PMCID string | Title string | Sentences string |
|---|---|---|
PMC12852540 | Choosing the right animal model for sarcoma research | The accompanying illustration depicts the creation of a humanised patient-derived xenograft (PDX) model to sarcoma research. |
PMC12852540 | Choosing the right animal model for sarcoma research | The illustration depicts the methodology employed for the engraftment of human immune cells into an immunodeficient mouse, followed by the implantation of sarcoma tissue derived from a patient. |
PMC12852540 | Choosing the right animal model for sarcoma research | Researchers are exploring embryonic systems like the chorioallantoic membrane (CAM) and zebrafish embryos as alternatives to mouse PDX models (Fig. 2) . |
PMC12852540 | Choosing the right animal model for sarcoma research | These systems offer a faster and more affordable approach for tumor and patient-derived cells engraftment. |
PMC12852540 | Choosing the right animal model for sarcoma research | These models are largely used to study invasion, early metastatic behaviour and angiogenesis, and to perform short-term drug screening in a time- and resource-efficient manner that complements slower mammalian models . |
PMC12852540 | Choosing the right animal model for sarcoma research | Also, the transposition of the EU Directive 2010/63/EU on protecting animals used for scientific purposes under national laws has resulted in strict regulation, reflecting the growing ethical concerns around the use of adult animal experimentation . |
PMC12852540 | Choosing the right animal model for sarcoma research | As a result, researchers are focusing on non-mammalian embryonic models, including zebrafish larvae and chick embryos . |
PMC12852540 | Choosing the right animal model for sarcoma research | Embryonic models are subject to less stringent regulation until they can feed independently (chick embryo: hatching; zebrafish: 5 days post-fertilisation) and, crucially, until they develop the capacity to experience pain (chick embryo: >13 egg development day; zebrafish: 5 days post-fertilisation) . |
PMC12852540 | Choosing the right animal model for sarcoma research | Mice are kept in environments that meet animal welfare standards, but these conditions do not accurately reflect their natural habitats. |
PMC12852540 | Choosing the right animal model for sarcoma research | In contrast, embryonic systems are not exposed to environmental stressors. |
PMC12852540 | Choosing the right animal model for sarcoma research | Embryonic systems offer improved manageability, eliminating the need for animal facilities, while providing increased throughput and reduced costs [135–137].Fig. |
PMC12852540 | Choosing the right animal model for sarcoma research | 2Steps to Develop a Zebrafish Model for Sarcoma Steps to Develop a Zebrafish Model for Sarcoma CAM (chorionic allantoic membrane) assays are increasingly being used in sarcoma research, particularly for rapid angiogenesis readouts, short-window xenograft growth and pilot drug response testing. |
PMC12852540 | Choosing the right animal model for sarcoma research | However, they remain supplementary to murine PDX/CDX/zebrafish pipelines rather than being the dominant preclinical standard, and therefore we only discuss their use briefly. |
PMC12852540 | Choosing the right animal model for sarcoma research | There are protocol papers and examples for fresh sarcoma tissue and cell-line grafts, including osteosarcoma and Ewing sarcoma, with extensions to rarer entities such as CIC-DUX4 and fibrosarcoma [138–142]. |
PMC12852540 | Choosing the right animal model for sarcoma research | Contemporary reviews characterise CAM as a low-cost and rapid procedure that is well-suited to the study of vascular and invasion biology. |
PMC12852540 | Choosing the right animal model for sarcoma research | However, these reviews also underscore the limitations that hinder its complete replacement of mouse models. |
PMC12852540 | Choosing the right animal model for sarcoma research | These limitations encompass a brief observation window, the presence of non-mammalian stroma, and an immature immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | Collectively, these factors elucidate its niche and complementary utilisation in sarcoma programmes . |
PMC12852540 | Choosing the right animal model for sarcoma research | In practice, the majority of translational sarcoma groups continue to anchor efficacy packages in murine PDX/CDX for durability, PK/PD, and immuno-oncology, using CAM selectively for early ranking or mechanism-specific assays . |
