PMCID string | Title string | Sentences string |
|---|---|---|
PMC12852540 | Choosing the right animal model for sarcoma research | Accurate animal models must reflect not only the molecular characteristics of these tumours, but also their microenvironment and dynamic interaction with the host immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | The diversity of this group of cancers presents different challenges for animal model selection, particularly as sarcoma-specific resources are very limited. |
PMC12852540 | Choosing the right animal model for sarcoma research | Therefore, we have reviewed in detail several types of models, including: syngeneic (e.g., MCA205 and KRIMS series), chemically induced (e.g., MCA, DMBA), cell-derived xenografts (CDX; e.g., KCS8 and KCS9 osteosarcoma lines), patient-derived xenograft (PDX; e.g., pleomorphic leiomyosarcoma and GIST models), including humanised PDX (huPDX; e.g. HuNOG-EXL), and zebrafish (e.g. tp53M214K PNST and EWS-FLI1 transgenics) - to illustrate their sarcoma-specific use cases and discuss their advantages and limitations. |
PMC12852540 | Choosing the right animal model for sarcoma research | Genetically engineered models and their development are not a subject of this review, as they represent a very broad subject independently and are discussed elsewhere. |
PMC12852540 | Choosing the right animal model for sarcoma research | Some sarcomas are driven by simple translocations (e.g. EWS-FLI1 in Ewing’s Sarcoma), others by complex karyotypic instability or recurrent mutations, with corresponding differences translate into variable biology - including immune-microenvironment profiles - across subtypes . |
PMC12852540 | Choosing the right animal model for sarcoma research | Clinically, this heterogeneity is reflected in generally poor outcomes: The 5-year overall survival (OS) for Soft Tissue Sarcomas (STS) is 90% for stage I, 81% for stage II, and 56% for stage III , with the influence of multiple factors beyond TNM stage, including surgical margins, age, anatomic location, and histological factors, especially grade and subtype . |
PMC12852540 | Choosing the right animal model for sarcoma research | Studies have shown that median OS after first documentation of metastatic disease is approximately 24 months, with 1-, 2- and 5-year OS rates of 70%, 49.9% and 24.8%, respectively . |
PMC12852540 | Choosing the right animal model for sarcoma research | Therefore, there is the urgent need for further therapies development. |
PMC12852540 | Choosing the right animal model for sarcoma research | Adequately-chosen models improve the fidelity of preclinical testing, allowing scientists to distinguish between drugs that are truly promising and those that are unlikely to succeed in the clinic. |
PMC12852540 | Choosing the right animal model for sarcoma research | Better animal models streamline the drug development pipeline, preventing costly failures and accelerating the introduction of effective therapies to patients in need. |
PMC12852540 | Choosing the right animal model for sarcoma research | Preclinical sarcoma research encompasses 2D monolayers, 3D spheroids, organoids, and organotypic tissue slices [6–8]. |
PMC12852540 | Choosing the right animal model for sarcoma research | While these platforms enable mechanistic interrogation and medium-to-high-throughput screening, they lack perfused vasculature, intact stroma and an adaptive immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | This limits analyses of exposure-response, metastatic tropism and host-tumour crosstalk [9–11]. |
PMC12852540 | Choosing the right animal model for sarcoma research | Animal models restore the pharmacokinetics, vascular transport and myeloid-lymphoid interactions of the whole organism that are required for metastasis, drug delivery and immunotherapy read-outs . |
PMC12852540 | Choosing the right animal model for sarcoma research | Humanised mouse systems incorporate human-specific immune effectors and have longer timelines, higher costs and constraints relating to xenogeneic graft-versus-host disease (xGvHD) . |
PMC12852540 | Choosing the right animal model for sarcoma research | Rapid non-mammalian assays, such as zebrafish xenografts and chick CAM, can triage angiogenesis, invasion and short-course drug responses within days. |
PMC12852540 | Choosing the right animal model for sarcoma research | This reduces the use of mammals, but the results must be confirmed in mammalian models [15–17]. |
PMC12852540 | Choosing the right animal model for sarcoma research | In line with the 3Rs and EU Directive 2010/63/EU, we cite non-animal methods where they credibly replace or reduce the need for animal studies, while reserving the use of mammalian models for questions that demand an intact organism. |
