scholarly journals Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hamid Khodayari ◽  
Saeed Khodayari ◽  
Solmaz Khalighfard ◽  
Arash Tahmasebifar ◽  
Mahboubeh Tajaldini ◽  
...  
Keyword(s):  
Gamma Radiation ◽  
High Capacity ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Whole Body ◽  
Cell Injection ◽  
Tumor Tissues ◽  
Post Radiation ◽  
Xenograft Models ◽  
Xenograft Mice

AbstractTumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-β, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

scholarly journals The Application Progress of Patient-Derived Tumor Xenograft Models After Cholangiocarcinoma Surgeries

2021 ◽  
Vol 11 ◽  
Author(s):  
Jun Wu ◽  
Jiyao Sheng ◽  
Hanjiao Qin ◽  
Mengying Cui ◽  
Yongsheng Yang ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Predictive Biomarkers ◽  
Basic Research ◽  
Tumor Xenograft ◽  
High Recurrence Rate ◽  
Signal Pathways ◽  
Targeted Drugs ◽  
Primary Tumors ◽  
Chemotherapy Drugs ◽  
Xenograft Models

Surgical treatment is the only possible cure for cholangiocarcinoma (CCA) at present. However, the high recurrence rate of postoperative CCA leads to a very poor prognosis for patients, effective postoperative chemotherapy is hence the key to preventing the recurrence of CCA. The sensitivity of CCA to cytotoxic chemotherapy drugs and targeted drugs varies from person to person, and therefore, the screening of sensitive drugs has become an important topic after CCA surgeries. Patient-Derived tumor Xenograft models (PDX) can stably retain the genetic and pathological characteristics of primary tumors, and better simulate the tumor microenvironment of CCA. The model is also of great significance in screening therapeutic targeted drugs after CCA, analyzing predictive biomarkers, and improving signal pathways in prognosis and basic research. This paper will review the current established methods and applications of the patient-derived tumor xenograft model of cholangiocarcinoma, aiming to provide new ideas for basic research and individualized treatment of cholangiocarcinoma after surgery.

scholarly journals Differential Angiogenic Potential of 3-Dimension Spheroid of HNSCC Cells in Mouse Xenograft

2021 ◽  
Vol 22 (15) ◽  
pp. 8245
Author(s):  
So-Young Choi ◽  
Soo Hyun Kang ◽  
Su Young Oh ◽  
Kah Young Lee ◽  
Heon-Jin Lee ◽  
...  
Keyword(s):  
Culture Media ◽  
3D Culture ◽  
Xenograft Model ◽  
Fluorescent Imaging ◽  
Tumor Xenograft ◽  
In Vivo Model ◽  
Mouse Tumor ◽  
Tumor Tissues ◽  
3D Spheroids

The experimental animal model is still essential in the development of new anticancer drugs. We characterized mouse tumors derived from two-dimensional (2D) monolayer cells or three-dimensional (3D) spheroids to establish an in vivo model with highly standardized conditions. Primary cancer-associated fibroblasts (CAFs) were cultured from head and neck squamous cell carcinoma (HNSCC) tumor tissues and co-injected with monolayer cancer cells or spheroids into the oral mucosa of mice. Mice tumor blood vessels were stained, followed by tissue clearing and 3D Lightsheet fluorescent imaging. We compared the effect of exosomes secreted from 2D or 3D culture conditions on the angiogenesis-related genes in HNSCC cells. Our results showed that both the cells and spheroids co-injected with primary CAFs formed tumors. Interestingly, vasculature was abundantly distributed inside the spheroid-derived but not the monolayer-derived mice tumors. In addition, cisplatin injection more significantly decreased spheroid-derived but not monolayer-derived tumor size in mice. Additionally, exosomes isolated from co-culture media of FaDu spheroid and CAF upregulated angiogenesis-related genes in HNSCC cells as compared to exosomes from FaDu cell and CAF co-culture media under in vitro conditions. The mouse tumor xenograft model derived from 3D spheroids of HNSCC cells with primary CAFs is expected to produce reliable chemotherapy drug screening results given the robust angiogenesis and lack of necrosis inside tumor tissues.

scholarly journals Double-targeted knockdown of miR-21 and CXCR4 inhibits malignant glioma progression by suppression of the PI3K/AKT and Raf/MEK/ERK pathways

2020 ◽  
Author(s):  
Feijiao Liu ◽  
Bo Yang
Keyword(s):  
Malignant Glioma ◽  
Xenograft Model ◽  
Glioma Cells ◽  
Invasion And Migration ◽  
Treatment Groups ◽  
Tumor Tissues ◽  
Two Factors ◽  
Xenograft Mice ◽  
And Migration ◽  
Glioma Progression

