The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Leendert H. J. Looijenga - One of the best experts on this subject based on the ideXlab platform.
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molecular heterogeneity and early metastatic clone selection in testicular Germ Cell cancer development
British Journal of Cancer, 2019Co-Authors: Lambert C J Dorssers, Hans Stoop, Ad J M Gillis, Ronald Van Marion, Marleen M Nieboer, Job Van Riet, Harmen J G Van De Werken, Wolter J Oosterhuis, Jeroen De Ridder, Leendert H. J. LooijengaAbstract:Testicular Germ Cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an Embryonic Germ Cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis. In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor Germ Cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed. Intratumour molecular heterogeneity did not correspond to the supposed primary tumour histological evolution. Metastases after systemic treatment could be derived from cancer stem Cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes. Our data strongly support the hypothesis that NS is initiated by whole-genome duplication, followed by chromosome copy number alterations in the cancer stem Cell population, and accumulation of low numbers of somatic mutations, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
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molecular heterogeneity and early metastatic clone selection in testicular Germ Cell cancer development
bioRxiv, 2018Co-Authors: Lambert C J Dorssers, Hans Stoop, Ad J M Gillis, Marleen M Nieboer, Wolter J Oosterhuis, Jeroen De Ridder, Ronald Van Marion, Job Van Riet, Harmen J G Van De Werken, Leendert H. J. LooijengaAbstract:Background: Testicular Germ Cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an Embryonic Germ Cell. This study determines intratumor heterogeneity to unravel tumor progression from initiation till metastasis. Methods: In total 42 purified samples of four treatment-resistant nonseminomatous TGCC (NS) were investigated, including the precursor Germ Cell neoplasia in situ (GCNIS) and metastatic specimens, using whole genome- and targeted sequencing. Their evolution was reconstructed. Results: Intratumor molecular heterogeneity did not correspond to the supposed primary tumor histological evolution. Metastases after systemic treatment could be derived from cancer stem Cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes. Conclusions: Our data strongly support the hypothesis that NS is initiated by whole genome duplication, followed by chromosome copy number alterations in the cancer stem Cell population, and accumulation of low numbers of somatic mutations. These observations of heterogeneity at all stages of tumorigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
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seminoma and embryonal carcinoma footprints identified by analysis of integrated genome wide epigenetic and expression profiles of Germ Cell cancer Cell lines
PLOS ONE, 2014Co-Authors: Yvonne G Van Der Zwan, Ad J M Gillis, Martin A Rijlaarsdam, Fernando J Rossello, Amanda J Notini, Suzan De Boer, Neil D Watkins, Lambert C J Dorssers, Stefan J White, Leendert H. J. LooijengaAbstract:textabstractBackground: Originating from Primordial Germ Cells/gonocytes and developing via a precursor lesion called Carcinoma In Situ (CIS), Germ Cell Cancers (GCC) are the most common cancer in young men, subdivided in seminoma (SE) and non-seminoma (NS). During physiological Germ Cell formation/maturation, epigenetic processes guard homeostasis by regulating the accessibility of the DNA to facilitate transcription. Epigenetic deregulation through genetic and environmental parameters (i.e. genvironment) could disrupt Embryonic Germ Cell development, resulting in delayed or blocked maturation. This potentially facilitates the formation of CIS and progression to invasive GCC. Therefore, determining the epigenetic and functional genomic landscape in GCC Cell lines could provide insight into the pathophysiology and etiology of GCC and provide guidance for targeted functional experiments. Results: This study aims at identifying epigenetic footprints in SE and EC Cell lines in genome-wide profiles by studying the interaction between gene expression, DNA CpG methylation and histone modifications, and their function in the pathophysiology and etiology of GCC. Two well characterized GCC-derived Cell lines were compared, one representative for SE (TCam-2) and the other for EC (NCCIT). Data were acquired using the Illumina HumanHT-12-v4 (gene expression) and HumanMethylation450 BeadChip (methylation) microarrays as well as ChIP-sequencing (activating histone modifications (H3K4me3, H3K27ac)). Results indicate known Germ Cell markers not only to be differentiating between SE and NS at the expression level, but also in the epigenetic landscape. Conclusion: The overall similarity between TCam-2/NCCIT support an erased Embryonic Germ Cell arrested in early gonadal development as common Cell of origin although the exact developmental stage from which the tumor Cells are derived might differ. Indeed, subtle difference in the (integrated) epigenetic and expression profiles indicate TCam-2 to exhibit a more Germ Cell-like profile, whereas NCCIT shows a more pluripotent phenotype. The results provide insight into the functional genome in GCC Cell lines.
