RESUMO
Pediatric ovarian tumors exhibit unique diagnostic and therapeutic challenges. This study evaluates the expression of SALL4 and OCT3/4 biomarkers in pediatric ovarian tumors and their associations with tumor subtype, stage, and clinical outcome. A retrospective analysis was conducted on 64 patients under 18 years old, examining demographic data, tumor characteristics, immunohistochemical staining, and clinical outcomes. Our results show that SALL4 was significantly expressed in adenocarcinoma, dysgerminoma (DSG), mixed germ cell tumors (GCTs), and immature teratoma, while OCT3/4 was highly expressed in DSG and mixed GCTs. Both markers are associated with a higher tumor grade and stage, indicating a more aggressive disease. The SALL4 positivity expression was correlated with high alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) levels, while OCT3/4 positivity significantly predicted the risk of subsequent metastasis. The mean progression-free survival (PFS) was notably shorter in patients with positive markers. These findings underscore the diagnostic and prognostic value of SALL4 and OCT3/4 in pediatric ovarian tumors, aligning with previous research and supporting their use in clinical practice for better disease management and patient outcomes.
Assuntos
Biomarcadores Tumorais , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Biomarcadores Tumorais/metabolismo , Criança , Adolescente , Pré-Escolar , Estudos Retrospectivos , Prognóstico , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Romênia/epidemiologia , Lactente , Fatores de Transcrição/metabolismo , Teratoma/metabolismo , Teratoma/diagnóstico , Teratoma/patologia , Teratoma/genéticaRESUMO
Human induced pluripotent stem cells (iPSCs) have good multi-lineage differentiation potential, which is an ideal model for studying the pathogenesis of diseases and drug screening.Here, we generated an iPSC line, SHUPLi002-A, from peripheral blood mononuclear cells (PBMCs) of a healthy 28-year-old female individual using episomal vectors. SHUPLi002-A is characterized by expression of classical pluripotent stem cell markers as well as teratoma formation assays to evaluate their differentiation capacity in vivo.
Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes Induzidas , Leucócitos Mononucleares , Humanos , Feminino , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Adulto , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia , Linhagem Celular , Teratoma/patologia , Teratoma/metabolismo , Camundongos , AnimaisRESUMO
Fibroblasts were extracted from the scalp of a healthy 55-year-old male and subsequently transformed into pluripotent stem cells by introducing episomal plasmids harboring essential reprogramming factors. These induced pluripotent stem cells exhibited a normal karyotype and demonstrated the capacity to differentiate into all three germ layers, as confirmed through teratoma assays. This specific cell line serves as a valuable reference for comparative investigations alongside other induced pluripotent stem cell lines generated from somatic cells of patients afflicted by genetic neurodegenerative disorders.
Assuntos
Células-Tronco Pluripotentes Induzidas , Teratoma , Humanos , Masculino , Pessoa de Meia-Idade , Diferenciação Celular , Linhagem Celular , Reprogramação Celular , Fibroblastos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Plasmídeos , Teratoma/metabolismoRESUMO
Teratoma formation is key for evaluating differentiation of human pluripotent stem cells into embryonic germ layers and serves as a model for understanding stem cell differentiation and developmental processes. Its potential for insights into epigenome and transcriptome profiling is significant. This study integrates the analysis of the epigenome and transcriptome of hESC-generated teratomas, comparing transcriptomes between hESCs and teratomas. It employs cell type-specific expression patterns from single-cell data to deconvolve RNA-Seq data and identify cell types within teratomas. Our results provide a catalog of activating and repressive histone modifications, while also elucidating distinctive features of chromatin states. Construction of an epigenetic signature matrix enabled the quantification of diverse cell populations in teratomas and enhanced the ability to unravel the epigenetic landscape in heterogeneous tissue contexts. This study also includes a single cell multiome atlas of expression (scRNA-Seq) and chromatin accessibility (scATAC-Seq) of human teratomas, further revealing the complexity of these tissues. A histology-based digital staining tool further complemented the annotation of cell types in teratomas, enhancing our understanding of their cellular composition. This research is a valuable resource for examining teratoma epigenomic and transcriptomic landscapes and serves as a model for epigenetic data comparison.
