dedifferentiation Dotaz Zobrazit nápovědu
Popisujeme prípad postradiačnej dediferenciácie meningoteliálneho meningeómu do chondroblastického osteosarkómu. Nádor vznikol u 61-ročného muža sedem rokov po adjuvantnom stereotaktickom ožiarení recidivujúceho meningeómu. Histologicky bol zachytený plynulý prechod z atypického meningeómu do klasického chondroblastického osteosarkómu. Pacient zomrel tri týždne po operácii, bez ďalšej onkologickej liečby. Podľa našich vedomostí ide iba o druhý popísaný prípad postradiačnej dediferenciácie meningeómu do osteosarkómu.
We report a case of post-radiation dedifferentiation of meningothelial meningioma into chondroblastic osteosarcoma. The tumor developed in a 61-year-old man, seven years after adjuvant stereotactical radiotherapy of recurring meningioma. Histologically, there was a continuous transition from atypical meningioma into chondroblastic osteosarcoma. The patient died three weeks after the surgery, without additional oncological treatment. To our knowledge, this case represents only the second reported case of post-radiation dedifferentiation of meningioma into osteosarcoma.
- MeSH
- adjuvantní radioterapie metody škodlivé účinky využití MeSH
- dediferenciace buněk účinky záření MeSH
- dospělí MeSH
- histologie MeSH
- imunohistochemie metody využití MeSH
- lidé MeSH
- meningeom diagnóza etiologie patologie MeSH
- neurochirurgické výkony metody využití MeSH
- osteosarkom diagnóza etiologie patologie MeSH
- počítačová rentgenová tomografie metody využití MeSH
- radiační onkologie metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The present study was undertaken to provide more information on the heterochromatin density in central and peripheral nuclear regions during “cell dedifferentiation“ represented by blastic transformation of mature T lymphocytes. Heterochromatin was visualized using a simple cytochemical method for the demonstration of DNA followed by computer-assisted densitometry of digitised images. The results indicated that the blastic transformation was accompanied by a marked and significant decrease in the heterochromatin density at the nuclear membrane. Thus, this nuclear peripheral region seems to be important not only for cell differentiation but also dedifferentiation events. It is also interesting that the non-stimulated resting mature cells in the present study were characterized by less condensed heterochromatin at the nuclear membrane than differentiated granulocytic or erythrocytic precursors and apoptotic myeloblasts or leukemic B lymphocytes described in the previous study. However, in contrast to these cells, resting and mature T lymphocytes in the present study are known to revert to cycling blastic cells after PHA treatment. In addition, it is also known that nuclear peripheral regions with heterochromatin represent sites of chromosomal attachments as well as “together crowded replicons“ and silent genes.
- MeSH
- aktivace lymfocytů genetika imunologie účinky léků MeSH
- dediferenciace buněk genetika imunologie účinky léků MeSH
- denzitometrie metody využití MeSH
- financování organizované využití MeSH
- fytohemaglutininy imunologie krev účinky léků MeSH
- heterochromatin genetika patologie MeSH
- interpretace statistických dat MeSH
Fibrotic diseases are a group of pathologies with high incidence and mortality. Despite extensive research efforts, effective therapies are still not available. Understanding the molecular mechanisms driving the onset, progression and possible resolution of fibrosis is a prerequisite to the development of successful therapies. The central role of the TGF-β pathway and myofibroblasts in the pathogenesis of fibrosis is now generally accepted. The possible mechanisms of myofibroblast elimination or dedifferentiation, on the other hand, are still almost uncharted territory. Here we show that sustained expression of some components of MAPK signaling pathway (PDGFB, Ha-Ras(G12V) or the transcription factor EGR4) in primary chicken embryo dermal myofibroblasts results in a loss of autocrine TGF-β signaling and suppression of the myofibroblastic phenotype, characterized by the loss of alpha smooth muscle actin fibers and a substantial reduction in the production of extracellular matrix. Detailed analysis of the possible molecular mechanisms employed by EGR4 revealed FOXG1, BAMBI, NAB1, NAB2 and DUSP5 genes forming an EGR4 regulated network counteracting autocrine TGF-β signaling. We have also found that a combination of chemical inhibition of TGF-β signaling and perturbation of MAPK signaling with phorbol ester mimics the anti-fibrotic effects of PDGFB, Ha-Ras(G12V) and EGR4.
- MeSH
- aktiny genetika metabolismus MeSH
- dediferenciace buněk * MeSH
- forbolové estery farmakologie MeSH
- kuřecí embryo MeSH
- mitogenem aktivované proteinkinasy metabolismus MeSH
- myofibroblasty cytologie metabolismus MeSH
- signální transdukce MeSH
- transformující růstový faktor beta metabolismus MeSH
- zvířata MeSH
- Check Tag
- kuřecí embryo MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The present study was undertaken to provide information on the nucleolar and cytoplasmic density in specimens stained for RNA during "cell dedifferentiation" represented by blastic transformation of mature T lymphocytes. Nucleolar and cytoplasmic RNA's were visualized using a simple cytochemical method followed by computer assisted densitometry and size measurements of digitised images. An increased nucleolar and cytoplasmic RNA density accompanying the blastic transformation was significant after 48 hours of cultivation with phytohemaglutinin (PHA) when stimulated cells were characterized the largest nucleolar size reflecting S or G2 phase of the cell cycle. On the other hand, significantly larger ratio of the nucleolar to cytoplasmic density was noted only after a shorter cultivation when stimulated cells were presumably in the G1 phase. Thus the increased nucleolar and cytoplasmic RNA density together represented an accompanying phenomenon of the cell proliferation and cycling state. From the methodical point of view, the nucleolar and cytoplasmic RNA densitometry appeared as a simple as well as useful additional method to study "dedifferentiation" or various cell states at the single cell level. In addition, it was also interesting that the increase of the nucleolar diameter in stimulated cells was much larger than that of the nucleolar density. Such difference suggested that the RNA content in nucleoli was related mainly to their size.