PMC12852540 | Choosing the right animal model for sarcoma research | Zebrafish (Danio rerio) have emerged as an alternative to traditional mammalian models due to their rapid developmental cycles, optical transparency and low cost of maintenance (Table 3). |
PMC12852540 | Choosing the right animal model for sarcoma research | Their use is more frequent in sarcoma studies than CAM. |
PMC12852540 | Choosing the right animal model for sarcoma research | These characteristics allow researchers to study sarcoma initiation and progression in vivo, providing real-time insights into cellular dynamics. |
PMC12852540 | Choosing the right animal model for sarcoma research | Disease modelling in zebrafish is adaptable and can be carried out using a variety of methods, including the generation of gene-targeted mutations and stable transgenes, as well as the generation of fish with transient overexpression or downregulation of specific genes. |
PMC12852540 | Choosing the right animal model for sarcoma research | Initial forward genetic screens in zebrafish have shown that common mutagens, including ethylnitrosourea (ENU) and N-methylnitrosoguanidine (MNNG), induce a variety of neoplasms, including adenomas and rhabdomyosarcomas (RMS) . |
PMC12852540 | Choosing the right animal model for sarcoma research | One of the first zebrafish cancer models identified by an ENU screen was the fish with a tumour suppressor gene tp53 (tp53M214K) mutation. |
PMC12852540 | Choosing the right animal model for sarcoma research | TP53 is the most commonly mutated tumour suppressor gene in human malignancies. |
PMC12852540 | Choosing the right animal model for sarcoma research | Mutant tp53-/- animals develop malignant peripheral nerve sheath tumours (PNST), which are classified as a subtype of sarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | PNST were rarely observed in wild-type (WT) fish. |
PMC12852540 | Choosing the right animal model for sarcoma research | The zebrafish phenotype partially mirrors the conditions seen in TP53-inactivated human patients. |
PMC12852540 | Choosing the right animal model for sarcoma research | They develop a variety of cancers in addition to sarcomas, including breast cancer, brain tumours and leukaemia . |
PMC12852540 | Choosing the right animal model for sarcoma research | A recent description describes a novel zebrafish model with a tp53del/del loss-of-function deletion allele developed in the CG1 syngeneic zebrafish strain. |
PMC12852540 | Choosing the right animal model for sarcoma research | These zebrafish exhibit a range of tumour types in addition to PNST, including leukaemia and germ cell tumours, paralleling conditions observed in human patients . |
PMC12852540 | Choosing the right animal model for sarcoma research | For instance, in rhabdomyosarcoma and liposarcoma can be induced in transgenic zebrafish by targeting the Ras-Raf-MEK-ERK and PI(3)K-Akt pathways, respectively, whereas hemangiosarcoma in zebrafish is associated with pten haploinsufficiency . |
PMC12852540 | Choosing the right animal model for sarcoma research | TP53 mutant zebrafish spontaneously develop PNST after around 8.5 months, which establishes Schwann-lineage sarcomagenesis in vivo Furthermore, engineered lines recapitulate driver-defined sarcomas. |
PMC12852540 | Choosing the right animal model for sarcoma research | RAS pathway activation is sufficient to induce embryonal rhabdomyosarcoma (RMS) in 49 out of 105 fish by 80 days post-fertilisation (dpf) Pten haploinsufficiency predisposes to haemangiosarcoma , and mosaic or Cre-inducible expression of EWSR1-FLI1 initiates Ewing sarcoma (ES)-like tumours with canonical markers, including CD99 . |
PMC12852540 | Choosing the right animal model for sarcoma research | The optical transparency of zebrafish embryos allows unparalleled visualisation of processes such as angiogenesis and metastasis . |
PMC12852540 | Choosing the right animal model for sarcoma research | In sarcoma studies, zebrafish models have been used to understand how tumours recruit blood vessels to support their growth and how cancer cells spread from primary tumours to distant sites. |
PMC12852540 | Choosing the right animal model for sarcoma research | Fluorescent imaging techniques allow cancer cells and their interactions with the tumour microenvironment to be tracked in real-time. |
