WO2022173212A1 - Modèle animal de cancer invasif du cerveau et son procédé de production - Google Patents
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- WO2022173212A1 WO2022173212A1 PCT/KR2022/001962 KR2022001962W WO2022173212A1 WO 2022173212 A1 WO2022173212 A1 WO 2022173212A1 KR 2022001962 W KR2022001962 W KR 2022001962W WO 2022173212 A1 WO2022173212 A1 WO 2022173212A1
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- brain cancer
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- glioblastoma
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0693—Tumour cells; Cancer cells
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/12—Animals modified by administration of exogenous cells
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0331—Animal model for proliferative diseases
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0393—Animal model comprising a reporter system for screening tests
Definitions
- the present invention relates to an animal model of invasive brain cancer and a method for preparing the same.
- Brain cancer occurs regardless of age, and has a higher incidence in children than other cancers.
- Brain cancer is divided into primary brain cancer that occurs in the brain tissue and the meninges that surround the brain, and secondary brain cancer that metastasizes from cancer that occurs in the skull or other parts of the body.
- glioma is a tumor that accounts for 60% of primary brain tumors and has a high incidence.
- glioblastoma is the most malignant, highly invasive, and aggressive variant compared to other brain cancers, resulting in a very poor prognosis. If not treated promptly, glioblastoma can have fatal consequences within a few weeks.
- the present invention was designed to solve the above problems, and relates to an animal model for invasive brain cancer and a method for preparing the same. Since the animal model according to the present invention implements a characteristic of strong invasiveness among brain cancers such as glioblastoma, it is expected that it can be actively used for the development of therapeutic agents for invasive brain cancer.
- One object of the present invention is to provide an animal model of invasive brain cancer.
- Another object of the present invention is to provide a preparation method for preparing an animal model of invasive brain cancer.
- Another object of the present invention is to provide an invasive brain cancer cell.
- Another object of the present invention is to provide a preparation method for the preparation of invasive brain cancer cells.
- Another object of the present invention is to provide an invasive brain cancer organoid.
- Another object of the present invention is to provide a preparation method for the preparation of invasive brain cancer organoids.
- Another object of the present invention is to provide a composition for promoting invasion of brain cancer cells.
- Another object of the present invention is to provide a method for screening a candidate substance that inhibits the invasion of brain cancer cells.
- Another object of the present invention is to provide a method for screening a candidate substance that inhibits brain cancer metastasis caused by infiltration of brain cancer cells.
- One embodiment of the present invention provides an animal model of invasive brain cancer, and a method for preparing the same.
- the method of the present invention comprises the steps of mixing brain cancer cells and ventricle mesenchymal stem like cells (vMSLC); and, transplanting the mixed cells to an individual other than a human.
- vMSLC ventricle mesenchymal stem like cells
- the "brain cancer” of the present invention refers to all tumors generated within the cranial cavity, and may be, for example, a glioma, but is not limited thereto.
- the "glioma” of the present invention is a tumor that accounts for 60% of primary brain tumors, has a high incidence and is difficult to treat, and is a malignant tumor that has no special treatment other than radiation therapy to date, for example, It may be astrocytoma, glioblastoma or oligodendroglioma, etc., and preferably may be glioblastoma, but is not limited thereto.
- the brain cancer of the present invention may be a cancer tumor cell, but is not limited thereto.
- cancer tumor cells refers to a cell aggregate in which some cells having characteristics similar to stem cells among cells constituting a cancer tissue can be formed in a three-dimensional culture condition.
- the "invasiveness" of the present invention refers to a phenomenon in which tumor cells generated in a primary organ acquire new genetic traits necessary for metastasis as cancer progresses, and then infiltrate into blood vessels and lymph glands.
- the tumor cells infiltrated into blood vessels and lymph glands circulate along the lymph, and after settling in tissues existing in other organs from the primary organ, they proliferate, and ultimately cancer can easily metastasize to other organs.
- the "MSLC (mesenchymal stem like cell)" of the present invention is a mesenchymal stem-like cell.
