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UNLABELLED: Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. SIGNIFICANCE: PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.
- MeSH
- heterografty * MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- nádory patologie MeSH
- objevování léků MeSH
- preklinické hodnocení léčiv MeSH
- translační biomedicínský výzkum * metody MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE: Understanding xenograft rejection is crucial for the potential introduction of xenotransplantation into clinical practice. Small-animal models play an essential role in this context and substantially contribute to our knowledge about mechanisms of xenograft rejection. METHODS: Rat-to-mouse corneal xenografts were performed by using 2 suturing techniques. Sutures were left either as long or as short as possible to limit the extent of a nonspecific inflammatory response. Cyclosporine A (CsA), monoclonal antibody anti-T cells, and a specific inhibitor of inducible NO synthase (alone or in a combination with CsA) were tested as immunosuppressants. RESULTS: Grafts with long sutures were rejected in 7.3 +/- 1.2 days, whereas those with short sutures were rejected after 11.8 +/- 1.0 days (P < 0.001). Similarly, long sutures induced more pronounced corneal neovascularization (P < 0.001). Although groups of recipients with long sutures all tested immunosuppressants significantly (P < 0.01-0.001) prolonged corneal graft survival, none of them showed a comparable efficacy in groups of recipients with short sutures. CONCLUSIONS: This study showed that suturing technique significantly affects the outcome of corneal concordant xenograft transplantation, influences the effectiveness of immunosuppressive regimens, and therefore must be taken into account when evaluating their efficacy.
- MeSH
- antigeny Thy-1 imunologie MeSH
- cyklosporin terapeutické užití MeSH
- financování organizované MeSH
- imunosupresiva terapeutické užití MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky terapeutické užití MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- potkani inbrední LEW MeSH
- přežívání štěpu fyziologie účinky léků MeSH
- rohovka fyziologie MeSH
- šicí techniky MeSH
- synthasa oxidu dusnatého, typ II antagonisté a inhibitory MeSH
- thiaziny terapeutické užití MeSH
- transplantace heterologní MeSH
- transplantace rohovky MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
The Anterior Gradient (AGR) genes AGR2 and AGR3 are part of the Protein Disulfide Isomerase (PDI) family and harbour core thioredoxin folds (CxxS motifs) that have the potential to regulate protein folding and maturation. A number of proteomics and transcriptomics screens in the fields of limb regeneration, cancer cell metastasis, pro-oncogenic oestrogen-signalling, and p53 regulation have identified AGR2 as a novel component of these signalling pathways. Curiously, despite the fact that the AGR2 and AGR3 genes are contiguous on chromosome 7p21.1-3, the AGR3 protein has rarely been identified in such OMICs screens along with AGR2 protein. Therefore there is little information on how AGR3 protein is expressed in normal and diseased states. A panel of three monoclonal antibodies was generated towards AGR3 protein for identifying novel clinical models that can be used to define whether AGR3 protein could play a positive or negative role in human cancer development. One monoclonal antibody was AGR3-specific and bound a linear epitope that could be defined using both pep-scan and phage-peptide library screening. Using this monoclonal antibody, endogenous AGR3 protein expression was shown to be cytosolic in four human ovarian cancer subtypes; serous, endometrioid, clear cell, and mucinous. Mucinous ovarian cancers produced the highest number of AGR3 positive cells. AGR3 expression is coupled to AGR2 expression only in mucinous ovarian cancers, whereas AGR3 and AGR2 expressions are uncoupled in the other three types of ovarian cancer. AGR3 expression in ovarian cancer is independent of oestrogen-receptor expression, which is distinct from the oestrogen-receptor dependent expression of AGR3 in breast cancers. Isogenic cancer cell models were created that over-express AGR3 and these demonstrated that AGR3 mediates cisplatin-resistance in mouse xenografts. These data indicate that AGR3 is over-expressed by a hormone (oestrogen-receptor alpha)-independent mechanism and identify a novel protein-folding associated pathway that could mediate resistance to DNA-damaging agents in human cancers. Copyright 2012 Elsevier B.V. All rights reserved.
Aberrant DNA methylation that results in silencing of genes has remained a significant interest in cancer research. Despite major advances, the success of epigenetic therapy is elusive due to narrow therapeutic window. A wide variety of naturally occurring epigenetic agents and synthetic molecules that can alter methylation patterns exist, however, their usefulness in epigenetic therapy remains unknown. This underlines the need for effective tumor models for large-scale screening of drug candidates with potent hypomethylation activity. In this study, we present the development of a cell-based DNA demethylation detection system, which is amenable for high content screening of epigenetic drugs in two-dimensional and three-dimensional cell culture models. Additionally, the detection system also supports the in vivo monitoring of demethylation efficacy of potential lead compounds from in vitro screens in tumor xenografts. The described detection system not only permits the continuous monitoring of demethylation but also of the induced cytostatic/cytotoxic drug effects in live cells, as a function of time. The detection system is fluorescence based and exploits the dominant ability of DNA methylation to inhibit gene transcription, and utilizes FLJ32130 gene, which is silenced on account of promoter hypermethylation in human colorectal cancer. The described work will provide the researchers with an efficient tool for epigenetic drug screens on a high throughput platform and would therefore benefit academic and industrial drug discovery. © 2016 International Society for Advancement of Cytometry.
- MeSH
- epigeneze genetická * MeSH
- kolorektální nádory farmakoterapie genetika MeSH
- lidé MeSH
- metylace DNA účinky léků MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- promotorové oblasti (genetika) MeSH
- protinádorové látky terapeutické užití MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antigeny CD4 terapeutické užití MeSH
- antigeny CD8 terapeutické užití MeSH
- dichlormethylendifosfonát terapeutické užití MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- potkani inbrední LEW MeSH
- přežívání štěpu MeSH
- rejekce štěpu prevence a kontrola MeSH
- transplantace heterologní MeSH
- transplantace rohovky imunologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.
- MeSH
- anaplastická lymfomová kináza MeSH
- anaplastický velkobuněčný lymfom * farmakoterapie patologie MeSH
- dítě MeSH
- heterografty MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- krizotinib farmakologie terapeutické užití MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- nádory plic * farmakoterapie MeSH
- nemalobuněčný karcinom plic * MeSH
- organofosforové sloučeniny farmakologie terapeutické užití MeSH
- tyrosinkinasové receptory terapeutické užití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