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Tumor risk and clinical follow-up in patients with disorders of sex development.
Pediatric endocrinology reviews : PER, 2011Co-Authors: Martine Cools, Leendert H. J. LooijengaAbstract:A subset of patients with disorders of sex development (DSD) is at risk for malignant Germ Cell tumors (GCTs). The degree of gonadal differentiation (or "testicularization" in the presence of a specific part of the Y chromosome), in combination with expression of Embryonic Germ Cell markers, and (a) Y specific gene(s) related to Cell-cycle control and proliferation, determines this risk. Incompletely matured Sertoli/granulosa Cells are insufficiently capable of directing the normal mitotic block/meiotic induction Germ Cell program, and as a result, Embryonic Germ Cells are delayed or blocked in their normal maturation process. Thereby, they remain pluripotent and gain increased mitotic and survival characteristics, being the first step in the pathogenesis of GCTs. The patient's underlying genetic defect and phenotype might be informative in assessing the degree of gonadal "testicularization" on a clinical basis. Current knowledge allows development of an informative cancer risk assessment of DSD patients.
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critical function of ap 2gamma tcfap2c in mouse Embryonic Germ Cell maintenance
Biology of Reproduction, 2010Co-Authors: Susanne Weber, Dawid Eckert, Daniel Nettersheim, Ad J M Gillis, Sabine Schafer, Peter Kuckenberg, Julia Ehlermann, Uwe Werling, Katharina Biermann, Leendert H. J. LooijengaAbstract:Formation of the Germ Cell lineage involves multiple processes, including repression of somatic differentiation and reacquisition of pluripotency as well as a unique epigenetic constitution. The transcriptional regulator Prdm1 has been identified as a main coordinator of this process, controlling epigenetic modification and gene expression. Here we report on the expression pattern of the transcription factor Tcfap2c, a putative downstream target of Prdm1, during normal mouse embryogenesis and the consequences of its specific loss in primordial Germ Cells (PGCs) and their derivatives. Tcfap2c is expressed in PGCs from Embryonic Day 7.25 (E 7.25) up to E 12.5, and targeted disruption resulted in sterile animals, both male and female. In the mutant animals, PGCs were specified but were lost around E 8.0. PGCs generated in vitro from Embryonic stem Cells lacking TCFAP2C displayed induction of Prdm1 and Dppa3. Upregulation of Hoxa1, Hoxb1, and T together with lack of expression of Germ Cell markers such Nanos3, Dazl, and Mutyh suggested that the somatic gene program is induced in TCFAP2C-deficient PGCs. Repression of TCFAP2C in TCam-2, a human PGC-resembling seminoma Cell line, resulted in specific upregulation of HOXA1, HOXB1, MYOD1, and HAND1, indicative of mesodermal differentiation. Expression of genes indicative of ectodermal, endodermal, or extraEmbryonic differentiation, as well as the finding of no change to epigenetic modifications, suggested control by other factors. Our results implicate Tcfap2c as an important effector of Prdm1 activity that is required for PGC maintenance, most likely mediating Prdm1-induced suppression of mesodermal differentiation.
Hans Stoop - One of the best experts on this subject based on the ideXlab platform.