- mesenchymal stem cells are pluripotent non-hematopoietic precursors originally isolated from bone marrow
- mesenchymal stem-like cells have been detected in various tissues, including brain tumors, and have pluripotent As a stromal cell, it refers to a cell having characteristics similar to mesenchymal stem cells.
- tMSLC tumor-derived mesenchymal stem-like cells
- vMSLC ventricular mesenchymal stem-like cells; ventricle MSLC
- SVZ subventricular zone
- the animal model of the present invention refers to an individual transplanted with brain cancer cells and vMSLC (ventricular mesenchymal stem-like cells).
- the animal model of the present invention may be a patient-derived cancer tissue transplant animal model (Patient Derived Xenograft).
- patient-derived cancer tissue transplantation animal model refers to a cancer patient-specific animal model produced by xenografting patient-derived cancer cells or cancer tissue into an immunodeficient animal. It is possible to provide conditions that reflect the genetic, physiological and environmental characteristics of cancer patients as they are similar, have the same or similar genetic environment, and have the same expression characteristics of cancer marker proteins.
- an anticancer drug candidate determined to have anticancer effect in a patient-derived xenograft animal model is treated with cancer cells or cancer tissue donor cancer patients, the same effect as that of treating the patient with these anticancer drug candidates can be confirmed, so the patient-derived Using a xenograft animal model has the advantage of being able to confirm whether an anticancer drug can actually show an appropriate effect on a patient.
- Another embodiment of the present invention provides an invasive brain cancer cell, and a method for preparing the same.
- the method of the present invention comprises the steps of obtaining a culture solution of vMSLC (ventricular mesenchymal stem-like cells); and culturing the brain cancer cells in the culture medium.
- vMSLC ventricular mesenchymal stem-like cells
- invasive brain cancer cell of the present invention and the method for producing the same, "brain cancer”, “glioma”, “cancer tumor cell”, “invasive”, and “vMSLC (ventricular mesenchymal stem-like cell)” are the animals of the invasive brain cancer It overlaps with that described in the model and the manufacturing method thereof, and is omitted below to avoid excessive complexity of the present specification.
- organoid refers to a culture body made by culturing or recombination of cells isolated from stem cells or organ cells, and refers to a structure that maintains the shape of a tissue in vitro, and includes artificial organs, bio-organs, mini-organs, spheroids, It can be interpreted in the same sense as a spheroid or embryoid body.
- the organoid is a cancer organoid and is characterized by being composed of cancer cells.
- the organoid is an invasive brain cancer organoid prepared by culturing brain cancer cells in a culture medium culturing ventricle mesenchymal stem like cells, and the brain cancer may be glioblastoma.
- Another embodiment of the present invention provides a composition for promoting invasion of brain cancer cells comprising vMSLC (ventricular mesenchymal stem-like cells), or a culture product thereof, as an active ingredient.
- vMSLC ventricular mesenchymal stem-like cells
- the "culture product" of the present invention is meant to include cells, cell lysates, or cell cultures, and the culture includes a culture medium used for cell culture, and by-products in the culture medium.
- composition for promoting invasion of brain cancer cells of the present invention "brain cancer”, “glioma”, “cancer tumor cell”, “invasive” meaning corresponding to invasion, and “vMSLC (ventricular mesenchymal stem-like cells)” It overlaps with that described in the animal model of invasive brain cancer, and a method for preparing the same, and is omitted to avoid excessive complexity of the present specification.
- invasiveness in the meaning corresponding to invasion is determined by measuring the expression level of a gene encoding a protein involved in invasion, or protein, or as an invasion area. can be checked
- Measuring the expression level of the gene is to determine the expression level of the gene to be measured included in the sample, a gene transcribed from the gene to be measured, for example, a method of measuring the level of mRNA transcribed from the gene can be implemented.
- the method includes RT-PCR, quantitative real time PCR (RPA), competitive RT-PCR (RT-PCR), real time quantitative RT-PCR (RT-PCR), RNase protection assay (RPA); RNase protection assay), Northern blot assay, DNA chip assay, etc. may be implemented using a primer pair or probe capable of specifically binding to an mRNA to be measured.
