Aberrant Expression of Ovary Determining Gene FOXL2 in the Testis and Juvenile Granulosa Cell Tumor in Children

ArticleinThe Journal of urology 180(4 Suppl):1810-3 · September 2008with56 Reads
Impact Factor: 4.47 · DOI: 10.1016/j.juro.2008.03.097 · Source: PubMed
Abstract

FOXL2 is the earliest known marker of ovarian differentiation in mammals. It is involved in ovarian somatic cell differentiation and further follicle maintenance. FOXL2 is not implicated in determination of the male gonad and it is absent in the testis. We investigated whether the rare JGCTT (juvenile granulose cell tumor of the testis), named for its histological similarity to ovarian tumor, could be the first illustration of aberrant expression of this ovary determining gene in the human testis. Between 1990 and 2004, 3 boys with JGCTT were reported from the TGM95 database of the French Society for Childhood Cancer and from 8 pediatric endocrinology centers. Orchiectomy was performed in these patients. Immunohistochemistry of FOXL2, and co-immunofluorescence of FOXL2 and SOX9 were performed on tumor sections. Testicular tumor cells showed aberrant expression of FOXL2, which resembled normal ovarian granulosa cells. The localization of FOXL2 expression was nuclear without any cytoplasmic sequestration, suggesting that FOXL2 had biological activity. Conversely SOX9, which is present in the nucleus of normal testicular cells, was sequestered in the cytoplasm of granulosa tumor cells or markedly under expressed in the nuclei. In this case of residual SOX9 nuclear expression the expression of FOXL2 and SOX9 was mutually exclusive. To our knowledge we report the first human model of aberrant intratesticular expression of an ovary determining gene along with the extinction of SOX9 and the transdifferentiation of a testicular cell into a granulosa tumor cell.

