PMCID string | Title string | Sentences string |
|---|---|---|
PMC10669128 | Preclinical Models of Visceral Sarcomas | The molecular biology of sarcomas is poorly understood, especially the interplay among signaling pathways, as well as the epigenetic modifications and regulatory RNA sequences. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Patient-derived 3D sarcoma models could be useful to recapitulate the three-dimensional structure of these neoplasms, clarifying the complex crosstalk between tumor cells and their microenvironment, and contributing to personalized medicine development . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Despite most of the available three-dimensional spheroid cultures and organoids being relevant to the study of skeletal sarcomas, 3D models have also been developed for visceral sarcomas. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | In this regard, Escudero and colleagues assessed the effect of eribulin (an antitumor agent approved for advanced liposarcoma treatment) on inhibiting the proliferation, migration, and invasion of LPSs and LMSs in 3D spheroid cell cultures. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | For the first time, they explored erilubin’s action under 3D conditions in LMSs and LPSs, demonstrating an increase in the GI50 (growth inhibitory concentration by 50%) values to a nanomolar range compared to in a 2D cellular context . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Roohani and colleagues conducted a pilot study on a STS 3D model developed from patient-derived cell cultures (PD3D) of an untreated localized UPS. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | They assessed a decrease in tumor cell viability at different time points (four and eight days after treatment) using increasing doses of photon and proton radiation. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | PD3D therefore could be a valuable tool to facilitate translational studies toward individualized subtype-specific radiotherapy in STS patients . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Nonetheless, it is still unclear how three-dimensional models will allow better predictability for treatments that target the microenvironment or involve radiation. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Furthermore, the available cell lines inadequately represent sarcoma diversity, and primarily encompass the most common groups like osteosarcomas, rhabdomyosarcomas, and leiomyosarcomas while lacking representation of rarer subtypes . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Therefore, new cell lines are urgently needed in the field of sarcoma research . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Cancer stem cells (CSCs) in soft tissue sarcomas can be reprogrammed toward a pluripotent state, using similar methods to those applied to normal cells (e.g., induced pluripotent stem cell (iPSC) technology) . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Recently, iPSCs have emerged as a valuable tool for disease modeling, already applied in the field of genetic and oncological disease. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | This is due to the possibility of replicating a cancer phenotype within the appropriate cell lineage. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | By generating genome-edited isogenic iPSC lines in correspondence to the oncogenic drivers within a specific tissue, it would be possible to faithfully reproduce the neoplasm in vitro. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | This could facilitate the study of the targeted treatment susceptibility of various tumor histotypes . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | While targeting CSCs is crucial for all cancer types, in STSs, it is more challenging since these neoplasms are less common and exhibit high cellular and molecular heterogeneity. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | However, STSs’ unique characteristics offer opportunities for further exploration, such as the identification of common CSC signatures across all STSs, which can be therapeutically targeted . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | By combining CRISPR-Cas9 technologies with HDR (homology-directed repair) in human embryonic stem cells (hES), Vanoli and colleagues developed an innovative approach to investigating the cell of origin in human cancers without a clear line of differentiation, including sarcomas with chromosomal translocations. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | They also demonstrated that chromosomal translocations are involved in hES differentiation in human embryonic-stem-derived mesenchymal progenitor cells (hES-MP), clarifying the role of gene fusion in sarcomagenesis under conditional expression . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | While several stem cell-based models of synovial sarcoma and skeletal sarcomas have been developed, especially for the study of osteosarcoma and Ewing’s sarcoma , visceral sarcomas need to be further explored. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Among the available animal models in cancer research, human tumor xenografts are the most widely used. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | They consist of the implantation of tumor cells into immunocompromised mice, either under the skin or into the same organ type of origin (Figure 1A). |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Athymic nude mice, severe combined immunodeficient (SCID) mice, or other immunocompromised mice can readily accept xenografts . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Several studies have been conducted on cell-derived xenograft (CDX) models to assess both the target therapy effectiveness and oncogenic activity in STSs. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | An example is the xenograft model investigated by Floris and colleagues, obtained from the IM-sensitive GIST882 cell line. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | For the first time, they used this nude xenograft model to evaluate the effects of the HDACi panobinostat on human GISTs with different oncogenic KIT mutations. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Panobinostat reduced proliferation and increased apoptosis in all xenografts, proving its anti-tumor activity . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Another STS xenograft model, applied to leiomyosarcomas, is the one established by Zhang‘s group by injecting SCID mice with SK-LMS-1 cells previously transfected with VEGF165 . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Approximately 21–25% of patients affected by STSs display VEGF overexpression, which correlates with a more advanced tumor grade and a worse prognosis . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Based on the established role of VEGF and its receptor VEGFR in angiogenesis, the authors tried to better clarify the role of VEGF165 in STS growth, metastasis, and chemoresistance. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | The obtained VEGR165-overexpressing xenograft model revealed the significant impact of VEGF expression on STSs’ ability to grow and metastasize, and the anti-VEGFR2 monoclonal antibody’s effects on enhancing the doxorubicin response . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | CDX models provide the advantage of replicating human tumor biology, despite the possibility of clone selection, which might not accurately represent the human disease . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | An alternative to cell line xenografts is the transplantation of small pieces of human-derived tumor samples into mice, obtaining so-called patient-derived xenograft (PDX) models (Figure 1B). |