AbstractBackgroundCurrently, miR-21 and CXCR4 are being extensively investigated as two unrelated key regulators in glioma malignancy. In this study, we investigated the combined effect of these two factors on glioma progression.MethodsWe confirmed the expression of miR-21 and CXCR4 in malignant glioma tissue and glioma cells with qRT-PCR and western blotting. Single-targeted knockdown of miR-21 and CXCR4, as well as double-targeted knockdown of miR-21 and CXCR4 lentiviral vectors were constructed and they were transfected to U87 and U251 cells. Cell proliferation, apoptosis, invasion, and migration from different treatment groups were assessed by MTT assay, Flow Cytometry analysis, Transwell analysis, and Scratch assay, respectively. U87 xenograft mice were constructed to detect roles and potential mechanisms of miR-21 and CXCR4 in malignant glioma tumor growth.ResultsThe expression of miR-21 and CXCR4 was increased in tumor tissues and cell lines. Inhibition of miR-21, CXCR4, and miR-21 and CXCR4 together all reduced the migration, invasiveness, proliferation and enhanced apoptosis in glioma cells, as well as reduced tumor volume and mass in xenograft model. The inhibition effect was strongest in double-targeted knockdown of miR-21 and CXCR4 group, whose downstream pathways involved in AKT axis and ERK axis activation.ConclusionsOur findings reported that double-targeted knockdown of miR-21 and CXCR4 could more effectively inhibit the proliferation, migration, invasion and growth of transplanted tumor and promote cell apoptosis, which were involved in the PI3K/AKT and Raf/MEK/ERK signaling pathways.

Anti Tumor Effect of 2-Oxoglutarate through Inhibition of Angiogenesis in a Murine Tumor Model.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1599-1599
Author(s):  
Ken Matsumoto ◽  
Naoshi Obara ◽  
Masaki Horie ◽  
Ayano Naka ◽  
Katsunori Utsugi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Hepatoma Cell ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Pcr Analysis ◽  
Hepatoma Cell Line ◽  
Rt Pcr ◽  
Vegf Gene ◽  
Murine Tumor ◽  
Tumor Tissues

Abstract Hypoxia-inducible factor 1 (HIF-1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of several genes in response to hypoxic stress and changes in growth factors. HIF-1 is a heterodimeric transcriptional activator and consists of inducible α and constitutive β subunits. In oxygenated cells, intracellular oxygen concentrations are directly sensed by proteins containing the prolyl hydroxylase domain (PHD), which tag HIF-1α subunits for polyubiquitination and proteasomal degradation by prolyl hydroxylation using 2-oxoglutarate (2-OX) and dioxygen. Our recent studies have shown that 2-OX reduces HIF-1α, erythropoietin, and vascular endothelial growth factor (VEGF) expression by hypoxia in the hepatoma cell line Hep3B (Matsumoto K et al.; J. Cell. Physiol., 2006). Similar results were obtained in Lewis lung cancer (LLC) cells in in vitro studies. Here, to address the clinical usefulness of 2-OX, we investigated its antitumor effect using a mouse dorsal air sac (DAS) assay and a murine tumor xenograft model. For the DAS assay, LLC cells suspended in PBS with 0, 7.5, or 15 mM 2-OX per Millipore chamber were implanted subcutaneously into C57BL/6J mice. The values of blood vessel area by LLC cells were 100 ± 20.8, 64.0 ± 9.4, and 45.6 ± 4.4%, respectively, by quantitative analysis with angiogenesis-measuring software. This result indicated that 2-OX clearly inhibited the growth of subcutaneous tumors. To elucidate the effect of 2-OX on tumor growth, 2-OX was administrated to C57BL/6J mice inoculated with LLC cells. LLC cells (1 × 106) in PBS were implanted into the right flank region of 7-week-old mice. Daily intraperitoneal (i.p.) injections of 2-OX were started on the next day after implantation. From 6 to 12 days after implantation, we measured tumors with calipers and calculated volumes as (length × width2) × 0.5. LLC tumors were removed from mice 12 days after implantation for quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical studies. Tumor volumes and weights 12 days after implantation were as follows: PBS alone, 330.8 ± 108.1 mm3 and 192.6 ± 66.4 mg; 50 mg/kg 2-OX, 128.8 ± 16.4 mm3 and 111.0 ± 64.5 mg; and 100 mg/kg 2-OX, 78.7 ± 43.7 mm3 and 88.8 ± 57.5 mg. Quantitative RT-PCR revealed that 2-OX treatment (100 mg/kg) decreased the expression levels of the VEGF gene 0.67-fold in tumor tissues compared with control. We observed quantitative differences in microvessel density (PBS alone, 100 ± 16.5%; 100 mg/kg 2-OX, 46.0 ± 13.5%) using immunostaining for the endothelial cell marker CD31. Intraperitoneal injection of 2-OX significantly inhibited tumor growth and angiogenesis in tumor tissues. Combination therapy is necessary for anti-angiogenic therapy in the human. To examine the effect of 2-OX in combination with 5-fluorouracil (5-FU) chemotherapy, we injected 5-FU i.p. on day 6 and/or 2-OX i.p. on each of days 6–15 in this mouse model. Tumor volumes and weights 15 days after implantation were as follows: PBS alone, 531.2 ± 144.9 mm3 and 306.3 ± 186.6 mg; 2-OX alone, 324.0 ± 156.5 mm3 and 308.7 ± 299.0 mg; 5-FU alone, 287.1 ± 155.2 mm3 and 204.7 ± 108.9 mg; and 5-FU + 2-OX, 98.7 ± 64.9 mm3 and 130.3 ± 113.5 mg. 5-FU combined with 2-OX significantly inhibited tumor growth in this model, which was accompanied by 53% reduction of VEGF gene expression in tumor tissues removed from mice 15 days after implantation, using quantitative RT-PCR analysis. These results suggest that 2-OX is a promising anti-angiogenic therapeutic agent. To examine whether the inhibitory effect of 2-OX is specific for PHD-containing proteins, an RNAi study will be performed.