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molecular heterogeneity and early metastatic clone selection in testicular Germ Cell cancer development
British Journal of Cancer, 2019Co-Authors: Lambert C J Dorssers, Hans Stoop, Ad J M Gillis, Ronald Van Marion, Marleen M Nieboer, Job Van Riet, Harmen J G Van De Werken, Wolter J Oosterhuis, Jeroen De Ridder, Leendert H. J. LooijengaAbstract:Testicular Germ Cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an Embryonic Germ Cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis. In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor Germ Cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed. Intratumour molecular heterogeneity did not correspond to the supposed primary tumour histological evolution. Metastases after systemic treatment could be derived from cancer stem Cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes. Our data strongly support the hypothesis that NS is initiated by whole-genome duplication, followed by chromosome copy number alterations in the cancer stem Cell population, and accumulation of low numbers of somatic mutations, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
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molecular heterogeneity and early metastatic clone selection in testicular Germ Cell cancer development
bioRxiv, 2018Co-Authors: Lambert C J Dorssers, Hans Stoop, Ad J M Gillis, Marleen M Nieboer, Wolter J Oosterhuis, Jeroen De Ridder, Ronald Van Marion, Job Van Riet, Harmen J G Van De Werken, Leendert H. J. LooijengaAbstract:Background: Testicular Germ Cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an Embryonic Germ Cell. This study determines intratumor heterogeneity to unravel tumor progression from initiation till metastasis. Methods: In total 42 purified samples of four treatment-resistant nonseminomatous TGCC (NS) were investigated, including the precursor Germ Cell neoplasia in situ (GCNIS) and metastatic specimens, using whole genome- and targeted sequencing. Their evolution was reconstructed. Results: Intratumor molecular heterogeneity did not correspond to the supposed primary tumor histological evolution. Metastases after systemic treatment could be derived from cancer stem Cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes. Conclusions: Our data strongly support the hypothesis that NS is initiated by whole genome duplication, followed by chromosome copy number alterations in the cancer stem Cell population, and accumulation of low numbers of somatic mutations. These observations of heterogeneity at all stages of tumorigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
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Reactivity of Germ Cell Maturation Stage-specific Markers in Classical and Spermatocytic Seminoma
Germ Cell Tumours V, 2002Co-Authors: Leendert H. J. Looijenga, Hans Stoop, Ruud J.h.l.m. Van Gurp, Ronald R De Krijger, J. W. OosterhuisAbstract:This paper presents data supporting the model that classical seminoma originates from a primordial Germ Cell/gonocyte in which maturation is blocked. Although spermatocytic seminoma might also originate from an Embryonic Germ Cell, it retains the capacity to undergo further maturation, including partial meiosis. Moreover, we identified immunohistochemical markers helpful in the diagnosis of spermatocytic seminomas.
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reactivity of Germ Cell maturation stage specific markers in spermatocytic seminoma diagnostic and etiological implications
Laboratory Investigation, 2001Co-Authors: Hans Stoop, Wolter Oosterhuis, Ruud J.h.l.m. Van Gurp, Ronald R De Krijger, Ad Geurts Van Kessel, Beate Koberle, Leendert H. J. LooijengaAbstract:It is generally accepted that testicular seminomas and spermatocytic seminomas have separate pathogeneses, although the origin of these two types of Germ Cell tumors of the adult testis remains a matter of debate. Although an Embryonic Germ Cell origin seems to be most likely for seminomas, a spermatogonia-spermatocyte origin has been suggested for spermatocytic seminoma. To shed more light on the etiology of spermatocytic seminomas, we undertook an immunohistochemical and molecular approach using SCP1 (synaptonemal complex protein 1), SSX (synovial sarcoma on X chromosome), and XPA (xeroderma pigmentosum type A) as targets. Although a stage-specific expression pattern has been reported for SCP1 and SSX in normal spermatogenesis, we demonstrate here that it also exists for XPA. In fact, immunohistochemistry shows that the proteins of SCP1 and XPA are specifically present in the stage of primary and pachytene spermatocytes. In contrast, SSX was found in spermatogonia and primary spermatocytes, as well as in Germ Cells, from at least the 17th week of intrauterine development onward. Although no protein encoded by any of these genes was detected in tumor Cells of a series of testicular seminomas, all tested spermatocytic seminomas were positive, in agreement with expression analysis. These data support the model that seminomas originate from an Embryonic Germ Cell, and they imply that the Cell of origin of spermatocytic seminomas is at least capable of maturing to the stage of spermatogonia-pachytene spermatocyte.