PMC12852540 | Choosing the right animal model for sarcoma research | The diversity of different models makes translational research in sarcoma particularly challenging. |
PMC12852540 | Choosing the right animal model for sarcoma research | Because each subtype is rare and biologically distinct, patients are underrepresented in clinical trials and subtype-specific data are scarce. |
PMC12852540 | Choosing the right animal model for sarcoma research | Similarly, approved treatments show highly variable responses between subtypes . |
PMC12852540 | Choosing the right animal model for sarcoma research | These factors - and the historically poor correlation between preclinical models and clinical outcomes - mean that many promising sarcoma therapies have stalled or failed in translation. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, the PDGFRα antibody olaratumab showed activity in cell line xenograft models and an initial phase II trial , but failed to improve survival in a definitive phase III STS trial . |
PMC12852540 | Choosing the right animal model for sarcoma research | This and similar discrepancies highlight how model selection can make or break translational success in sarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Syngeneic tumour models are among the oldest and most widely used preclinical models for testing anticancer therapies. |
PMC12852540 | Choosing the right animal model for sarcoma research | Syngeneic models involve transplanting tumour cells into immunocompetent mice of the same genetic background, enabling the study of tumour behaviour within a fully functional immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | Some of the earliest cancer models in mice were created using cell lines derived from tumours that developed spontaneously in inbred mouse strains . |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumor cells are derived from the same mouse strain as the host, ensuring consistent tumor engraftment and growth without rejection, enhancing experimental reliability. |
PMC12852540 | Choosing the right animal model for sarcoma research | The driver mutations in these tumours usually do not match those found in human cancers of the same type. |
PMC12852540 | Choosing the right animal model for sarcoma research | While some spontaneous tumour-derived models show immune responses, these responses are generally weak or only partially induced. |
PMC12852540 | Choosing the right animal model for sarcoma research | Additionally, the models vary significantly from one another, making it challenging to determine which secondary models are most suitable for validating results . |
PMC12852540 | Choosing the right animal model for sarcoma research | This model is particularly relevant for understanding the interactions between tumours and the immune microenvironment, which are vital for the development and progression of sarcoma . |
PMC12852540 | Choosing the right animal model for sarcoma research | By using inbred mouse strains like C57BL/6, BALB/c, and FVB, researchers can develop tumour cell lines from spontaneous, carcinogen-induced, or transgenic sources, expand them in vitro, and then introduce them into similar wild-type mice to create a tumour-bearing system . |
PMC12852540 | Choosing the right animal model for sarcoma research | For instance, Nafia et al. used a syngeneic mouse model of sarcoma, specifically the MCA205 fibrosarcoma cell line, to study the immune response to anti-PDL1 immunotherapy. |
PMC12852540 | Choosing the right animal model for sarcoma research | MCA205 is a methylcholanthrene-induced fibrosarcoma derived on the C57BL/6 background - a canonical syngeneic model used for immuno-oncology studies. |
PMC12852540 | Choosing the right animal model for sarcoma research | As previously stated, in syngeneic models, tumour cells are derived from the same species and genetic background as the host, allowing for a fully functional immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | This makes them particularly valuable for immuno-oncology research as they more accurately reflect immune responses than models lacking immune components. |
PMC12852540 | Choosing the right animal model for sarcoma research | The MCA205 model allows researchers to study how immune checkpoint inhibitors, such as anti-PDL1, affect tumour growth in an immunocompetent environment. |
PMC12852540 | Choosing the right animal model for sarcoma research | This model is useful because it reflects specific tumour-immune interactions seen in sarcomas, including immune-related metabolic features. |