scholarly journals Subcutaneous and orthotopic xenograft models of human bladder carcinoma in nude mice for epidermal growth factor receptor-targeted treatment

2018 ◽  
Vol 17 (2) ◽  
pp. 31-40
Author(s):  
M. S. Vorontsova ◽  
T. A. Karmakova ◽  
E. A. Plotnikova ◽  
N. B. Morozova ◽  
M. A. Abakumov ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Orthotopic Xenograft ◽  
Egfr Expression ◽  
Tumor Tissues ◽  
Epidermal Growth ◽  
Xenograft Models

Introduction.Approaches based on the principles of a targeted therapy are considered a promising strategy that is capable to improve the effectiveness of treatment for bladder cancer (BC) patients.The purposeof the study was to establish an orthotopic xenograft model of human BC in mice and to prove its suitability for experimental examination of drugs targeting the epidermal growth factor receptor (EGFR).Materials and methods.The objects of the study were ectopic subcutaneous and orthotopic human BC xenografts established using EJ and 5637 human BC cell lines. The growth of orthotopic xenografts in vivo was assessed by magnetic resonance imaging. Tumor tissues were investigated using histological and immunohistochemical techniques.Results.It was shown that EJ and 5637 xenografts exhibit a good reproducibility, a sufficient blood supply of the tumor tissues, a high level of EGFR expression, and different pattern of a subcellular receptor localization. Implantation and subsequent proliferation of human EJ or 5637 cells in the murine bladder mucosa presumably results in muscle-non-invasive tumor formation.Conclusions.The EJ and 5637 xenograft models can be useful for investigation of the efficacy of EGFR-targeted biotherapeutic treatments.

scholarly journals LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bo Jia ◽  
Junfeng Dao ◽  
Jiusong Han ◽  
Zhijie Huang ◽  
Xiang Sun ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Cell Cycle Regulators ◽  
Normal Tissues ◽  
Stat3 Signaling ◽  
Long Intergenic Noncoding Rna

Abstract Background Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2′-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Conclusions Our findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

scholarly journals Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Sungryong Oh ◽  
Joohee Jung
Keyword(s):  
Liver Cancer ◽  
Adverse Effects ◽  
Anticancer Drugs ◽  
Clinical Data ◽  
Xenograft Model ◽  
In Vitro Test ◽  
Incidence And Mortality ◽  
Significant Difference ◽  
Xenograft Models

Abstract Background The incidence and mortality of liver cancer show a great difference between the sexes. We established sex-dependent liver cancer xenograft models and investigated whether such sex-dependent models could be used to simultaneously evaluate the therapeutic and adverse effects of anticancer drugs for drug screening. Results In the in-vitro test, the cytotoxicity of anticancer drugs (cisplatin, 5-fluorouracil, and doxorubicin) was compared between male- and female-derived liver cancer cell lines. Cisplatin and 5-fluorouracil exhibited cytotoxicity without sex-difference, but doxorubicin showed dose-dependently significant cytotoxicity only in male-derived cells. Our results showed a strong correlation between preclinical and clinical data with the use of sex-dependent liver cancer xenograft models. Moreover, the male-derived Hep3B-derived xenograft model was more sensitive than the female-derived SNU-387-derived xenograft model against doxorubicin treatment. Doxorubicin showed more severe cardiotoxicity in the male xenograft model than in the female model. We investigated the occurrence frequency of doxorubicin-related cardiotoxicity using data obtained from the Korea Institute of Drug Safety & Risk Management Database, but no significant difference was observed between the sexes. Conclusions Our results suggest that sex-dependent xenograft models are useful tools for evaluating the therapeutic and adverse effects of anticancer drugs, because sex is an important consideration in drug development.

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