Tohru Kimura - One of the best experts on this subject based on the ideXlab platform.
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induction of primordial Germ Cell like Cells from mouse Embryonic stem Cells by erk signal inhibition
Stem Cells, 2014Co-Authors: Tohru Kimura, Yoshiaki Kaga, Hiroshi Ohta, Mika Odamoto, Yoichi Sekita, Noriko Yamano, Keita Fujikawa, Ayako Isotani, Norihiko Sasaki, Masashi ToyodaAbstract:Primordial Germ Cells (PGCs) are Embryonic Germ Cell precursors. Specification of PGCs occurs under the influence of mesodermal induction signaling during in vivo gastrulation. Although bone morphogenetic proteins and Wnt signaling play pivotal roles in both mesodermal and PGC specification, the signal regulating PGC specification remains unknown. Coculture of mouse Embryonic stem Cells (ESCs) with OP9 feeder Cells induces mesodermal differentiation in vitro. Using this mesodermal differentiation system, we demonstrated that PGC-like Cells were efficiently induced from mouse ESCs by extraCellular signal-regulated kinase (ERK) signaling inhibition. Inhibition of ERK signaling by a MAPK/ERK kinase (MEK) inhibitor upregulated Germ Cell marker genes but downregulated mesodermal genes. In addition, the PGC-like Cells showed downregulation of DNA methylation and formed pluripotent stem Cell colonies upon treatment with retinoic acid. These results show that inhibition of ERK signaling suppresses mesodermal differentiation but activates Germline differentiation program in this mesodermal differentiation system. Our findings provide a new insight into the signaling networks regulating PGC specification.
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Regulation of Stem Cell Systems by PI3K/Akt Signaling
Regulatory Networks in Stem Cells, 2009Co-Authors: Tohru Kimura, Toru NakanoAbstract:Stem Cells can replenish their own population while supplying the Cells necessary to maintain tissue homeostasis. Pluripotent stem Cells, which have broader developmental potency than tissue stem Cells, are derived from the same source in mice and humans. In this review, we summarize the functions of phosphoinositide-3 kinase (PI3K) and its downstream serine/threonine kinase Akt in a variety of stem Cell systems. Primordial Germ Cells (PGCs), which are Embryonic Germ Cell precursors, are unique in that they acquire pluripotency under cultural and pathological conditions. PGCs lacking Pten, which encodes a phosphatase that antagonizes PI3K signaling, give rise to early-onset testicular teratomas in vivo and augment the derivation of pluripotent Embryonic Germ (EG) Cells in vitro. Transient activation of Akt sufficiently recapitulates the effects of Pten deficiency on EG Cell derivation. Enhanced EG Cell derivation is brought about by the Akt-mediated inhibition of the tumor suppressor p53. In Embryonic stem (ES) Cells, PI3K/Akt signaling plays a pivotal role in maintaining pluripotency in part via transcriptional activation of the pluripotent transcription factor Nanog. In turn, the expression of Tcl1, a cofactor of Akt, is activated by pluripotent transcription factors, including Oct-3/4. Therefore, PI3K/Akt signaling and the transcription factor network constitute the positive feedback circuitry necessary to maintain pluripotency in ES Cells. In tissue stem Cells, such as hair follicular, intestinal, and hematopoietic stem Cells, PI3K/Akt signaling activates quiescent stem Cells, leading to the generation of committed progenitors and cancer stem Cells. These findings underscore the idea that PI3K/Akt signaling regulates “stemness” in many stem Cell systems.
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AKT signaling promotes derivation of Embryonic Germ Cells from primordial Germ Cells.