PMC12852540 | Choosing the right animal model for sarcoma research | One of the studies using zebrafish to study metastasis in primary bone tumour including sarcomas obtained from surgical resections and prepared for implantation . |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour fragments were excised, cut into small pieces (~ 1/5 to 1/2 the size of zebrafish yolk) and stained with fluorescent dyes such as CM-DIL for visualisation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Zebrafish embryos at two days post-fertilisation (dpf) were dechorionated and anaesthetised with tricaine to facilitate manipulation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Transgenic zebrafish lines such as Tg(fli1:eGFP) with fluorescent vasculature were used to improve imaging of tumour interactions with blood vessels. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumor fragments or dissociated cells were injected via fine needles into the yolk sac or zebrafish embryos liver. |
PMC12852540 | Choosing the right animal model for sarcoma research | The yolk sac serves as a nutrient-rich site to support tumour growth, while liver implantation provides an organotypic environment to assess metastasis. |
PMC12852540 | Choosing the right animal model for sarcoma research | Confocal laser scanning microscopy was used to live track tumour cell invasion, migration and micrometastasis formation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour behaviour, including intravasation into blood vessels, circulation and colonisation of distant sites, was observed as early as 24 h post-transplantation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour cells infiltrated zebrafish tissues within hours of transplantation, indicating a high metastatic potential. |
PMC12852540 | Choosing the right animal model for sarcoma research | The cells also spread through the vasculature and colonised distant tissues such as the liver, intestine and caudal fin. |
PMC12852540 | Choosing the right animal model for sarcoma research | These behaviours mimicked metastatic patterns observed in human cancers, including sarcomas. |
PMC12852540 | Choosing the right animal model for sarcoma research | The implanted tumour cells exhibited migration and invasion distinct from non-malignant control tissues, which remained confined to the injection site. |
PMC12852540 | Choosing the right animal model for sarcoma research | The metastatic behaviour was critically dependent on the zebrafish vasculature. |
PMC12852540 | Choosing the right animal model for sarcoma research | In cloche mutant zebrafish lacking functional blood vessels, metastatic spread was significantly impaired, confirming that intravasation and vascular dissemination are essential for metastasis. |
PMC12852540 | Choosing the right animal model for sarcoma research | Also, Vasileva et al. . |
PMC12852540 | Choosing the right animal model for sarcoma research | developed an innovative zebrafish model of Ewing sarcoma (ES) to address critical gaps in understanding the role of the tumour microenvironment in ES initiation and progression. |
PMC12852540 | Choosing the right animal model for sarcoma research | ES is a highly aggressive bone and soft tissue tumour driven by the fusion oncogene EWSR1-FLI1 (EF1), a key driver of tumourigenesis. |
PMC12852540 | Choosing the right animal model for sarcoma research | The researchers created a Cre-inducible zebrafish model that allowed mosaic expression of the human EF1 fusion oncogene in a subset of zebrafish cells. |
PMC12852540 | Choosing the right animal model for sarcoma research | This broad mosaic expression resulted in the rapid onset of ES with high penetrance, closely mimicking the aggressive behaviour of human ES. |
PMC12852540 | Choosing the right animal model for sarcoma research | The model incorporated GFP-tagged cancer cells, allowing real-time imaging of tumour initiation and progression in the living organism. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumours generated in the zebrafish expressed canonical EF1 target genes and known ES markers such as CD99, validating the relevance of the model. |
PMC12852540 | Choosing the right animal model for sarcoma research | The ability of the zebrafish model to faithfully reproduce these molecular features confirmed its utility in studying ES biology. |
PMC12852540 | Choosing the right animal model for sarcoma research | Using live imaging, the researchers tracked the invasive behaviour of GFP-tagged cancer cells and analysed their interactions with the surrounding microenvironment during tumour initiation and progression. |