- the "primer” is a nucleotide sequence having a short free 3' hydroxyl group and can form a base pair with a complementary template strand, and functions as a starting point for template strand copying. It means a short nucleotide sequence that The primer can initiate DNA synthesis in the presence of four different nucleoside triphosphates and reagents for polymerization (ie, DNA polymerase or reverse transcriptase) in an appropriate buffer solution and temperature.
- the “probe” refers to a nucleic acid fragment such as RNA or DNA corresponding to a base capable of forming a specific binding with the gene or mRNA transcribed from the gene, and such a probe is the presence or absence of a specific mRNA, expression It may be labeled so that the level (expression amount) can be confirmed.
- the probe may be manufactured in the form of an oligonucleotide probe, a single-stranded DNA probe, a double-stranded DNA probe, an RNA probe, and the like, but is not limited thereto.
- the primer or probe can be easily prepared by a known method by a person skilled in the art with reference to a known nucleotide sequence, for example, the known nucleotide sequence of Zeb1, an invasion marker.
- Measuring the expression level of the protein is to determine the expression level of the protein encoded by the gene to be measured included in the sample, by using an antibody or aptamer that can specifically bind to the protein to be measured.
- the method includes Western blot assay, Enzyme linked immunosorbent assay (ELISA), Radioimmunoassay (RIA), Radioimmunodiffusion, Ouchterlony immunodiffusion method, rocket Rocket immunoelectrophoresis, Immunohistochemical staining, Immunoprecipitation Assay, Complement Fixation Assay, Immunofluorescence, Immunochromatography, FACS It may be implemented using an antibody or an aptamer used in methods such as (Fluorescenceactivated cell sorter analysis) and protein chip technology assay.
- the “antibody” refers to a protein molecule capable of specifically binding to an antigenic site of a protein or peptide molecule.
- the form of the antibody is not particularly limited, and as long as it has a polyclonal antibody, a monoclonal antibody, or antigen-binding property, even a part of the antibody may be included, and all types of immunoglobulin antibodies may be included.
- Special antibodies such as humanized antibodies may also be included, which include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains.
- a functional fragment of an antibody molecule refers to a fragment having at least an antigen-binding function, and may be Fab, F(ab'), F(ab') 2, Fv, etc., but is not limited thereto.
- the “aptamer” refers to a single-stranded oligonucleotide, and refers to a nucleic acid molecule having binding activity to a predetermined target molecule.
- the aptamer may have various three-dimensional structures according to its nucleotide sequence, and may have high affinity for a specific substance, such as an antigen-antibody reaction.
- the aptamer may inhibit the activity of a given target molecule by binding to the given target molecule.
- the aptamer may be RNA, DNA, modified nucleic acid, or a mixture thereof, and the aptamer may have a linear or annular pattern.
- the antibody can be prepared by a conventional method after cloning a known nucleotide sequence into an expression vector according to a conventional method to obtain a protein encoded by the gene, and the aptamer is A person skilled in the art can easily manufacture it according to a known method.
- Another embodiment of the present invention provides a method for screening a candidate substance that inhibits the invasion of brain cancer cells.
- the screening method of the present invention comprises the steps of: treating the animal model of the invasive brain cancer of the present invention, or the invasive brain cancer cell of the present invention with a candidate substance that inhibits the invasion of brain cancer cells; and, when the candidate substance inhibits invasion of brain cancer cells, determining the candidate substance as a substance that inhibits invasion of brain cancer cells.
- brain cancer In the method of screening a candidate substance for inhibiting invasion of brain cancer cells of the present invention, "brain cancer”, “glioma”, “cancer tumor cell”, “invasive”, and “vMSLC (ventricular mesenchymal stem-like cells)" It overlaps with that described in the animal model of invasive brain cancer, and a method for preparing the same, and is omitted to avoid excessive complexity of the present specification.
- Another embodiment of the present invention provides a method for screening a candidate substance that inhibits brain cancer metastasis caused by infiltration of brain cancer cells.
- the screening method of the present invention comprises the steps of: treating the animal model of the invasive brain cancer of the present invention, or the invasive brain cancer cell of the present invention with a candidate substance that inhibits the invasion of brain cancer cells; and, when the infiltration of brain cancer cells is inhibited by the candidate substance, determining the candidate substance as a substance that inhibits brain cancer metastasis caused by infiltration of brain cancer cells.