Development (Cambridge England), 2008Co-Authors: Tohru Kimura, Noriko Yamano, Maya Tomooka, Kazushige Murayama, Shogo Matoba, Hiroki Umehara, Yoshiakira Kanai, Toru NakanoAbstract:Primordial Germ Cells (PGCs) are Embryonic Germ Cell precursors. Although the developmental potency of PGCs is restricted to the Germ lineage, PGCs can acquire pluripotency, as verified by the in vitro establishment of Embryonic Germ (EG) Cells and the in vivo production of testicular teratomas. PGC-specific inactivation of PTEN, which is a lipid phosphatase antagonizing phosphoinositide-3 kinase (PI3K), enhances both EG Cell production and testicular teratoma formation. Here, we analyzed the effect of the serine/threonine kinase AKT, one of the major downstream effectors of PI3K, on the developmental potency of PGCs. We used transgenic mice that expressed an AKT-MER fusion protein, the kinase activity of which could be regulated by the ligand of modified estrogen receptor (MER), 4-hydroxytamoxifen. We found that hyperactivation of AKT signaling in PGCs at the proliferative phase dramatically augmented the efficiency of EG Cell establishment. Furthermore, AKT signaling activation substituted to some extent for the effects of bFGF, an essential growth factor for EG Cell establishment. By contrast, AKT activation had no effect on Germ Cells that were in mitotic arrest or that began meiosis at a later Embryonic stage. In the transgenic PGCs, AKT activation induced phosphorylation of GSK3, which inhibits its kinase activity; enhanced the stability and nuclear localization of MDM2; and suppressed p53 phosphorylation, which is required for its activation. The p53 deficiency, but not GSK3 inhibition, recapitulated the effects of AKT hyperactivation on EG Cell derivation, suggesting that p53 is one of the crucial downstream targets of the PI3K/AKT signal and that GSK3 is not.
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conditional loss of pten leads to testicular teratoma and enhances Embryonic Germ Cell production
Development, 2003Co-Authors: Tohru Kimura, Akira Suzuki, Yukiko Fujita, Kentaro Yomogida, Hilda Lomeli, Noriko Asada, Megumi Ikeuchi, Andras Nagy, Tak W Mak, Toru NakanoAbstract:The tumor suppressor gene PTEN, which is frequently mutated in human cancers, encodes a lipid phosphatase for phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3] and antagonizes phosphatidylinositol 3 kinase. Primordial Germ Cells (PGCs), which are the Embryonic precursors of gametes, are the source of testicular teratoma. To elucidate the intraCellular signaling mechanisms that underlie Germ Cell differentiation and proliferation, we have generated mice with a PGC-specific deletion of the Pten gene. Male mice that lacked PTEN exhibited bilateral testicular teratoma, which resulted from impaired mitotic arrest and outgrowth of Cells with immature characters. Experiments with PTEN-null PGCs in culture revealed that these Cells had greater proliferative capacity and enhanced pluripotent Embryonic Germ (EG) Cell colony formation. PTEN appears to be essential for Germ Cell differentiation and an important factor in testicular Germ Cell tumor formation.
Toru Nakano - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Stem Cell Systems by PI3K/Akt Signaling
Regulatory Networks in Stem Cells, 2009Co-Authors: Tohru Kimura, Toru NakanoAbstract:Stem Cells can replenish their own population while supplying the Cells necessary to maintain tissue homeostasis. Pluripotent stem Cells, which have broader developmental potency than tissue stem Cells, are derived from the same source in mice and humans. In this review, we summarize the functions of phosphoinositide-3 kinase (PI3K) and its downstream serine/threonine kinase Akt in a variety of stem Cell systems. Primordial Germ Cells (PGCs), which are Embryonic Germ Cell precursors, are unique in that they acquire pluripotency under cultural and pathological conditions. PGCs lacking Pten, which encodes a phosphatase that antagonizes PI3K signaling, give rise to early-onset testicular teratomas in vivo and augment the derivation of pluripotent Embryonic Germ (EG) Cells in vitro. Transient activation of Akt sufficiently recapitulates the effects of Pten deficiency on EG Cell derivation. Enhanced EG Cell derivation is brought about by the Akt-mediated inhibition of the tumor suppressor p53. In Embryonic stem (ES) Cells, PI3K/Akt signaling plays a pivotal role in maintaining pluripotency in part via transcriptional activation of the pluripotent transcription factor Nanog. In turn, the expression of Tcl1, a cofactor of Akt, is activated by pluripotent transcription factors, including Oct-3/4. Therefore, PI3K/Akt signaling and the transcription factor network constitute the positive feedback circuitry necessary to maintain pluripotency in ES Cells. In tissue stem Cells, such as hair follicular, intestinal, and hematopoietic stem Cells, PI3K/Akt signaling activates quiescent stem Cells, leading to the generation of committed progenitors and cancer stem Cells. These findings underscore the idea that PI3K/Akt signaling regulates “stemness” in many stem Cell systems.