PMC12852540 | Choosing the right animal model for sarcoma research | Proteomic analysis revealed that EF1 expression dysregulates heparan sulphate proteoglycan (HSPG) metabolism and activates HSPG-mediated ERK signalling, pathways that promote cancer cell survival and proliferation. |
PMC12852540 | Choosing the right animal model for sarcoma research | The study also showed that the specific heparan sulphate antagonist Surfen effectively reduced ERK1/2 signalling and impaired the tumourigenicity of ES cells both in vitro and in vivo in the zebrafish model. |
PMC12852540 | Choosing the right animal model for sarcoma research | This Cre-inducible system overcame the limitations of low tumour initiation rates commonly seen in mammalian models by ensuring efficient and rapid tumour formation. |
PMC12852540 | Choosing the right animal model for sarcoma research | GFP labelling allowed direct visualisation of cancer cell behaviour, including invasion, proliferation and interactions with the extracellular matrix, in real time. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the zebrafish model allowed ES to be studied in a complex developmental and microenvironmental context, providing insights that are difficult to achieve in traditional mouse models. |
PMC12852540 | Choosing the right animal model for sarcoma research | The main advantage of zebrafish models in sarcoma research is their unique combination of cost effectiveness, rapid generation times and transparency, making them an exceptional tool for studying tumour development, angiogenesis and metastasis in real time. |
PMC12852540 | Choosing the right animal model for sarcoma research | The model’s pipeline is renowned for its short cycle times. |
PMC12852540 | Choosing the right animal model for sarcoma research | Injection at two days post-fertilisation yields invasion, dissemination and early treatment response readouts within 48–72 h post-engraftment. |
PMC12852540 | Choosing the right animal model for sarcoma research | This is enabled by the absence of a mature adaptive immune system until around 14 days post-fertilisation Across multiple series, concordance between drug sensitivity and dissemination and clinical behaviour has been demonstrated within a 3–5 day assay window, including patient-derived samples. |
PMC12852540 | Choosing the right animal model for sarcoma research | This supports the rapid execution of experiments that enable informed decision-making . |
PMC12852540 | Choosing the right animal model for sarcoma research | Practically, this compresses the end-to-end timeline for zebrafish xenografts to ≤ 1 week from sample preparation to the first pharmacodynamic readout under standard conditions . |
PMC12852540 | Choosing the right animal model for sarcoma research | The model’s pipeline is renowned for its short cycle times. |
PMC12852540 | Choosing the right animal model for sarcoma research | Injection at two days post-fertilisation yields invasion, dissemination and early treatment response readouts within 48–72 h post-engraftment. |
PMC12852540 | Choosing the right animal model for sarcoma research | This is enabled by the absence of a mature adaptive immune system until around 14 days post-fertilisation . |
PMC12852540 | Choosing the right animal model for sarcoma research | Across multiple series, concordance between drug sensitivity and dissemination and clinical behaviour has been demonstrated within a 3–5 day assay window, including patient-derived samples. |
PMC12852540 | Choosing the right animal model for sarcoma research | This supports the rapid execution of experiments that enable informed decision-making . |
PMC12852540 | Choosing the right animal model for sarcoma research | Practically, this compresses the end-to-end timeline for zebrafish xenografts to ≤ 1 week from sample preparation to the first pharmacodynamic readout under standard conditions . |
PMC12852540 | Choosing the right animal model for sarcoma research | Optical transparency of this model allows sarcoma cell behaviour visualisation, such as metastasis and dissemination, at high resolution without invasive procedures. |
PMC12852540 | Choosing the right animal model for sarcoma research | This is particularly useful for studying metastatic sarcomas such as osteosarcoma, which often spread to the lungs and other tissues. |
PMC12852540 | Choosing the right animal model for sarcoma research | Using fluorescently labelled tumour cells, zebrafish models allow direct observation of cellular dynamics, including interactions with the tumour microenvironment (TME) and blood vessels. |