PMC12852540 | Choosing the right animal model for sarcoma research | Within the MCA205 tumour, the researchers observed distinct metabolic features such as kynurenine pathway activation, arginase activity and adenosine production - factors that contribute to the immunosuppressive tumour microenvironment and may influence response to therapies. |
PMC12852540 | Choosing the right animal model for sarcoma research | The model was further analysed using advanced techniques such as intratumoral microdialysis to assess pathways and flow cytometry and immunohistofluorescence to map immune cell populations within the tumour. |
PMC12852540 | Choosing the right animal model for sarcoma research | This allowed detailed profiling of immune dynamics, revealing increased CD8 + T cells and shifts in macrophage populations following treatment, highlighting the utility of this syngeneic sarcoma model for dissecting specific immune mechanisms. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the model confirmed that CD8 + T cells are essential for the anti-PDL1 response, as their depletion abolished the efficacy of the treatment. |
PMC12852540 | Choosing the right animal model for sarcoma research | Unlike xenograft models that use immunodeficient mice, syngeneic models maintain a functional immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | Therefore, it was used in a separate osteosarcoma syngeneic model to evaluate the combination of trabectedin and oncolytic herpes simplex virus (oHSV) therapy . |
PMC12852540 | Choosing the right animal model for sarcoma research | Osteosarcoma cells were subcutaneously or orthotopically implanted into syngeneic mice to generate tumors. |
PMC12852540 | Choosing the right animal model for sarcoma research | The site of implantation was chosen to replicate key features of osteosarcoma growth and to allow for effective monitoring of tumor size. |
PMC12852540 | Choosing the right animal model for sarcoma research | Trabectedin was administered systemically at doses optimized for murine models to evaluate its ability to modulate the tumor microenvironment and reduce immunosuppressive cells. |
PMC12852540 | Choosing the right animal model for sarcoma research | oHSV was delivered intratumorally to target and lyse tumor cells directly while promoting an immune response against tumor. |
PMC12852540 | Choosing the right animal model for sarcoma research | Trabectedin significantly reduced the number of immunosuppressive Tregs and TAMs in the tumour microenvironment. |
PMC12852540 | Choosing the right animal model for sarcoma research | This effect was enhanced by oHSV, which promoted immune recognition of tumour cells. |
PMC12852540 | Choosing the right animal model for sarcoma research | Increased infiltration of NK cells and CD8 + T cells was observed, indicating a shift towards a more immune-activating tumour microenvironment. |
PMC12852540 | Choosing the right animal model for sarcoma research | While trabectedin alone demonstrated moderate anti-tumour activity, its combination with oHSV resulted in enhanced tumour regression and prolonged survival in the syngeneic mice. |
PMC12852540 | Choosing the right animal model for sarcoma research | This synergy was attributed to the dual mechanisms of immune modulation by trabectedin and the oHSV-induced immune response. |
PMC12852540 | Choosing the right animal model for sarcoma research | As a murine model, it lacked the full genetic diversity and heterogeneity of human osteosarcomas, which may affect the applicability of the results to clinical settings. |
PMC12852540 | Choosing the right animal model for sarcoma research | This limitation was illustrated by Guttierrez et al. . |
PMC12852540 | Choosing the right animal model for sarcoma research | investigated syngeneic mouse models specifically derived from the K-Ras Induced Murine Sarcoma (KRIMS) series, which are derived from primary genetically engineered mouse models (GEMMs) designed to study undifferentiated pleomorphic sarcoma (UPS) and rhabdomyosarcoma (RMS). |
PMC12852540 | Choosing the right animal model for sarcoma research | The KRIMS series was developed by harvesting tumour cells from GEMM-derived sarcomas with Kras activation and p53 loss, and then transplanting these cells into immunocompetent syngeneic mice. |
PMC12852540 | Choosing the right animal model for sarcoma research | The syngeneic KRIMS models showed a different distribution of CD8 + T cells and Treg (regulatory T cells) compared to primary GEMM tumours. |
