• Toxicological Research
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• 제30권1호
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• pp.1-5
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• 2014

Xenograft models of human cancer play an important role in the screening and evaluation of candidates for new anticancer agents. The models, which are derived from human tumor cell lines and are classified according to the transplant site, such as ectopic xenograft and orthotopic xenograft, are still utilized to evaluate therapeutic efficacy and toxicity. The metastasis model is modified for the evaluation and prediction of cancer progression. Recently, animal models are made from patient-derived tumor tissue. The patient-derived tumor xenograft models with physiological characters similar to those of patients have been established for personalized medicine. In the discovery of anticancer drugs, standard animal models save time and money and provide evidence to support clinical trials. The current strategy for using xenograft models as an informative tool is introduced.

• Genomics & Informatics
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• 제16권2호
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• pp.30-35
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• 2018

Patient-derived xenograft (PDX) models are useful tools for tumor biology research and testing the efficacy of candidate anticancer drugs targeting the druggable mutations identified in tumor tissue. However, it is still unknown how much of the genetic alterations identified in primary tumors are consistently detected in tumor tissues in the PDX model. In this study, we analyzed the genetic alterations of three primary colorectal cancers (CRCs) and matched xenograft tissues in PDX models using a next-generation sequencing cancer panel. Of the 17 somatic mutations identified from the three CRCs, 14 (82.4%) were consistently identified in both primary and xenograft tumors. The other three mutations identified in the primary tumor were not detected in the xenograft tumor tissue. There was no newly identified mutation in the xenograft tumor tissues. In addition to the somatic mutations, the copy number alteration profiles were also largely consistent between the primary tumor and xenograft tissue. All of these data suggest that the PDX tumor model preserves the majority of the key mutations detected in the primary tumor site. This study provides evidence that the PDX model is useful for testing targeted therapies in the clinical field and research on precision medicine.

• Genomics & Informatics
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• 제18권1호
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• pp.3.1-3.8
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• 2020

Patient-derived xenograft (PDX) mouse models are frequently used to test the drug efficacy in diverse types of cancer. They are known to recapitulate the patient characteristics faithfully, but a systematic survey with a large number of cases is yet missing in lung cancer. Here we report the comparison of genomic characters between mouse and patient tumor tissues in lung cancer based on exome sequencing data. We established PDX mouse models for 132 lung cancer patients and performed whole exome sequencing for trio samples of tumor-normal-xenograft tissues. Then we computed the somatic mutations and copy number variations, which were used to compare the PDX and patient tumor tissues. Genomic and histological conclusions for validity of PDX models agreed in most cases, but we observed eight (~7%) discordant cases. We further examined the changes in mutations and copy number alterations in PDX model production and passage processes, which highlighted the clonal evolution in PDX mouse models. Our study shows that the genomic characterization plays complementary roles to the histological examination in cancer studies utilizing PDX mouse models.

• Genomics & Informatics
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• 제18권1호
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• pp.6.1-6.9
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• 2020

Acute leukemia represents the most common pediatric malignancy comprising diverse subtypes with varying prognosis and treatment outcomes. New and targeted treatment options are warranted for this disease. Patient-derived xenograft (PDX) models are increasingly being used for preclinical testing of novel treatment modalities. A novel approach involving targeted error-corrected RNA sequencing using ArcherDX HemeV2 kit was employed to compare 25 primary pediatric acute leukemia samples and their corresponding PDX samples. A comparison of the primary samples and PDX samples revealed a high concordance between single nucleotide variants and gene fusions whereas other complex structural variants were not as consistent. The presence of gene fusions representing the major driver mutations at similar allelic frequencies in PDX samples compared to primary samples and over multiple passages confirms the utility of PDX models for preclinical drug testing. Characterization and tracking of these novel cryptic fusions and exonal variants in PDX models is critical in assessing response to potential new therapies.

• 대한의생명과학회지
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• 제23권3호
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• pp.238-250
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• 2017

Patient's primary tumor-derived tumor cell lines likely represent ideal tools for human tumor biology in vitro and in vivo. Here, we describe eight human gastric carcinoma cell lines derived from established tumors in vivo upon subcutaneous transplantation of primary gastric carcinoma specimens in BALB/c nude mice. These xenografted gastric tumor cell lines (GTX) displayed close similarity with primary gastric tumor tissues in their in vivo growth pattern and genomic alterations. GTX-085 cells were resistant to cisplatin, while GTX-087 was the most sensitive cell line. GTX-085 was the only cell line showing a metastatic potential. Epithelial cell adhesion molecule (EPCAM) expression was especially strong in all tissue samples, as well as in cell cultures. GTX-139, the largest tumor graft obtained after injection, displayed distinct expression of CD44v6, fibroblast growth factor receptor 2 (FGFR2), and prominin 1 (PROM1, also known as CD133). In summary, we established eight xenograft gastric cancer cell lines from gastric cancer patient tissues, with their histological and molecular features consistent with those of the primary tumors. The established GTX cell lines will enable future studies of their responses to various treatments for gastric cancer.