- brain cancer In the method of screening a candidate substance for inhibiting brain cancer metastasis caused by invasion of brain cancer cells of the present invention, "brain cancer”, “glioma”, “cancer tumor cell”, “invasive”, and “vMSLC (ventricular mesenchymal Stem-like cells)" overlaps with those described in the animal model of invasive brain cancer, and a method for preparing the same, and is omitted to avoid excessive complexity of the present specification.
- vMSLC ventricular mesenchymal Stem-like cells
- the animal model of invasive brain cancer of the present invention implements a characteristic of strong invasiveness among brain cancers such as glioblastoma, it is possible to screen a candidate substance that inhibits the invasion of brain cancer cells, or a candidate substance that inhibits brain cancer metastasis caused by invasion of brain cancer cells. It is expected to be actively used for the development of therapeutic agents for invasive brain cancer, such as screening for
- FIG. 1 is a diagram showing the locations of TS (tumor sphere), VS (ventricle sphere), tMSLC (tumor mesenchymal stem like cell), and vMSLC (ventricle mesenchymal stem like cell) in the brain, according to an embodiment of the present invention. .
- FIGS. 2A to 2D are diagrams showing the results of confirming whether the cells extracted from the brain are tMSLC or vMSLC according to an embodiment of the present invention through morphology, differentiation, and mesenchymal stem like cell (MSLC) surface markers.
- MSLC mesenchymal stem like cell
- 3A and 3B are diagrams showing the results of confirming the difference in invasiveness of TS by tMSLC and vMSLC as an invasion area and an expression level of an invasion-related protein, according to an embodiment of the present invention.
- 4A to 4D are diagrams showing the results of analyzing the difference in gene expression between tMSLC and vMSLC using gene expression profiles of tMSLC and vMSLC, according to an embodiment of the present invention.
- 5A and 5B are diagrams showing the results of confirming the difference in the invasive ability of VS according to the culture medium as the invasive area and the expression level of the invasion-related protein according to an embodiment of the present invention.
- 6A to 6C are diagrams illustrating the results of confirming the difference in invasiveness of cancer cells in a mouse animal model transplanted with TS, TS+tMSLC, or TS+vMSLC according to an embodiment of the present invention.
- tMSLCs or vMSLCs as glioblastoma tumorspheres (GBM TSs, 5x10 5 per mouse) were placed in the right frontal lobe of the mouse with a guide-screw system. was used and implanted at a depth of 4.5 mm.
- GBM TSs glioblastoma tumorspheres
- Zeb1 an invasion marker, increased in the order of control (TS) ⁇ tMSLC ⁇ vMSLC.
- MR images were taken using an Achieva 3.0T system (Philips Medical Systems) within 7 days before surgery to remove cancer tissue in each patient.
- An axial image was taken to be parallel to the anterior and posterior edges of the corpus callosum.
- TS tumor sphere
- VS ventricle sphere
- tMSLC tumor mesenchymal stem like cell
- vMSLC vMSLC
- glioblastoma glioblastoma
- TS medium containing DMEM/F-12 (Corning), 1x B27 (Invitrogen), 20 ng/mL bFGF, and 20 ng/mL EGF (Novoprotein).
- MEM ⁇ 10% FBS (Lonza), 2 mM L-glutamine (Mediatech), 100x antibiotic-antimycotic solution (Gibco) were used for culturing tMSLC (tumor mesenchymal stem like cell) and vMSLC (ventricle mesenchymal stem like cell).
- tMSLC tumor mesenchymal stem like cell
- vMSLC ventricle mesenchymal stem like cell
- tMSLC or vMSLC was seeded by adding 70% or more MSC medium to the culture dish, and after cells were attached, the MSC medium was removed and TS medium was added for additional incubation for 24 hours.
- tMSLC conditioned media tMSLC conditioned media
- vMSLC conditioned media vMSLC conditioned media
- Example 1 Whether the cells extracted in Example 1 are tMSLC or vMSLC was always confirmed through morphology, differentiation, and mesenchymal stem like cell (MSLC) surface markers, which are shown in FIGS. 2A to 2D .