PMC12852540 | Choosing the right animal model for sarcoma research | Specifically, KRIMS tumours contained a higher proportion of CD8 + T cells, which are key players in the antitumor immune response, but with an altered activation state. |
PMC12852540 | Choosing the right animal model for sarcoma research | This difference in T-cell profiles may indicate an enhanced immune response in KRIMS models, which could influence the outcome of immunotherapy trials. |
PMC12852540 | Choosing the right animal model for sarcoma research | This model-specific immune variation highlights the complex interactions within the tumour microenvironment and demonstrates that while syngeneic models reflect certain features of the primary tumour, they also have unique immune profiles. |
PMC12852540 | Choosing the right animal model for sarcoma research | Unlike primary GEMMs, which can take months to develop spontaneous tumours, the KRIMS syngeneic models allow for rapid and consistent tumour formation upon injection, making them more time-efficient and accessible for high-throughput experiments. |
PMC12852540 | Choosing the right animal model for sarcoma research | The syngeneic model enables repeated, reliable tumour formation under standardised conditions, reducing the variability often seen with spontaneous GEMM tumour models and lowering the cost per experiment . |
PMC12852540 | Choosing the right animal model for sarcoma research | This reproducibility is particularly useful in preclinical studies where consistent tumour characteristics are critical. |
PMC12852540 | Choosing the right animal model for sarcoma research | The main advantage of this model is that it allows tumours to be studied in a fully functional, immunocompetent host. |
PMC12852540 | Choosing the right animal model for sarcoma research | Because the tumor cells and the host animal share the same genetic background, the immune response to the tumor remains intact, closely resembling the complex interplay between cancer cells and the immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | This facilitates the evaluation of immunotherapies, tumour-infiltrating immune cells and immune-mediated resistance mechanisms, providing valuable insights that are often not possible in immunodeficient or artificially humanised systems. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, syngeneic models are relatively inexpensive, easy to establish and amenable to genetic manipulation, allowing for straightforward and reproducible experiments. |
PMC12852540 | Choosing the right animal model for sarcoma research | The main limitation of this model is its low translational relevance to human cancers. |
PMC12852540 | Choosing the right animal model for sarcoma research | Mouse tumours and their immune environment, including their stromal and vascular structures, often differ significantly from their human counterparts. |
PMC12852540 | Choosing the right animal model for sarcoma research | This can lead to discrepancies in how therapies, particularly immunomodulatory treatments, perform in the model compared with the clinic. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the genetic homogeneity, rapid tumor growth and sometimes less complex microenvironment found in syngeneic models may not accurately reflect the heterogeneity, slow progression and treatment-resistant nature of many human cancers. |
PMC12852540 | Choosing the right animal model for sarcoma research | While genetically engineered mouse (GEM) models are excellent at recapitulating specific genetic drivers of tumorigenesis and providing precise, reproducible insights into cancer biology, they often lack the genetic diversity and mutational complexity found in human cancers. |
PMC12852540 | Choosing the right animal model for sarcoma research | This limitation makes them less suitable for studying cancers with high mutational burden or exploring novel, unpredictable oncogenic pathways. |
PMC12852540 | Choosing the right animal model for sarcoma research | To address these gaps, chemically induced models offer an alternative approach, relying on random mutagenesis to generate tumours with significant heterogeneity that better reflect the complexity of human malignancies . |
PMC12852540 | Choosing the right animal model for sarcoma research | Chemically induced models involve administering carcinogenic compounds, such as MCA and 7,12-dimethylbenz[a]anthracene (DMBA), to induce tumour formation in laboratory animals . |
PMC12852540 | Choosing the right animal model for sarcoma research | This approach mimics the environmental contributions to cancer development and allows studying tumour biology in a controlled setting . |