High-grade transformation (HGT) or dedifferentiation has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, secretory carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, low-grade mucoepidermoid carcinoma, and hyalinizing clear cell carcinoma. High-grade (HG) transformed tumors are composed of a conventional low-grade component characterized by specific microscopic and immunohistochemical features for the given entity, intermingled with or juxtaposed to areas of HG morphology. This is usually either poorly differentiated adenocarcinoma, carcinoma not otherwise specified, or undifferentiated carcinoma, in which the original line of differentiation is lost. The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component. The molecular genetic mechanisms responsible for HGT of salivary gland carcinomas are largely unknown, though p53 inactivation and human epidermal growth factor receptor 2 overexpression and/or gene amplification have been demonstrated in the HG component in a few examples, the frequency varies for each histologic type. Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection. HGT of salivary gland carcinoma can occur either at initial presentation or less commonly at the time of recurrence, sometimes following postoperative radiotherapy. The potential for HGT in almost any type of salivary gland carcinoma warrants a thorough sampling of all salivary gland malignancies to prevent oversight of a HG component.
- MeSH
- dediferenciace buněk fyziologie MeSH
- karcinom genetika patologie MeSH
- lidé MeSH
- nádorová transformace buněk genetika patologie MeSH
- nádorové biomarkery genetika MeSH
- nádory slinných žláz genetika patologie MeSH
- receptor erbB-2 genetika MeSH
- slinné žlázy patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Sarkomatoidní podtyp karcinomu ledviny se vyskytuje vzácně. Je charakteristický velmi špatnou prognózou a nízkou odpovědí na terapii tyrosinkinázovými inhibitory. Novým standardem léčby se stávají check-point inhibitory (inhibitory kontrolních bodů) v kombinaci ipilimumab + nivolumab. Tato kazuistika představuje pacienta se světlobuněčným karcinomem ledviny se sarkomatoidní dediferenciací, který byl již vstupně generalizovaný a se špatnou prognózou. Pacient byl léčen kombinací ipilimumab + nivolumab s dobrou klinickou odezvou, radiologickou odezvou v podobě stabilizace nemoci a přežitím více než 2 roky.
Sarcomatoid renal cell carcinoma occurs rarely. It is characterized by a very poor prognosis and a low response to treatment with tyrosine kinase inhibitors. Combination of the checkpoint inhibitors ipilimumab and nivolumab is becoming a new standard of treatment. The case report presents a patient with clear-cell renal cell carcinoma with sarcomatoid dedifferentiation that was already generalized at presentation and had a poor prognosis. The patient was treated with the combination of ipilimumab and nivolumab, resulting in a good clinical response, a radiological response in the form of disease stabilization, and a survival of more than two years.
- MeSH
- imunoterapie metody MeSH
- inhibitory kontrolních bodů farmakologie terapeutické užití MeSH
- karcinom z renálních buněk * farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory ledvin * farmakoterapie MeSH
- nádory plic farmakoterapie sekundární MeSH
- nivolumab farmakologie terapeutické užití MeSH
- protokoly protinádorové léčby MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73β-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73β caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73β had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73β upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73β may promote malignant dedifferentiation of HCC cells.
- Publikační typ
- časopisecké články MeSH
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of renal neoplasm predominantly affecting younger individuals. It is characterized by germline mutations in SDHx genes, particularly type B. Histologically, SDH-deficient RCC features eosinophilic cytoplasmic cells forming solid nests or microcysts, sometimes entrapping normal tubules. We present three SDH-deficient RCC cases with overlapping morphological features with fumarate hydratase-deficient RCC and TFEB-rearranged RCC, an appearance that has not been previously described. All tumors lacked SDHB expression and harbored pathogenic SDHB mutations, with the germline nature confirmed in two cases. Metastasis developed in two patients. Our case set highlights the diagnostic challenges of molecularly defined renal tumors and expands the morphological spectrum of SDH-deficient RCC with unusual histological features. Clinically, these tumors appear to be aggressive.
- MeSH
- dediferenciace buněk MeSH
- dospělí MeSH
- fumarasa nedostatek genetika MeSH
- karcinom z renálních buněk * genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery genetika analýza MeSH
- nádory ledvin * patologie genetika MeSH
- sukcinátdehydrogenasa * nedostatek genetika MeSH
- transkripční faktory BHLH-Zip genetika MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.
- MeSH
- dediferenciace buněk MeSH
- DNA-helikasy analýza metabolismus MeSH
- dospělí MeSH
- fenotyp MeSH
- imunohistochemie MeSH
- jaderné proteiny analýza metabolismus MeSH
- karcinom z renálních buněk patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory ledvin patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transkripční faktory analýza metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