Assuntos
Cromatina , Teratoma , Humanos , Teratoma/genética , Teratoma/patologia , Teratoma/metabolismo , Cromatina/metabolismo , Cromatina/genética , Epigênese Genética , Transcriptoma/genética , Perfilação da Expressão Gênica/métodos , Diferenciação Celular/genética , Código das Histonas , Análise de Célula Única/métodos , Epigenoma , Células-Tronco Embrionárias Humanas/metabolismo , RNA-SeqRESUMO
BACKGROUND: Germ cell tumors (GCT) might undergo transformation into a somatic-type malignancy (STM), resulting in a cell fate switch to tumors usually found in somatic tissues, such as rhabdomyosarcomas or adenocarcinomas. STM is associated with a poor prognosis, but the molecular and epigenetic mechanisms triggering STM are still enigmatic, the tissue-of-origin is under debate and biomarkers are lacking. METHODS: To address these questions, we characterized a unique cohort of STM tissues on mutational, epigenetic and protein level using modern and high-throughput methods like TSO assays, 850k DNA methylation arrays and mass spectrometry. RESULTS AND CONCLUSIONS: For the first time, we show that based on DNA methylation and proteome data carcinoma-related STM more closely resemble yolk-sac tumors, while sarcoma-related STM resemble teratoma. STM harbor mutations in FGF signaling factors (FGF6/23, FGFR1/4) highlighting the corresponding pathway as a therapeutic target. Furthermore, STM utilize signaling pathways, like AKT, FGF, MAPK, and WNT to mediate molecular functions coping with oxidative stress, toxin transport, DNA helicase activity, apoptosis and the cell cycle. Collectively, these data might explain the high therapy resistance of STM. Finally, we identified putative novel biomarkers secreted by STM, like EFEMP1, MIF, and DNA methylation at specific CpG dinucleotides.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Teratoma , Humanos , Metilação de DNA , Proteoma/genética , Proteoma/metabolismo , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologia , Biomarcadores/metabolismo , Proteínas da Matriz Extracelular/genéticaRESUMO
The teratomas formation has severely hindered the application of embryonic stem cells (ESCs) in clinical trials. Apurinic/apyrimidinic endonuclease 1 (APE1) is strongly involved in the development of tumors and differentiation process of stem cells. However, the role of APE1 in teratomas remains unknown. The expression of APE1 was examined in mouse ESCs (mESCs) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The role and mechanism of APE1 in the proliferation, pluripotency and differentiation of E14 cells were determined by cell counting, flow cytometry and western blot assays. Besides, the role of APE1 in teratomas was also probed in xenografted mice. The expression of APE1 was upregulated in mESCs with differentiation. Knockdown of APE1 reduced the cell numbers, induced the arrest of the G2/M phase, and decreased the expression of cell cycle-related proteins in E14 cells. Besides, loss- and gain-of-function assays revealed that APE1 enhanced the levels of proteins involved in pluripotency, reduced the protein expression of ectoderm markers, and increased the protein levels of endoderm markers in E14 cells. Mechanically, inhibition of APE1 downregulated the expression of GDNF and GFRα1 in E14 cells. GDNF reversed the role of APE1 in the proliferation, pluripotency and embryogenesis of E14 cells. Moreover, suppression of APE1 reduced the teratoma volume and the relative protein expression of endoderm markers, but increased the relative protein expression of ectoderm markers in xenografted mice. Collectively, knockdown of APE1 attenuated proliferation, pluripotency and embryogenesis of mESCs via GDNF/GFRα1 axis.
Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial , Teratoma , Animais , Camundongos , Diferenciação Celular , Proliferação de Células , Células-Tronco Embrionárias/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Teratoma/metabolismo , HumanosRESUMO
Teratomas in mice, composed of different tissue types, are derived from primordial germ cells in the fetal gonads. Previously, we identified a locus responsible for experimental testicular teratoma (ETT) formation on chromosome 18, referred to as ett1. The strongest candidate sequence in the ett1 locus was found to be a missense mutation in the melanocortin 4 receptor (Mc4r), Mc4rG25S. We established a strain with a point mutation in the Mc4r gene in the ETT-nonsusceptible LT strain, called LT- Mc4rG25S, by genome editing. Surprisingly, highly developed ovarian teratomas (OTs), rather than testicular teratomas, appeared in the LT-Mc4rG25S strain. The results demonstrated that Mc4r is also one of the genes responsible for OT formation and suggested that missense mutations in Mc4r promote teratoma formation in both sexes. In this study, we performed ETT experiments in different host-graft combinations of the LT-Mc4rG25S and LT strains. Furthermore, the expression of MC4R in germ cells in the testis was demonstrated. Expression of Mc4r in testis was also confirmed by RT-PCR. The results demonstrated that MC4R is expressed in germ cells in the testis and that a point mutation in the Mc4r gene is responsible for ETT formation.
Assuntos
Teratoma , Neoplasias Testiculares , Masculino , Humanos , Feminino , Camundongos , Animais , Teratoma/metabolismo , Neoplasias Testiculares/genética , Receptor Tipo 4 de MelanocortinaRESUMO
Peripheral blood mononuclear cells (PBMCs) have been widely considered as a more convenient and almost unlimited reprogramming resource, while the reprogramming procedure and efficiency still need to be improved. We reprogrammed the PBMCs by using non-integrative non-viral vectors liposome electrotransfer containing the reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The iPSC lines exhibited a normal karyotype with their corresponding PBMCs and exhibited significant cellular pluripotency. Teratoma formation assay revealed that the iPSCs we generated could differentiate into three embryonic germ layers. Our study provides a more effective procedure for peripheral blood monocyte reprogramming to iPSC, and promotes its future application.
Assuntos
Células-Tronco Pluripotentes Induzidas , Teratoma , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Reprogramação Celular , Leucócitos Mononucleares/metabolismo , Fator 4 Semelhante a Kruppel , Teratoma/metabolismo , Diferenciação CelularRESUMO
Pluripotent stem cell research has revolutionized the modern era for the past 14 years with the advent of induced pluripotent stem cells. Before this time, scientists had access to human and mouse embryonic stem cells primarily for basic research and an attempt towards lineage-specific differentiations for cell therapy applications. Regarding pluripotent stem cells, expression of bonafide marker proteins such as Oct4, Nanog, Sox2, Klf4, c-Myc, and Lin28 have been considered giving a perfect readout for pluripotent stem cells and assessed using an analytical flow cytometer. In addition to the intracellular markers, surface markers such as stage-specific embryonic antigen-1 for mouse cells and SSEA-4 for human cells are needed to sort pure populations of stem cells for further downstream applications for cell therapy. The surface marker SSEA-4 is the most appropriate for obtaining pure populations of human pluripotent stem cells. When differentiated in a controlled manner using growth factors or small molecules, it is mandatory to assess the downregulation of pluripotency markers (Oct4, Nanog, Sox2, and Klf4) with subsequent up-regulation of stage-specific differentiation markers. Such assessments are done using flow cytometry. Pluripotent stem cells have a high teratoma-forming potential in vivo. Small amounts of undifferentiated PSCs might lead to dangerous teratomas upon transplantation if leftover in the pool of differentiated cells. Hence, flow cytometry is essential for sorting out PSC populations with teratoma-forming potential. The pure populations of differentiated progenitors need to be flow-sorted before differentiating them further for cell therapy applications. For example, Glycoprotein 2 is a specific cell-surface marker for pancreatic progenitors that enables one to sort the pancreatic progenitors differentiated from human PSCs. Taken together, analytical flow cytometry, and cell sorting provide indispensable tools in PSC research and cell therapy.
Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Teratoma , Animais , Humanos , Camundongos , Citometria de Fluxo , Pesquisa Translacional Biomédica , Diferenciação Celular/fisiologia , Teratoma/metabolismo , BiologiaRESUMO
BACKGROUND: Mature cystic teratomas of the ovary are the most common type of germ cell tumor, comprising 33% of ovarian tumors. Studying these tumors may result in a better understanding of their stepwise developmental processes and molecular bases and provide useful information for the development of tissue-engineering technologies. METHODS: In the present study, 9 mature cystic teratomas of the ovary were analyzed by whole-exome sequencing and the results were compared with the Catalogue of Somatic Mutations in Cancer and dbSNP databases. RESULTS: Mutations were validated in 15 genes with alterations in all 9 (100%) samples and changes in protein coding. The top 10 mutated genes were FLG, MUC17, MUC5B, RP1L1, NBPF1, GOLGA6L2, SLC29A3, SGK223, PTGFRN, and FAM186A. Moreover, 7 variants in exons with changes in protein coding are likely of importance in the development of mature cystic teratomas of the ovary, namely PTGFRN, DUSP5, MPP2, PHLDA1, PRR21, GOLGA6L2, and KRTAP4-2. CONCLUSIONS: These genetic alterations may play an important etiological role in teratoma formation. Moreover, novel mutations in DUSP5 and PHLDA1 genes found on whole-exome sequencing may help to explain the characteristics of teratomas.
Assuntos
Neoplasias Ovarianas , Teratoma , Feminino , Humanos , Sequenciamento do Exoma , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Mutação , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Fatores de Transcrição/genética , Proteínas de Transporte de Nucleosídeos/genéticaRESUMO
Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for ß cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinical application. Here, we hypothesized that pretreatment of iPSC-derived insulin-producing cells with an anti-CD30 antibody−drug conjugate could prevent in vivo teratoma formation by selectively killing residual undifferentiated cells. CD30 is expressed in all human iPSCs clones tested by flow cytometry (n = 7) but not in iPSC-derived ß cells (ißs). Concordantly, anti-CD30 treatment in vitro for 24 h induced a dose-dependent cell death (up to 90%) in human iPSCs while it did not kill ißs nor had an impact on iß identity and function, including capacity to secrete insulin in response to stimuli. In a model of teratoma assay associated with iß transplantation, the pretreatment of cells with anti-CD30 for 24 h before the implantation into NOD-SCID mice completely eliminated teratoma development (0/10 vs. 8/8, p < 0.01). These findings suggest that short-term in vitro treatment with clinical-grade anti-CD30, targeting residual undifferentiated cells, eliminates the tumorigenicity of iPSC-derived ß cells, potentially providing enhanced safety for iPSC-based ß cell replacement therapy in clinical scenarios.
Assuntos
Antineoplásicos , Imunoconjugados , Células-Tronco Pluripotentes Induzidas , Teratoma , Animais , Antineoplásicos/farmacologia , Diferenciação Celular , Humanos , Imunoconjugados/farmacologia , Insulina/metabolismo , Antígeno Ki-1/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Teratoma/etiologia , Teratoma/metabolismo , Teratoma/prevenção & controleRESUMO
OBJECTIVES: Transplantation of neural progenitor cells (NPCs) derived from human-induced pluripotent stem cells (hiPSCs) is one of the promising treatment strategies for motor neuron diseases (MNDs). However, the inefficiency in committed differentiation of NPCs in vivo limits its application. Here, we tried to establish a potential therapeutic strategy for MNDs by in vivo directional differentiation of hiPSCs engineered with motor neuron (MN) specific transcription factors and Tet-On system. MATERIALS AND METHODS: We engineered hiPSCs with three MN-specific transcription factors and Tet-On system. The engineered cells were directly transplanted into immunodeficient mice through subcutaneous, intra-spinal cord and intracerebroventricular injections. Following doxycycline (Dox) induction, teratoma formation, and motor MN differentiation were evaluated. RESULTS: We generated genetically engineered hiPSCs, in which the expression of Ngn2, Isl1, and Lhx3 was controlled by a drug-inducible transgenic system. These cells showed normal pluripotency and proliferative capacity, and were able to directionally differentiate into mature motor neurons (MNs) and NPCs with high efficiency in spinal cords and cerebral lateral ventricles under the induction of Dox. The grafts showed long-term survival in the recipient mice without formation of teratoma. CONCLUSIONS: The induced mature MNs and NPCs were expected to replace the damaged endogenous MNs directly, and play a role of de novo stem cell stock for long-term neuron damage repair, respectively. Therefore, in vivo directional differentiation of the hiPSCs engineered with MN-specific transcription factors and Tet-On system via Dox induction could be a potential therapeutic strategy for MNDs with high efficacy and safety.
