells and its ligand CXCL12 is expressed by the supporting Sertoli cells (Diez‐Torre et al ., ) and results described above. Interestingly, disrupted interaction(s) between germ cells and supporting Sertoli cells have previously been proposed to contribute to the development of CIS cells and consequently germ cell tumours (Looijenga et al ., ).…”

Section: Discussionsupporting

confidence: 62%

“…CXCL12 was expressed strongly within the stroma of the tumours and in scattered tumour cells indicating that tumour development may also require the support of the somatic tissue. Stromal differentiation is key to the development of seminoma and non‐seminoma as the stroma supplies essential survival and proliferation factors (Diez‐Torre et al ., ), including CXCL12 (Fig. ).…”

Section: Discussionmentioning

confidence: 99%

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The chemokine CXCL12 and its receptor CXCR4 are implicated in human seminoma metastasis

McIver¹,

Loveland

Roman³

et al. 2013

Andrology

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SUMMARYSeminoma and non-seminoma tumours increasingly occur within the western population. These tumours originate from carcinoma in situ (CIS) cells, which arise from dysfunctional gonocytes. CXCL12 and its receptors, CXCR4 and CXCR7, have been implicated in migration, proliferation and survival of gonocytes and their precursors and progeny, primordial germ cells and spermatogonial stem cells respectively. We previously found evidence that several miRNA molecules predicted to modulate CXCR4 signalling are differentially expressed during the differentiation of gonocytes into spermatogonia in mice. Bioinformatic analysis predicted these miRNA to modulate CXCR4 signalling, leading us to hypothesize that CXCL12-mediated CXCR4 signalling is involved in the disrupted differentiation of gonocytes that underpins CIS formation. Indeed, we detected CXCL12 in Sertoli cells of normal human testis, and relatively high expression in tumour stroma with concomitant weak staining in dispersed tumour cells. In contrast, CXCR4 was expressed in spermatogonial and meiotic germ cells of normal testis and in the majority of tumour cells. Quantitative RT-PCR identified elevated CXCR4 transcript levels in seminoma compared with normal testis and to non-seminoma, potentially reflecting the higher proportion of dysfunctional germ cells within seminomas. In the normal testis, expression of CXCR4 downstream signalling molecules phospho-MEK1/2 and phospho-ERK1/2 correlated with CXCR4/CXCL12 expression. Strikingly, this correlation was absent in seminoma and non-seminoma samples, suggesting that CXCL12 signalling is disrupted. Proliferation rate and cell survival were not altered by CXCL12 in either seminoma (TCam-2) or non-seminoma (833ke) cell lines. However, CXCL12 exposure induced TCam-2 cell invasion though simulated basement membrane, while in contrast, we provide the novel evidence that CXCR4-expressing non-seminoma cell lines 833ke and NTera2/D1 do not invade in response to CXCL12. These findings indicate that CXCL12 expression in the human testis may selectively influence seminoma migration and metastasis, correlating with its importance in gonocyte and spermatogonial stem cell biology.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

The chemokine CXCL12 and its receptor CXCR4 are implicated in human seminoma metastasis

McIver¹,

Loveland

Roman³

et al. 2013

Andrology

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“…An acknowledged disadvantage of ectopic expression is that outcomes may not accurately reflect in situ outcomes. This might be even more critical when genes transverse germ to soma; micro-environmental influence is thought to be especially instrumental in the development of human GCTs (Diez-Torre et al, 2010;Luo et al, 2016). We therefore reiterate the massive potential of Drosophila testes as a model of GCT-study, particularly where the cause of GCTs is sex-specific, and pathological expectations include visible overgrowth.…”

Section: Testes As a Model For Studying Overgrowth-typed Germline Celmentioning

confidence: 99%

CTP synthase regulation by miR-975 controls cell proliferation and differentiation inDrosophila melanogaster

Dzaki

Azzam

2018

Preprint

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CTP synthase (CTPsyn) is an essential metabolic enzyme. As a key regulator of the nucleotide pool, the protein has been found to be elevated in cancer models. In many organisms, CTPsyn compartmentalizes into filaments termed cytoophidia. For D. melanogaster, it is only its Isoform C i.e. CTPsynIsoC which forms the structure. The fruit fly's testis is home to somatic and germline stem cells. Both micro and macro-cytoophidia are normally seen in the transit amplification regions close to its apical tip, where the stem-cell niche is located and development is at its most rapid. Here, we report that CTPsynIsoC overexpression causes the lengthening of cytoophidia throughout the entirety of the testicular body. A bulging apical tip is found in approximately one-third of like-genotyped males. Immunostaining shows that the cause of this tumour-like phenotype is most likely due to increased numbers of both germline cells and spermatocytes. We also report that under conditions whereby miR-975 is overexpressed, greater incidences of the same bulged-phenotype coincides with induced upregulation of CTPsynIsoC. However, RT-qPCR assays reveal that either overexpression genotype provokes a differential response in expression of a number of genes concurrently associated with CTPsyn and cancer, showing that the pathways CTPsynIsoC affect and miR-975 regulate may be completely independent of each other. This study presents the first instance of consequences of miRNA-asserted regulation upon CTPsyn in D. melanogaster, and further reaffirms the enzyme's close ties to cancer and carcinogenesis.

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“…Insulin-like signaling is an important component of PGC migration and possibly TGCT pathogenesis [119]. Studies have shown that insulin-like signaling is important for teratocarcinoma cells, though no studies have investigated the response of human EC cells to insulin-like signaling growth factors [135][136][137].…”

Section: Hypomethylation At the Paternally Imprinted Igf2-h19 Locus Imentioning

confidence: 99%

“…Chief among these associations identified thus far is hypomethylation at the IGF2-H19 locus [36][37][38]. While the participation of growth factors such as IGF2 in insulin-like signaling has been implicated in TGCT development, a recent study found the H19 lncRNA to be necessary for the maintenance of EC stem-like cells [18,119].…”

Section: Introductionmentioning

confidence: 99%

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

Sellers¹

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The role of microenvironment in testicular germ cell tumors

Cited by 27 publications

References 82 publications

The chemokine CXCL12 and its receptor CXCR4 are implicated in human seminoma metastasis

The chemokine CXCL12 and its receptor CXCR4 are implicated in human seminoma metastasis

CTP synthase regulation by miR-975 controls cell proliferation and differentiation inDrosophila melanogaster

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

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