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AKT signaling promotes derivation of Embryonic Germ Cells from primordial Germ Cells.
Development (Cambridge England), 2008Co-Authors: Tohru Kimura, Noriko Yamano, Maya Tomooka, Kazushige Murayama, Shogo Matoba, Hiroki Umehara, Yoshiakira Kanai, Toru NakanoAbstract:Primordial Germ Cells (PGCs) are Embryonic Germ Cell precursors. Although the developmental potency of PGCs is restricted to the Germ lineage, PGCs can acquire pluripotency, as verified by the in vitro establishment of Embryonic Germ (EG) Cells and the in vivo production of testicular teratomas. PGC-specific inactivation of PTEN, which is a lipid phosphatase antagonizing phosphoinositide-3 kinase (PI3K), enhances both EG Cell production and testicular teratoma formation. Here, we analyzed the effect of the serine/threonine kinase AKT, one of the major downstream effectors of PI3K, on the developmental potency of PGCs. We used transgenic mice that expressed an AKT-MER fusion protein, the kinase activity of which could be regulated by the ligand of modified estrogen receptor (MER), 4-hydroxytamoxifen. We found that hyperactivation of AKT signaling in PGCs at the proliferative phase dramatically augmented the efficiency of EG Cell establishment. Furthermore, AKT signaling activation substituted to some extent for the effects of bFGF, an essential growth factor for EG Cell establishment. By contrast, AKT activation had no effect on Germ Cells that were in mitotic arrest or that began meiosis at a later Embryonic stage. In the transgenic PGCs, AKT activation induced phosphorylation of GSK3, which inhibits its kinase activity; enhanced the stability and nuclear localization of MDM2; and suppressed p53 phosphorylation, which is required for its activation. The p53 deficiency, but not GSK3 inhibition, recapitulated the effects of AKT hyperactivation on EG Cell derivation, suggesting that p53 is one of the crucial downstream targets of the PI3K/AKT signal and that GSK3 is not.
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conditional loss of pten leads to testicular teratoma and enhances Embryonic Germ Cell production
Development, 2003Co-Authors: Tohru Kimura, Akira Suzuki, Yukiko Fujita, Kentaro Yomogida, Hilda Lomeli, Noriko Asada, Megumi Ikeuchi, Andras Nagy, Tak W Mak, Toru NakanoAbstract:The tumor suppressor gene PTEN, which is frequently mutated in human cancers, encodes a lipid phosphatase for phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3] and antagonizes phosphatidylinositol 3 kinase. Primordial Germ Cells (PGCs), which are the Embryonic precursors of gametes, are the source of testicular teratoma. To elucidate the intraCellular signaling mechanisms that underlie Germ Cell differentiation and proliferation, we have generated mice with a PGC-specific deletion of the Pten gene. Male mice that lacked PTEN exhibited bilateral testicular teratoma, which resulted from impaired mitotic arrest and outgrowth of Cells with immature characters. Experiments with PTEN-null PGCs in culture revealed that these Cells had greater proliferative capacity and enhanced pluripotent Embryonic Germ (EG) Cell colony formation. PTEN appears to be essential for Germ Cell differentiation and an important factor in testicular Germ Cell tumor formation.
Kam W Leong - One of the best experts on this subject based on the ideXlab platform.
