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

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.

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

Scientific Reports ◽

10.1038/s41598-020-80428-5 ◽

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.

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Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer

Molecules ◽

10.3390/molecules24122338 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2338 ◽

Cited By ~ 11

Author(s):

Di Chen ◽

Yangmin Ma ◽

Peiqi Li ◽

Meng Liu ◽

Yuan Fang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Xenograft Model ◽

Tumor Xenograft ◽

Stat3 Pathway ◽

Suppression Effect ◽

Chemotherapy Drugs ◽

Induced Apoptosis

Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.

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Double-Edged Lipid Nanoparticles Combining Liposome-Bound TRAIL and Encapsulated Doxorubicin Showing an Extraordinary Synergistic Pro-Apoptotic Potential

Cancers ◽

10.3390/cancers11121948 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1948 ◽

Cited By ~ 3

Author(s):

Diego De Miguel ◽

Ana Gallego-Lleyda ◽

Miguel Martinez-Ara ◽

Javier Plou ◽

Alberto Anel ◽

...

Keyword(s):

Cytotoxic Activity ◽

Molecular Mechanisms ◽

Xenograft Model ◽

Carcinoma Cells ◽

Tumor Xenograft ◽

Cytotoxic Potential ◽

Primary Tumors ◽

Soluble Trail

Although TRAIL (TNF-related apoptosis-inducing ligand, also known as Apo2L) was described as capable of inducing apoptosis in transformed cells while sparing normal cells, limited results obtained in clinical trials has limited its use as an anti-tumor agent. Consequently, novel TRAIL formulations with enhanced bioactivity are necessary for overcoming resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumors. Our group has generated artificial liposomes with sTRAIL anchored on their surface (large unilamellar vesicle (LUV)-TRAIL), which have shown a greater cytotoxic activity both in vitro and in vivo when compared to sTRAIL against distinct hematologic and epithelial carcinoma cells. In this study, we have improved LUV-TRAIL by loading doxorubicin (DOX) in its liposomal lumen (LUVDOX-TRAIL) in order to improve their cytotoxic potential. LUVDOX-TRAIL killed not only to a higher extent, but also with a much faster kinetic than LUV-TRAIL. In addition, the concerted action of the liposomal DOX and TRAIL was specific of the liposomal DOX and was not observed when with soluble DOX. The cytotoxicity induced by LUVDOX-TRAIL was proven to rely on two processes due to different molecular mechanisms: a dynamin-mediated internalization of the doxorubicin-loaded particle, and the strong activation of caspase-8 exerted by the liposomal TRAIL. Finally, greater cytotoxic activity of LUVDOX-TRAIL was also observed in vivo in a tumor xenograft model. Therefore, we developed a novel double-edged nanoparticle combining the cytotoxic potential of DOX and TRAIL, showing an exceptional and remarkable synergistic effect between both agents.

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DDRE-43. SCREENING OF FDA-APPROVED COMPOUNDS FOR THE TREATMENT OF CHORDOMA, WITH IN VIVO VALIDATION USING THREE DIFFERENT XENOGRAFT MODELS, IDENTIFIES BRIGATINIB AS A POTENTIAL TREATMENT

Neuro-Oncology ◽

10.1093/neuonc/noab196.327 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi83-vi84

Author(s):

Philip Tatman ◽

Tadeusz Wroblewski ◽

Anthony Fringuello ◽

Sam Scherer ◽

William Foreman ◽

...

Keyword(s):

Skull Base ◽

Cell Lines ◽

Xenograft Model ◽

Drug Screen ◽

Skull Base Tumor ◽

Primary Tumors ◽

Mobile Spine ◽

Xenograft Models ◽

In Vivo Validation

Abstract BACKGROUND Chordoma is a rare malignant tumor with poor surgical control and no existing pharmacotherapies. Therefore, these tumors require additional research into novel therapeutics for their treatment. METHODS In this study we created a high-throughput drug screen and culture system to evaluate the efficacy of existing FDA-approved compounds in 10 chordoma cell lines and primary tumors. The cell lines were graciously donated by the Chordoma Foundation. Primary tumors were collected from our operating room. In vivo validation using three separate chordoma xenograft models was also performed through the Chordoma Foundation. One model was a primary clival pediatric tumor, the second was a metastatic sacral tumor, and the third model was a recurrent skull base tumor. RESULTS Using a 127 FDA-approved compound library, we screened 6 donated chordoma cell lines and 4 tumors resected from our institution. 5 of the chordomas were primary, 3 were recurrent, and 2 were metastatic. 6 chordoma were located in the sacrum, three were located in the mobile spine, and one was located in the clivus. Five tumors came from female patients and five came from male patients. After a single 72-hour 1um dose of brigatinib, the average tumor viability in our drug screen was reduced to 81.5% +/-9.5SD (p=1.61x10-13). In the in vivo studies, brigatinib achieved a full response in the metastatic sacral chordoma xenograft model (TGI=100%, p< 0.0001), a partial response in the recurrent skull base xenograft model (TGI=54%, p=0.3048), and no response in the primary clival pediatric xenograft model (TGI = 0%, p >0.9). CONCLUSIONS Brigatinib may be a viable treatment option for recurrent and metastatic chordomas.

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Faculty Opinions recommendation of PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732064759.793541571 ◽

2018 ◽

Author(s):

Manuel Corpas

Keyword(s):

Tumor Xenograft ◽

Xenograft Models ◽

Minimal Information

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

Cancer Cell International ◽

10.1186/s12935-021-01808-z ◽

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.

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

Laboratory Animal Research ◽

10.1186/s42826-021-00087-z ◽

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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MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

BioMed Research International ◽

10.1155/2015/192406 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Brian Shuch ◽

Ryan Falbo ◽

Fabio Parisi ◽

Adebowale Adeniran ◽

Yuval Kluger ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Predictive Biomarkers ◽

Cell Renal Cell Carcinoma ◽

Primary Tumors ◽

Distant Tissue ◽

Significant Expression ◽

Metastatic Sites

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available.Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39).Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

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