Search

Simple Summary: With both prevalence and mortality increasing, endometrial cancer (EC) is the most common gynecological cancer in high-income countries. Despite significant advances in EC research and management, there are still unmet needs. Patients suffering from advanced-stage and recurrent EC lack treatment options and have poor prognosis. Robust preclinical models are crucial in the development of novel therapies, and xenograft models have recently gained increasing interest in drug discovery and precision medicine. A clear overview of all developed EC mouse xenograft models is currently lacking. The aim of this review is to summarize these studies, reporting on their methodology and main findings. The different models are grouped based on the source material used to generate the xenografts, i.e., cell lines, patient-derived tumors, or patient-derived tumor organoids, and on the location of tumor formation, i.e., heterotopic or orthotopic. Finally, the advantages and disadvantages of the different tumor source material and xenograft locations, as well as some considerations on the translational potential, limitations, and future directions of EC xenograft models, are discussed. Murine xenograft models are valuable and increasingly used preclinical tools in cancer research to understand disease pathogenesis and guide treatment options. The aim of this narrative review is to summarize the studies that employed mouse xenograft models, using cell lines, patient-derived tumors, or organoids, in endometrial cancer (EC) research, detailing their methodology and main findings. We identified 27 articles reporting on heterotopic EC xenografts, including subcutaneous, subrenal capsule, intraperitoneal, and retro-orbital models, and 18 articles using orthotopic xenografts. Subcutaneous xenografts generated using either cell lines or patient tumors have been widely used; however, their low engraftment rates and the inability to recapitulate main clinical features such as metastases limit their translational value. Subrenal capsule models showed improved engraftment rates compared to subcutaneous models, but tumors exhibited slower and constrained tumor growth. Orthotopic models are technically more challenging to generate and monitor, but tumor growth occurs in a relevant microenvironment and EC ortho-xenografts exhibit high engraftment rates and metastases to clinically relevant sites. Cell line-based xenograft (CDX) models are attractive tools because they are convenient, easy to use, and amenable to genetic modifications, making them suitable for proof-of-concept approaches and large-scale studies. EC xenografts developed from patient tumors (PDTXs) are more labor/cost-intensive for their establishment but can capture the genetic and molecular heterogeneity within and across histologic subtypes and can inform personalized patient treatment. EC organoid-based xenograft (PDOX) models combine the advantages of both CDXs and PDTXs since they are more time- and cost-effective, faithfully maintain tumor characteristics and therapeutic responses, and can be genetically modified. Despite substantial progress in EC management, there are still several unmet needs. Efficient targeted treatments are currently indicated only for a small subgroup of patients, while women with recurrent or advanced-stage EC have very few therapeutic options and their prognosis remains unfavorable. Novel (targeted) drugs, combinational regimens and tools to predict the real drug response in patients are urgently needed. Xenograft models are expected to inform about disease mechanisms and to help identify novel therapeutic options and suitable target patients. [ABSTRACT FROM AUTHOR]

Background: The p38&agr; Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38&agr; in atherosclerosis development, in Apolipoprotein E deficient (ApoE-/-) mice. Methodology/Principal Findings: ApoE-/- mice with macrophage or endothelial cell-specific p38&agr; deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38&agr;-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38&agr; ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38&agr; did not affect atherosclerotic plaque development in ApoE-/- mice. Conclusions: Although previous studies implicated p38&agr; signaling in atherosclerosis, our in vivo experiments suggest that p38&agr; function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line—modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC. [ABSTRACT FROM AUTHOR]