Assuntos
Células-Tronco Pluripotentes Induzidas , Teratoma , Humanos , Camundongos , Animais , Neurônios Motores/metabolismo , Diferenciação Celular , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Teratoma/metabolismoRESUMO
Human pluripotent stem cell (hPSC)-derived pancreatic progenitors (PPs) can be differentiated into beta-like cells in vitro and in vivo and therefore have therapeutic potential for type 1 diabetes (T1D) treatment. However, the purity of PPs varies across different hPSC lines, differentiation protocols, and laboratories. The uncommitted cells may give rise to non-pancreatic endodermal, mesodermal, or ectodermal derivatives in vivo, hampering the safety of hPSC-derived PPs for clinical applications and their differentiation efficiency in research settings. Recently, proteomics and transcriptomics analyses identified glycoprotein 2 (GP2) as a PP-specific cell surface marker. The GP2-enriched PPs generate higher percentages of beta-like cells in vitro, but their potential in vivo remains to be elucidated. Here, we demonstrate that the GP2-enriched-PPs give rise to all pancreatic cells in vivo, including functional beta-like cells. Remarkably, GP2 enrichment eliminates the risk of teratomas, which establishes GP2 sorting as an effective method for PP purification and safe pancreatic differentiation.
Assuntos
Células Secretoras de Insulina , Células-Tronco Pluripotentes , Teratoma , Diferenciação Celular/fisiologia , Endoderma , Humanos , Células Secretoras de Insulina/metabolismo , Pâncreas , Células-Tronco Pluripotentes/metabolismo , Teratoma/etiologia , Teratoma/metabolismoRESUMO
BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is a rare malignant neoplasm in the pediatric population. ATRT is characterized by rhabdoid cells combined with the loss of either the INI1 (integrase interactor 1) or BRG1 (Brahma-related gene-1) protein. OBJECTIVE: To systematically review and analyze patient and tumor characteristics, prognosis, and impact of treatment on survival in pediatric patients with ATRT confirmed by alterations in INI1 or BRG1. This systematic review is the first to include only pediatric cases of ATRT confirmed with either INI1 or BRG1 alterations. METHODS: MEDLINE was searched using the terms "atypical teratoid/rhabdoid tumor" AND "paediatric/pediatric." Cases were included if confirmed by loss of INI1 or BRG1. The extracted dataset was analyzed using descriptive statistics, log-rank test, and Kaplan-Meier survival analysis via SPSS. RESULTS: A total of 38 articles were included in this study. The average age at diagnosis was 3 years. The most common locations reported are the supratentorial region and cerebral hemispheres. Ninety-three patients were reported to show evidence of dissemination. The average overall survival was 29 months. A significant difference in survival was noted between the tumor location groups, particularly worse outcomes for patients with spinal ATRT (P < 0.001). Extent of resection and adjuvant therapy were significant for survival (χ2 = 10.107, P = 0.018 and χ2 = 20.38, P < 0.0001, respectively). CONCLUSIONS: ATRT of the central nervous system in pediatric populations is a rare neoplasm associated with a poor prognosis in most patients. Future studies should be directed to find a standardized treatment protocol.
Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Neuroepiteliomatosas , Tumor Rabdoide , Teratoma , Criança , Humanos , Tumor Rabdoide/metabolismo , Tumor Rabdoide/cirurgia , Análise de Sobrevida , Teratoma/metabolismo , Teratoma/cirurgiaRESUMO
Otosclerosis is caused by abnormal bone remodeling in the middle ear, resulting in progressive hearing loss, dizziness, balance problems, and tinnitus. Previous infection, stress fractures of the bony tissue surrounding the inner ear, immune disorders, and genetic factors are believed to contribute to this disease. Currently, no effective drug treatment for otosclerosis is known. Herein, we generated an induced pluripotent stem cell line from the peripheral blood mononuclear cells of an otosclerosis patient. The cell line exhibited normal morphology, karyotype, and pluripotency marker expression. A teratoma assay revealed successful differentiation into all three germ layers.