PMC10669128 | Preclinical Models of Visceral Sarcomas | In this case, the advantage is represented by the close resemblance of the model to the primary tumor sample . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | For instance, copy number alterations observed in STS PDXs are also detected in sarcoma patients, suggesting that these alterations correlate with actual tumor progression rather than experimental model alterations . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Several models have been successfully established, achieving an overall engraftment success rate of 32% to 69% and efficiently reproducing the genetic and phenotypic characteristics of the original tumor . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | PDXs can be considered superior to classical cell-line-derived xenografts in accurately predicting patient response to therapy . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | In this regard, Gebreyohannes and colleagues proved the anti-tumor efficacy of cabozantinib, a novel tyrosine kinase inhibitor, by reducing tumor growth, proliferation, and angiogenesis in IM-sensitive and IM-resistant PDX models of GISTs . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Similarly, Van Looy’s team demonstrated the effectiveness of three PI3K inhibitors combined with imatinib in reducing tumor volumes and enhancing apoptosis in GIST PDXs . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Analogous research has been conducted on sarcoma xenograft models to explore the antitumor effects of target therapies. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | This is the case for Li and colleagues, who established two PDX models of DDLPS by implanting pieces of patient-derived sarcomas inro athymic nude NMRI mice. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Significantly decreased proliferation and angiogenesis inhibition characterized all the xenografts treated with the TKRi pazopanib . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Zuco’s group conducted a direct comparison between the first-in-class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy for sarcomas, in three DDLPS PDXs. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | They demonstrated selinexor’s potential as a therapeutic agent for DDLPS, given its superiority in terms of the umor response in all PDXs when compared to doxorubicin, regardless of the MDM2 amplification and histological differentiations . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | The few preclinical models of leiomyosarcoma and the lack of fidelity of the established LMS cell lines to their mesenchymal neoplasm of origin limit the translational understanding of the disease. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | In this regard, Hemming and colleagues characterized LMS PDX models assessing that, across multiple xenograft passages, the parental tumor histological appearance, copy number variation, and transcriptional program were maintained. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Additionally, LMS PDXs were susceptible to cyclin-dependent kinase (CDK) inhibition, which alters the oncogenic transcriptional program driven by E2F and hinders tumor growth. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Thus, CDK inhibitors can be a valuable therapeutic strategy for patients with LMS . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | As previously discussed, PDXs are useful to assess the effects of combined therapies. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | This was further supported by Perez’s team, who demonstrated the potential therapeutic strategies of doxorubicin and olaparib against sarcomas in UPS PDXs. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | The combined treatment efficacy in tumors with high levels of pH2AX and MAP17 suggested that both biomarkers could potentially identify patients who would benefit more from the therapy . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Similarly, Stacchioti’s group investigated the preclinical antitumor activity of EPZ-011989, an EZH2 inhibitor, in INI1-deficient proximal-type epithelial sarcoma (ES) PDXs. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | EPZ-011989, gemcitabine, and a doxorubicin–ifosfamide combination exhibited comparable antitumor activity in treated mice, supporting their clinical use as effective therapies. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Moreover, EZH2 was confirmed as a viable therapeutic target in ESs, suggesting autophagy as a possible protective mechanism against EZH2 inhibition . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Interestingly, an established patient-derived orthotopic nude mouse xenograft of a retroperitoneal STS was developed by Hiroshima and colleagues. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | This model recapitulated the histology of the original tumor better than the same subcutaneous ectopic model . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Hence, PDXs are largely used for the assessment of human tumor biology and have a broad range of applications in preclinical drug testing, in therapeutic target identification, and for the establishment of stable xenograft cell lines . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Furthermore, these models could represent an option for personalized medicine strategies, allowing for direct testing of potential drug treatments on a model matching the patient . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | However, recent advances in immunotherapy highlighted the importance of immune response in cancer progression and treatment, and thus the need to develop new PDX models to investigate human cancer and immune system interactions . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Wang’s team established an in vivo humanized mouse xenograft model by transplanting human CD34+ hematopoietic progenitor and stem cells into NGS mice, originating humanized NGS (HuNGS) mice with human hematopoietic and immune systems. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Then, they implanted PDXs of various cancers (sarcoma, non-small cell lung cancer, bladder, triple-negative breast cancer) into HuNGSs. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Treatment with PD-1 checkpoint inhibitor pemrolizumab significantly inhibited the tumor growth of PDX tumors in HuNGS mice, assessing the potential utility of the model for preclinical immunotherapy research . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Patient-derived models (PDMs) are widely applied in cancer research, drug development, and clinical applications. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Since PDMs are directly derived from patients, they can predict treatment response and could help to identify the best personalized treatment strategy . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Research findings support that sarcoma patient-derived cells predict STS patient response to therapy since these models preserve the genetic characteristics of the original tumor and the association between drug sensitivity and patient response . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Nonetheless, there are still challenges and limitations to overcome, such as costs and time, as well as tumor heterogeneity, which might not be represented by PDMs, potentially affecting the accuracy of drug testing . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Among other animal models used in sarcoma research, it is worthwhile to mention the genome-engineered mouse model (GEMM), in which mice display an altered genetic profile by mutating, deleting, or overexpressing one or several oncogenes (Figure 1C). |