• BMB Reports
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• 제56권1호
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• pp.24-31
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• 2023

Urological cancers such as kidney, bladder, prostate, and testicular cancers are the most common types of cancers worldwide with high mortality and morbidity. To date, traditional cell lines and animal models have been broadly used to study pre-clinical applications and underlying molecular mechanisms of urological cancers. However, they cannot reflect biological phenotypes of real tissues and clinical diversities of urological cancers in vitro system. In vitro models cannot be utilized to reflect the tumor microenvironment or heterogeneity. Cancer organoids in three-dimensional culture have emerged as a promising platform for simulating tumor microenvironment and revealing heterogeneity. In this review, we summarize recent advances in prostate and kidney cancer organoids regarding culture conditions, advantages, and applications of these cancer organoids.

• International Journal of Stem Cells
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• 제16권3호
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• pp.315-325
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• 2023

Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

• Journal of Gastric Cancer
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• 제20권1호
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• pp.60-71
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• 2020

Purpose: The utility of 18-fluordesoxyglucose positron emission tomography ([¹⁸F]-FDG-PET) combined with computer tomography or magnetic resonance imaging (MRI) in gastric cancer remains controversial and a rationale for patient selection is desired. This study aims to establish a preclinical patient-derived xenograft (PDX) based [¹⁸F]-FDG-PET/MRI protocol for gastric cancer and compare different PDX models regarding tumor growth and FDG uptake. Materials and Methods: Female BALB/c nu/nu mice were implanted orthotopically and subcutaneously with gastric cancer PDX. [¹⁸F]-FDG-PET/MRI scanning protocol evaluation included different tumor sizes, FDG doses, scanning intervals, and organ-specific uptake. FDG avidity of similar PDX cases were compared between ortho- and heterotopic tumor implantation methods. Microscopic and immunohistochemical investigations were performed to confirm tumor growth and correlate the glycolysis markers glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) with FDG uptake. Results: Organ-specific uptake analysis showed specific FDG avidity of the tumor tissue. Standard scanning protocol was determined to include 150 μCi FDG injection dose and scanning after one hour. Comparison of heterotopic and orthotopic implanted mice revealed a long growth interval for orthotopic models with a high uptake in similar PDX tissues. The H-score of GLUT1 and HK2 expression in tumor cells correlated with the measured maximal standardized uptake value values (GLUT1: Pearson r=0.743, P=0.009; HK2: Pearson r=0.605, P=0.049). Conclusions: This preclinical gastric cancer PDX based [¹⁸F]-FDG-PET/MRI protocol reveals tumor specific FDG uptake and shows correlation to glucose metabolic proteins. Our findings provide a PET/MRI PDX model that can be applicable for translational gastric cancer research.

• Journal of Korean Neurosurgical Society
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• 제65권6호
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• pp.790-800
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• 2022

Objective : EID3 (EP300-interacting inhibitor of differentiation) was identified as a novel member of EID family and plays a pivotal role in colorectal cancer development. However, its role in glioma remained elusive. In current study, we identified EID3 as a novel oncogenic molecule in human glioma and is critical for glioma cell survival, proliferation and invasion. Methods : A total of five patients with glioma were recruited in present study and fresh glioma samples were removed from patients. Four weeks old male non-obese diabetic severe combined immune deficiency (NOD/SCID) mice were used as transplant recipient models. The subcutaneous tumor size was calculated and recorded every week with vernier caliper. EID3 and AMP-activated protein kinase α1 (AMPKα1) expression levels were confirmed by real-time polymerase chain reaction and Western blot assays. Colony formation assays were performed to evaluate cell proliferation. Methyl thiazolyl tetrazolium (MTT) assays were performed for cell viability assessment. Trypan blue staining approach was applied for cell death assessment. Cell Apoptosis DNA ELISA Detection Kit was used for apoptosis assessment. Results : EID3 was preferentially expressed in glioma tissues/cells, while undetectable in astrocytes, neuronal cells, or normal brain tissues. EID3 knocking down significantly hindered glioma cell proliferation and invasion, as well as induced reduction of cell viability, apoptosis and cell death. EID3 knocking down also greatly inhibited tumor growth in SCID mice. Knocking down of AMPKα1 could effectively rescue glioma cells from apoptosis and cell death caused by EID3 absence, indicating that AMPKα1 acted as a key downstream regulator of EID3 and mediated suppression effects caused by EID3 knocking down inhibition. These findings were confirmed in glioma cells generated patient-derived xenograft models. AMPKα1 protein levels were affected by MG132 treatment in glioma, which suggested EID3 might down regulate AMPKα1 through protein degradation. Conclusion : Collectively, our study demonstrated that EID3 promoted glioma cell proliferation and survival by inhibiting AMPKα1 expression. Targeting EID3 might represent a promising strategy for treating glioma.