Assuntos
Células-Tronco Pluripotentes Induzidas , Otosclerose , Teratoma , Linhagem Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares , Otosclerose/metabolismo , Teratoma/metabolismoRESUMO
Mouse embryonic stem cells (mESCs) are characterized by self-renewal and pluripotency and can undergo differentiation into the three germ layers (ectoderm, mesoderm, and endoderm). Melanoma-associated antigen D1 (Maged1), which is expressed in all developing and adult tissues, modulates tissue regeneration and development. In the present study, we examined the expression and function of Maged1 in mESCs. Maged1 protein and mRNA expression increased during mESC differentiation. The pluripotency of mESCs was significantly reduced through extracellular signal-regulated kinase 1/2 phosphorylation upon knockdown of Maged1, and through G1 cell cycle arrest during cell division, resulting in significantly reduced mESC proliferation. Moreover, the diameter of the embryoid bodies was significantly reduced, accompanied by increased levels of ectodermal differentiation markers and decreased levels of mesodermal and endodermal differentiation markers. Maged1-knockdown mESC lines showed significantly reduced teratoma volumes and inhibition of teratoma formation in nude mice. Additionally, we observed increased ectodermal markers but decreased mesodermal and endodermal markers in teratoma tissues. These findings show that Maged1 affects mESC pluripotency, proliferation, cell cycle, and differentiation, thereby contributing to our understanding of the basic molecular biological mechanisms and potential roles of Maged1 as a regulator of various mESC properties.
Assuntos
Células-Tronco Embrionárias Murinas , Animais , Antígenos de Diferenciação/metabolismo , Ciclo Celular/genética , Morte Celular , Diferenciação Celular/genética , Divisão Celular , Camundongos , Camundongos Nus , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologiaRESUMO
We performed spatial epigenetic and transcriptomic analyses of a highly unusual low-grade diffusely infiltrative tumour with INI1 deficiency (CNS LGDIT-INI1), which harboured a high-grade component corresponding to an atypical teratoid/rhabdoid tumour (AT/RT). Methylation profiles of both low-grade and high-grade components yielded high similarity with AT/RTs of the MYC subgroup, whereas RNA expression analyses revealed increased translational activity and MYC pathway activation in the high-grade component. Close follow-up of patients harbouring CNS LGDIT-INI1 is warranted.
Assuntos
Neoplasias do Sistema Nervoso Central , Tumor Rabdoide , Teratoma , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Tumor Rabdoide/metabolismo , Proteína SMARCB1/genética , Teratoma/genética , Teratoma/metabolismoRESUMO
The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the foundational framework of tumors. Here we review and extend the gametogenesis-related hypothesis of tumors, because high embryonic/germ cell traits are common in tumors. The century-old gametogenesis-related hypothesis of tumors postulated that tumors arise from displaced/activated trophoblasts, displaced (lost) germ cells, and the reprogramming/reactivation of gametogenic program in somatic cells. Early primordial germ cells (PGCs), embryonic stem (ES) cells, embryonic germ cells (EGCs), and pre-implantation embryos at the stage from two-cell stage to blastocysts originating from fertilization or parthenogenesis have the potential to develop teratomas/teratocarcinomas. In addition, the teratomas/teratocarcinomas/germ cells occur in gonads and extra-gonads. Undoubtedly, the findings provide strong support for the hypothesis. However, it was thought that these tumor types were an exception rather than verification. In fact, there are extensive similarities between somatic tumor types and embryonic/germ cell development, such as antigens, migration, invasion, and immune escape. It was documented that embryonic/germ cell genes play crucial roles in tumor behaviors, e.g. tumor initiation and metastasis. Of note, embryonic/germ cell-like tumor cells at different developmental stages including PGC and oocyte to the early embryo-like stage were identified in diverse tumor types by our group. These embryonic/germ cell-like cancer cells resemble the natural embryonic/germ cells in morphology, gene expression, the capability of teratoma formation, and the ability to undergo the process of oocyte maturation and parthenogenesis. These embryonic/germ cell-like cancer cells are derived from somatic cells and contribute to tumor formation, metastasis, and drug resistance, establishing asexual meiotic embryonic life cycle. p53 inhibits the reactivation of embryonic/germ cell state in somatic cells and oocyte-like cell maturation. Based on earlier and our recent studies, we propose a novel model to complete the gametogenesis-related hypothesis of tumors, which can be applied to certain somatic tumors. That is, tumors tend to establish a somatic asexual meiotic embryonic cycle through the activation of somatic female gametogenesis and parthenogenesis in somatic tumor cells during the tumor progression, thus passing on corresponding embryonic/germ cell traits leading to the malignant behaviors and enhancing the cells' independence. This concept may be instrumental to better understand the nature and evolution of tumors. We rationalize that targeting the key events of somatic pregnancy is likely a better therapeutic strategy for cancer treatment than directly targeting cell mitotic proliferation, especially for those tumors with p53 inactivation.