PMC10669128 | Preclinical Models of Visceral Sarcomas | GEMMs allow us to monitor the effects of induced genetic alterations over time and to evaluate tumor response to treatment in vivo . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Conditional transgenic mice expressing oncogenic human fusion genes, as well as immunodeficient mice that enable the growth of human tumor cells or tumor fragments cultured in vitro, have allowed the implementation of the available preclinical models for translational research . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | An example of an in vivo visceral sarcoma model is represented by the MMTV-CR-1 transgenic mice generated by Strizzi and colleagues, in which CR-1 transgene expression is regulated by the MMTV (the mouse mammary tumor virus) long terminal repeat promoter and leads to uterine leiomyosarcoma development. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | CR-1 plays a role in uterine tumor onset via the direct activation of c-src and Akt or via crosstalk with the canonical Wnt signaling pathway . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Many transgenic mouse models have also been generated to study gastrointestinal stromal tumors. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | For instance, Sommer’s group created a knock-in mouse with an exon 11 KIT-activating mutation (KITV558 deletion), previously found in the case of human familial GIST syndrome. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Through this model, they reproduced gastrointestinal pathology in mice with remarkable penetrance, demonstrating that the constitutive activation of KIT signaling is pivotal and sufficient to cause neoplastic growth in mice . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Likewise, Rubin’s team developed a homozygous knock-in mouse model harboring a KIT-activating mutation K641E, resulting in GIST development with 100% penetrance. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | They also showed the model effectiveness for the study of KIT pathway activation, GIST pathogenesis, and preclinical validation of GIST therapies and drug response . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Regarding the study of undifferentiated pleomorphic sarcoma, for the first time, Buchakjian and colleagues generated a viral Cre-mediated TRP53/PTEN mouse model, by injecting adenoviral Cre recombinase into TRP53flox/flox/PTENflox/flox lox–stop–lox luciferase mice. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | All the injected mice developed STSs, identified for 93% as invasive pleomorphic sarcomas characterized by lymphocytic infiltrate (64%) and PD-L1 expression (71%). |
PMC10669128 | Preclinical Models of Visceral Sarcomas | The model could represent a valuable tool for liposarcoma preclinical studies since the homozygous loss of TRP53 and PTEN in mouse adipose tissue also characterizes this sarcoma histotype . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Within the realm of liposarcoma research, Pèrez-Mancera’s group generated CHOP and FUS ± CHOP transgenic mice, by introducing CHOP or the FUS-CHOP transgene into mouse genomes. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Interestingly, only the latter mouse group developed LPSs. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | This demonstrated the critical role of the FUS domain in the liposarcoma pathogenesis and pioneeringly proved the in vivo correlation between gene fusions and solid tumor onset . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | A few years later, the same group generated double-transgenic FUS-CHOP mice to investigate the significance of the FUS-CHOP interaction. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | As a result, FUS expression in CHOP transgenic mice restored liposarcoma development, indicating that the FUS and CHOP domains cooperate in mutual liposarcoma restoration . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | As previously mentioned, unfortunately, angiosarcomas lack valid clinical models that allow new therapy development. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | However, Salter’s team generated an autochthonous AS mouse model driven by p53 deregulation in VE-cadherin-expressing endothelial cells, using Cdh5-Cre mice. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | AS arose in mice with a penetrance of 100% upon homozygous deletion of TRP53. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | The re-implantation of AS fragments from Cdh5-Cre, Trp53 mice yielded a reliable and rapid angiosarcoma model. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Moreover, transferring tumor fragments within mice allowed them to establish a novel AS model suitable for preclinical studies and for new therapy development . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | In this review, we summarize the most used in vitro and in vivo models adopted for the study of visceral sarcomas (Figure 2). |
PMC10669128 | Preclinical Models of Visceral Sarcomas | However, all of them present both advantages and limitations. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Sarcoma cell lines have a central role in cancer research, as they can be easily employed to develop new potential drugs, allowing rapid identification of compounds with anti-cancer activity. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Moreover, cell lines can be genetically manipulated to study the effects of specific mutations on tumor growth and invasiveness, and to investigate the molecular mechanisms of visceral sarcomas. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Nonetheless, not all the therapeutic approaches can be tested in vitro. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Additionally, cell lines might not accurately represent tumors’ microenvironment complexity and their interactions with stromal and immune cells. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Thus, the immune system and the effects of drugs targeting the microenvironment cannot be evaluated in cultured cell lines . |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Furthermore, in vitro studies cannot fully recapitulate the genetic and epigenetic landscape of primary tumors. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Finally, when maintained in cultures, cells display gene expression and cellular behavior changes over time, which might lead to biased results. |
PMC10669128 | Preclinical Models of Visceral Sarcomas | Therefore, in vivo models can compensate for in vitro weaknesses. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.