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enhanced extraCellular matrix production and differentiation of human Embryonic Germ Cell derivatives in biodegradable poly e caprolactone co ethyl ethylene phosphate scaffold
Acta Biomaterialia, 2006Co-Authors: Evelyn K F Yim, Jie Wen, Kam W LeongAbstract:Abstract ExtraCellular environment regulates Cell behavior and also influences the differentiation of stem Cells. Two Cell lines of pluriopotent human Embryonic Germ Cell derivatives (EBD Cells) were cultured on a biodegradable poly(e-caprolactone-co-ethyl ethylene phosphate) (PCLEEP) and non-degradable Cellulose acetate scaffold. Their Cell behaviors including proliferation, differentiation, Cell distribution and extraCellular matrix production were studied for 4 weeks and 10 months. The proliferation of the EBD Cells was enhanced in both of the three-dimensional scaffolds in the first 5 weeks of culture, regardless of the material difference, compared to monolayer culture. While the gene expression profile remained multilineage for the EBD Cells cultured in the Cellulose acetate fibrous scaffold, much of the neuronal lineage markers were down-regulated in EBD Cells cultured in the PCLEEP scaffold. On the other hand, extraCellular matrix production was significantly enhanced in the PCLEEP scaffold. The study showed that the polymer substrate could influence the differentiation and growth of pluripotent stem Cells in the absence of exogenous biochemical signals.
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Enhanced extraCellular matrix production and differentiation of human Embryonic Germ Cell derivatives in biodegradable poly(ε-caprolactone-co-ethyl ethylene phosphate) scaffold
Acta Biomaterialia, 2006Co-Authors: Evelyn K F Yim, Jie Wen, Kam W LeongAbstract:ExtraCellular environment regulates Cell behavior and also influences the differentiation of stem Cells. Two Cell lines of pluriopotent human Embryonic Germ Cell derivatives (EBD Cells) were cultured on a biodegradable poly(ε-caprolactone-co-ethyl ethylene phosphate) (PCLEEP) and non-degradable Cellulose acetate scaffold. Their Cell behaviors including proliferation, differentiation, Cell distribution and extraCellular matrix production were studied for 4 weeks and 10 months. The proliferation of the EBD Cells was enhanced in both of the three-dimensional scaffolds in the first 5 weeks of culture, regardless of the material difference, compared to monolayer culture. While the gene expression profile remained multilineage for the EBD Cells cultured in the Cellulose acetate fibrous scaffold, much of the neuronal lineage markers were down-regulated in EBD Cells cultured in the PCLEEP scaffold. On the other hand, extraCellular matrix production was significantly enhanced in the PCLEEP scaffold. The study showed that the polymer substrate could influence the differentiation and growth of pluripotent stem Cells in the absence of exogenous biochemical signals. © 2006 Acta Materialia Inc.
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Proliferation and differentiation of human Embryonic Germ Cell derivatives in bioactive polymeric fibrous scaffold
Journal of biomaterials science. Polymer edition, 2005Co-Authors: Evelyn K F Yim, Kam W LeongAbstract:Human Embryonic Germ Cell derivatives, a heterogeneous population of uncommitted embryoid body derived (EBD) Cells, were studied in a bioactive three-dimensional (3D) fibrous culture. Their proliferation, morphology, gene expression and differentiation were investigated to gain insights on development of 3D bioactive scaffold for pluripotent stem Cells. The expansion of the EBD Cells in 3D environment was significantly higher than their two-dimensional controls after 21 days. No apparent differentiation of the EBD Cells cultured in the 3D environment, as indicated by histology and gene expression profile analysis, was evident. ExtraCellular matrix production was weak in the long-term 3D culture, and the EBD Cells maintained their multilineage gene expressions for the period studied. When nerve growth factor (NGF) was surface-immobilized on the fibrous scaffold via chemically-modified Pluronic, the EBD Cells cultured in this scaffold showed evidence of entering the neural pathway. An upregulation of tyrosine hydroxylase mRNA expression was observed when EBD Cells were cultured in the NGF-immobilized fibrous scaffold, as demonstrated by real-time PCR and immunofluorescence staining. The study suggests the value of such fibrous 3D culture in manipulating stem Cell proliferation/differentiation and as a model for developing a bioactive scaffold.