Assuntos
Teratocarcinoma , Teratoma , Feminino , Gametogênese , Células Germinativas/metabolismo , Humanos , Gravidez , Teratocarcinoma/metabolismo , Teratocarcinoma/patologia , Teratoma/metabolismo , Teratoma/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Background: Neuroendocrine neoplasms are a heterogeneous group of cancers that develop from enterochromaffin cells of the diffuse endocrine system, with an increase in incidents over the last years. Ovarian neuroendocrine tumors (NET) are rare neoplasms, comprising 0.1% of all ovarian neoplasms and less than 5% of all neuroendocrine tumors. They may arise alone (as monodermal, specialized teratoma - ovarian carcinoid) or as a part of other ovarian lesion: cystic mature or immature teratomas. Due to the rarity and limited amount of such cases reported in the literature, there is no consensus on diagnostic and therapeutic procedures in this group of patients. Materials and Methods: The group of 10 patients at the age of 19 to 77 years (mean 42.8 ± 17.9), diagnosed with unilateral NET within ovarian teratoma were analyzed. The histopathological type of tumor, progression free survival after surgical treatment and presence of hormonally active syndrome were assessed. Results: 70% (n=7) of patients was diagnosed with mature cystic teratomas containing NET component and 30% (n=3) with monodermal teratoma (strumal carcinoid). All cases of monodermal teratomas were found in women at premenopausal age. Determined Ki67 ranged from 2% to 9%. Ninety percent of lesions (n=9) stained positive for synaptophysin and chromogranin, while markers: CK20, CK7, TTF-1 and CDX2 were negative in all cases, which ruled out their metastatic nature. None of the patients presented with carcinoid syndrome. All followed-up patients remain progression-free, which confirms surgical intervention being a crucial and sufficient method of treatment. Conclusions: The prognosis and clinical behavior of NETs associated with ovarian teratomas are good with long progression-free survival.
Assuntos
Tumores Neuroendócrinos/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Teratoma/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Prognóstico , Teratoma/metabolismo , Adulto JovemRESUMO
Sox2 is a core transcription factor in embryonic stem cells (ESCs), and O-GlcNAcylation is a type of post-translational modification of nuclear-cytoplasmic proteins. Although both factors play important roles in the maintenance and differentiation of ESCs and the serine 248 (S248) and threonine 258 (T258) residues of Sox2 are modified by O-GlcNAcylation, the function of Sox2 O-GlcNAcylation is unclear. Here, we show that O-GlcNAcylation of Sox2 at T258 regulates mouse ESC self-renewal and early cell fate. ESCs in which wild-type Sox2 was replaced with the Sox2 T258A mutant exhibited reduced self-renewal, whereas ESCs with the Sox2 S248A point mutation did not. ESCs with the Sox2 T258A mutation heterologously introduced using the CRISPR/Cas9 system, designated E14-Sox2TA/WT, also exhibited reduced self-renewal. RNA sequencing analysis under self-renewal conditions showed that upregulated expression of early differentiation genes, rather than a downregulated expression of self-renewal genes, was responsible for the reduced self-renewal of E14-Sox2TA/WT cells. There was a significant decrease in ectodermal tissue and a marked increase in cartilage tissue in E14-Sox2TA/WT-derived teratomas compared with normal E14 ESC-derived teratomas. RNA sequencing of teratomas revealed that genes related to brain development had generally downregulated expression in the E14-Sox2TA/WT-derived teratomas. Our findings using the Sox2 T258A mutant suggest that Sox2 T258 O-GlcNAc has a positive effect on ESC self-renewal and plays an important role in the proper development of ectodermal lineage cells. Overall, our study directly links O-GlcNAcylation and early cell fate decisions.