PMC12852540 | Choosing the right animal model for sarcoma research | DMBA primarily induces mutations by forming DNA adducts that cause specific A→T transversions at certain hotspot codons, particularly in the ras gene family. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition to genetic mutations, DMBA also induces oxidative stress and cellular damage that contribute to tumourigenesis. |
PMC12852540 | Choosing the right animal model for sarcoma research | Its effects are well suited to study the carcinogen-induced fibrosarcomas, particularly in rodent models. |
PMC12852540 | Choosing the right animal model for sarcoma research | DMBA induces fibrosarcomas through its ability to form DNA adducts, leading to mutations in key oncogenes such as the ras gene family. |
PMC12852540 | Choosing the right animal model for sarcoma research | The researchers aimed to analyse the relationship between DMBA-induced chromosomal abnormalities, in particular gains in rat chromosome 2 (RNO2), and mutations in the Hras, Kras and Nras oncogenes . |
PMC12852540 | Choosing the right animal model for sarcoma research | Rats of the BN/Han and LE/Mol strains were used and crossed to produce genetically uniform F1 progeny. |
PMC12852540 | Choosing the right animal model for sarcoma research | DMBA was injected subcutaneously in two doses (1 mg or 2 mg) dissolved in tricapryline, resulting in tumour formation in 62% of the animals over a period of 220 days. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour cells were analysed by karyotyping, PCR and DNA sequencing to identify chromosomal alterations and ras gene mutations. |
PMC12852540 | Choosing the right animal model for sarcoma research | A high frequency of tetraploid cells was observed in the tumours, with notable numerical increases in RNO2 gene material. |
PMC12852540 | Choosing the right animal model for sarcoma research | RNO2 gains were consistent across sarcomas, highlighting their importance in DMBA-induced carcinogenesis. |
PMC12852540 | Choosing the right animal model for sarcoma research | Mutations were found in codon 61 of Kras (CAA→CAT) and Nras (CAA→CTA), with an amino acid substitution to histidine and leucine, respectively. |
PMC12852540 | Choosing the right animal model for sarcoma research | These mutations were present in 18% of the tumours, suggesting an important but not exclusive role in tumour initiation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite being induced in genetically uniform animals, tumours displayed diverse genetic alterations, reflecting the stochastic nature of DMBA carcinogenesis. |
PMC12852540 | Choosing the right animal model for sarcoma research | DMBA preferentially induces RAS pathway lesions and broad aneuploidy, and canonical RAS mutations are uncommon in human adult-type fibrosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | In the initial reports, tumour classification relied on histology and immunophenotype rather than molecular criteria. |
PMC12852540 | Choosing the right animal model for sarcoma research | Consequently, while the model is informative for carcinogen-driven fibroblastic sarcomagenesis, it should be considered only hypothesis-generating, rather than confirmatory, for adult fibrosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Unlike DMBA, which predominantly targets the ras gene family, MCA’s mutagenic effects are less specific, affecting multiple oncogenes and tumor suppressors . |
PMC12852540 | Choosing the right animal model for sarcoma research | MCA is used to model slowly progressing tumours and to study interactions with the immune system, including immune editing and the role of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). |
PMC12852540 | Choosing the right animal model for sarcoma research | It is valuable for studying the immune microenvironment but requires long tumour development times, making it less suitable for rapid studies. |
PMC12852540 | Choosing the right animal model for sarcoma research | MCA typically produces high-grade spindle-cell sarcomas with UPS- or fibrosarcoma-like histology, as well as polygenic mutation spectra that are shaped by immune editing. |
PMC12852540 | Choosing the right animal model for sarcoma research | While these tumours recapitulate slow carcinogenesis and immune suppression, they only partially mirror human driver architecture. |
PMC12852540 | Choosing the right animal model for sarcoma research | Consequently, they are better suited to studying tumour-immune dynamics and carcinogen responses than genotype-matched targeted therapy. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.