PMC12852540 | Choosing the right animal model for sarcoma research | Zebrafish models are excellent at recapitulating key aspects of the TME, such as vascular development and immune interactions, which are critical for sarcoma progression. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, studies of soft tissue sarcomas have shown how tumour cells exploit angiogenesis to sustain growth and facilitate metastasis. |
PMC12852540 | Choosing the right animal model for sarcoma research | The conserved vascular architecture between zebrafish and humans allows researchers to study the effects of anti-angiogenic therapies, such as VEGF inhibitors like bevacizumab, in a physiologically relevant context . |
PMC12852540 | Choosing the right animal model for sarcoma research | The rapid development of zebrafish embryos also allows high-throughput screening of drug candidates, enabling the identification of novel therapies for sarcomas with limited treatment options, such as synovial sarcoma or alveolar rhabdomyosarcoma . |
PMC12852540 | Choosing the right animal model for sarcoma research | Another major advantage of the zebrafish model is that it is easily amenable to genetic manipulation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Techniques such as CRISPR-Cas9 genome editing or morpholino oligonucleotide knockdowns can be used to rapidly generate zebrafish with genetic alterations that mimic human sarcoma drivers, such as TP53 mutations or fusion oncogenes such as EWS-FLI1 . |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, zebrafish models of Ewing sarcoma have been generated by expressing the EWS-FLI1 fusion gene in mesenchymal progenitor cells, resulting in tumours with histological and molecular features similar to the human disease. |
PMC12852540 | Choosing the right animal model for sarcoma research | These models are invaluable for understanding how specific genetic alterations contribute to sarcomagenesis and for testing targeted therapies that target these genetic drivers. |
PMC12852540 | Choosing the right animal model for sarcoma research | Zebrafish also provide an efficient platform for studying sarcoma metastasis. |
PMC12852540 | Choosing the right animal model for sarcoma research | By injecting sarcoma cells into the bloodstream of zebrafish embryos, researchers can follow metastatic spread to secondary sites, such as the caudal fin or liver, in real time. |
PMC12852540 | Choosing the right animal model for sarcoma research | This ability has been particularly useful for investigating the mechanisms underlying lung metastasis of osteosarcoma, a major cause of patient mortality. |
PMC12852540 | Choosing the right animal model for sarcoma research | Zebrafish models have revealed how osteosarcoma cells interact with endothelial cells and the extracellular matrix to establish metastatic niches, providing insights into potential therapeutic targets to prevent metastasis . |
PMC12852540 | Choosing the right animal model for sarcoma research | The cost-effectiveness and scalability of zebrafish models further enhance their utility in sarcoma research. |
PMC12852540 | Choosing the right animal model for sarcoma research | Zebrafish are inexpensive to maintain compared to mouse models, and their high fecundity allows researchers to generate large cohorts for experiments in a short period of time. |
PMC12852540 | Choosing the right animal model for sarcoma research | This scalability makes zebrafish ideal for high-throughput drug screening, allowing thousands of compounds to be screened for anti-tumour activity. |
PMC12852540 | Choosing the right animal model for sarcoma research | Finally, zebrafish models provide valuable insights into sarcoma-immune interactions. |
PMC12852540 | Choosing the right animal model for sarcoma research | Although zebrafish lack an adaptive immune system during early stages of development, their innate immune system is functional and shares similarities with humans. |
PMC12852540 | Choosing the right animal model for sarcoma research | This makes them a useful model for studying innate immune responses to sarcoma, such as the recruitment of macrophages or neutrophils to the tumour site. |
PMC12852540 | Choosing the right animal model for sarcoma research | Recent advances in humanised zebrafish models, in which human immune cells are introduced, have further extended their applicability to immunotherapy studies, including the evaluation of immune checkpoint inhibitors or CAR-T cell therapies. |
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