    • "...otes male development while simultaneously inhibiting the network that drives ovarian development [25]. SRY is expressed from 6 GW [21] in human testis and in contrast to mice remains expressed in low l..."
      SOX9 in turn upregulates additional genes involved in Sertoli cell differentiation and proliferation [21]. The network of signalling factors downstream of SRY/SOX9 promotes male development while simultaneously inhibiting the network that drives ovarian development [25]. SRY is expressed from 6 GW [21] in human testis and in contrast to mice remains expressed in low levels throughout adult life [26].
    [Show abstract] [Hide abstract] ABSTRACT: Development of human gonads is a sex-dimorphic process which evolved to produce sex-specific types of germ cells. The process of gonadal sex differentiation is directed by the action of the somatic cells and ultimately results in germ cells differentiating to become functional gametes through spermatogenesis or oogenesis. This tightly controlled process depends on the proper sequential expression of many genes and signalling pathways. Disturbances of this process can be manifested as a large spectrum of disorders, ranging from severe disorders of sex development (DSD) to - in the genetic male - mild reproductive problems within the testicular dysgenesis syndrome (TDS), with large overlap between the syndromes. These disorders carry an increased but variable risk of germ cell neoplasia. In this review, we discuss the pathogenesis of germ cell neoplasia associated with gonadal dysgenesis, especially in individuals with 46,XY DSD. We summarise knowledge concerning development and sex differentiation of human gonads, with focus on sex-dimorphic steps of germ cell maturation, including meiosis. We also briefly outline the histopathology of germ cell neoplasia in situ (GCNIS) and gonadoblastoma (GDB), which are essentially the same precursor lesion with morphological structure dependent upon the masculinisation of the somatic niche. To assess the risk of germ cell neoplasia in different types of DSD, we have performed a PubMed search and provide here a synthesis of the evidence from studies published since 2006. We present a model for pathogenesis of GCNIS/GDB in TDS/DSD, with the risk of malignancy determined by the presence of the testis-inducing Y-chromosome and the degree of masculinisation. The associations between phenotype and the risk of neoplasia are likely further modulated in each individual by the constellation of the gene polymorphisms and environmental factors.
    No preview · Article · Sep 2015 · Seminars in Cell and Developmental Biology
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    • "...] while the SOX9 gene is down regulated in the event of ovarian differentiation. [25] Kalfa et al. [22] thus hypothesized that the aberrant cytoplasmic expression of SOX9 and nuclear expression of FOXL2 ..."
      [23] In the undifferentiated gonad, the SOX9 protein is sequestered in the cytoplasm and nuclear localization is noted only after commitment toward testicular differentiation, [24] while the SOX9 gene is down regulated in the event of ovarian differentiation. [25] Kalfa et al. [22] thus hypothesized that the aberrant cytoplasmic expression of SOX9 and nuclear expression of FOXL2 suggest transdifferentiation of Sertoli cells toward granulosa cells. However, we believe that this could also be explained by a much simpler explanation that granulosa cell tumor arose within the remnants of the undifferentiated gonads within the testis.
    [Show abstract] [Hide abstract] ABSTRACT: Background: Granulosa cell tumor of testis is a rare tumor accounting for less than 4% of adult testicular tumors though they account for nearly 30% of childhood testicular tumors. Due to the rarity of these tumors, exact etiology, pathogenesis, prognostic factors and best treatment approach are not well known. The molecular events in pathogenesis of these stromal tumors have begun to unravel and these developments put forth a reasonable and scientific explanation for the association of these tumors with developmental anomalies like undescended testis. However, many questions remain unanswered. Materials and methods: We performed a retrospective analysis of clinicopathological features of all Granulosa Cell Tumors of testis from our archives in addition to an extensive literature search using PUBMED with the key words "Granulosa Cell Tumor, testis". Results: We found six cases in our archives, two of which were of juvenile type and four of adult type. One out of these six cases presented with metastases. All cases underwent radical orchidectomy. Morphology and immunohistochemistry were classical in all cases and there was no diagnostic dilemma. Literature search revealed 63 cases of testicular Granulosa Cell Tumor in addition to highlighting the similarities in the biology and the dissimilarities in the clinical behavior as compared to ovarian Granulosa Cell Tumor. Conclusion: Testicular Granulosa Cell Tumor is a rare tumor, which although histologically similar to its ovarian counterpart, differs in clinical behavior. Further detailed investigations are needed to reveal the mystery behind the differing clinical behavior despite histological and immunohistochemical similarity between the testicular and ovarian Granulosa Cell Tumors.
    Full-text · Article · Oct 2014 · Indian Journal of Pathology and Microbiology
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    • "...ade by Kalfa et al, who noted FOXL2 immunochemistry to be decreased or absent in juveniletype GCTs [24,25]. The aim of this investigation was to identify FOXL2 transcriptional targets with relevance to G..."
      Whilst KGN is shown to have abundant FOXL2 expression, this gene is almost absent in COV434 [13,21]. This finding correlates to observations made by Kalfa et al, who noted FOXL2 immunochemistry to be decreased or absent in juveniletype GCTs [24,25]. The aim of this investigation was to identify FOXL2 transcriptional targets with relevance to GCT by analysing the effect of altering FOXL2 expression on the transcriptome of GCT cell lines.
    [Show abstract] [Hide abstract] ABSTRACT: Despite their distinct biology, granulosa cell tumours (GCTs) are treated the same as other ovarian tumours. Intriguingly, a recurring somatic mutation in the transcription factor Forkhead Box L2 (FOXL2) 402C>G has been found in nearly all GCTs examined. This investigation aims to identify the pathogenicity of mutant FOXL2 by studying its altered transcriptional targets. The expression of mutant FOXL2 was reduced in the GCT cell line KGN, and wildtype and mutant FOXL2 were overexpressed in the GCT cell line COV434. Total RNA was hybridised to Affymetrix U133 Plus 2 microarrays. Comparisons were made between the transcriptomes of control cells and cells altered by FOXL2 knockdown and overexpression, to detect potential transcriptional targets of mutant FOXL2. The overexpression of wildtype and mutant FOXL2 in COV434, and the silencing of mutant FOXL2 expression in KGN, has shown that mutant FOXL2 is able to differentially regulate the expression of many genes, including two well known FOXL2 targets, StAR and CYP19A. We have shown that many of the genes regulated by mutant FOXL2 are clustered into functional annotations of cell death, proliferation, and tumourigenesis. Furthermore, TGF-β signalling was found to be enriched when using the gene annotation tools GATHER and GeneSetDB. This enrichment was still significant after performing a robust permutation analysis. Given that many of the transcriptional targets of mutant FOXL2 are known TGF-β signalling genes, we suggest that deregulation of this key antiproliferative pathway is one way mutant FOXL2 contributes to the pathogenesis of adult-type GCTs. We believe this pathway should be a target for future therapeutic interventions, if outcomes for women with GCTs are to improve.
    Full-text · Article · Jul 2012 · PLoS ONE
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