- MSLC mesenchymal stem like cell
- tMSLC or vMSLC was cultured with MSC medium at a density of 4 ⁇ 10 4 cells/well in a 6-well culture dish. After the cells were attached, adipogenic differentiation BulletKit (Lonza Walkersville, Walkersville, MD, USA) medium was added, and the medium was replaced once every 3 to 4 days for 3 weeks.
- tMSLC or vMSLC was cultured with MSC medium at a density of 3 ⁇ 10 4 cells/well in a 6-well culture dish.
- osteogenic differentiation BulletKit (Lonza Walkersville) medium was added, and the medium was replaced once every 3 to 4 days for 3 weeks. After 3 weeks, the medium was removed, the cells were washed with PBS, fixed with 70% ethanol (Sigma-Aldrich) at refrigerated temperature for 1 hour, and after washing with PBS, 40 mM Alizarin Red (pH 4.2; Sigma-Aldrich) for 10 minutes It was dyed at room temperature. This was observed after washing 5 times with distilled water.
- FACS buffer (10% FBS + 90% PBS) was used to prepare 1x10 6 cells / 100ul in an EP tube. did.
- 2-5ul of CD16 (DB pharmingen) was treated in all EP tubes at 4°C for 15-20 minutes, and the cell pellet was left through centrifugation, washed once with FACS buffer, and then pelleted using 100ul of FACS buffer. released This was treated with 5-10ul/100ul of the primary antibody at 4°C for 30 minutes, centrifuged and cells were washed, and the secondary antibody was treated with 1-20ul/100ul of the secondary antibody at 4°C for 30 minutes.
- a 96-well culture dish was filled with Matrigel, collagen type I (Corning Incorporated), and TS medium, and one tumor sphere was seeded into each well.
- TS medium, tMSLC conditioned medium, or vMSLC conditioned medium is added and cultured for 72 hours and observed. After 72 hours, the invasion area of the tumor cells was measured and compared with day 0. This is shown in Figures 3a and 3b.
- Total RNA was extracted from glioblastoma tumor cells and the tissue of the patient using the Qiagen RNeasy Plus Mini kit (Qiagen, USA) according to the method provided by the manufacturer.
- the extracted total RNA was loaded onto an Illumina HumanHT-12 v4 Expression BeadChip (Illumina HumanHT-12 v4 Expression BeadChip, Illumina, USA).
- Illumina HumanHT-12 v4 Expression BeadChip Illumina HumanHT-12 v4 Expression BeadChip, Illumina, USA.
- a quantile normalization method using the R/Bioconductor lumi package was used for stabilization and standardization of data transformation. Average linkage hierarchical clustering was performed using Pearson's correlation as a distance metric using GENE-E software, and the expression level of each gene was represented as a heat map.
- tMSLC and vMSLC were similar in whole gene expression profiles, but the existence of 643 differentially expressed genes (DEGs) was confirmed. Specifically, in the case of vMSLC, the expression of genes related to invasion-related cell migration, chemokine production, and chemotaxis was high.
- VS was always cultured in TS medium, tMSLC conditioned medium, or vMSLC conditioned medium using the matrix of Example 3, cell lysates, and SDS- in 10% Tris-glycine gels PAGE was performed. Electrophoresed proteins are transferred to nitrocellulose membranes, ⁇ -catenin (BD Biosciences), N-cadherin (R&D Systems), Zeb1 (Sigma-Aldrich), CD44 (Cell Signaling Technology), or GAPDH (Santa) Cruz Biotechnology) was treated with the primary antibody.
- ⁇ -catenin BD Biosciences
- N-cadherin R&D Systems
- Zeb1 Sigma-Aldrich
- CD44 Cell Signaling Technology
- GAPDH Cell Signaling Technology
- mice Male thymus nude mice (6 weeks old, Central Lab. Animal Inc.) were used for the experiment after having an acclimatization period in a sterilized state with light, temperature, and humidity control for 1 week before the experiment.
- the same number of tMSLCs or vMSLCs as glioblastoma tumorspheres (GBM TSs, 5x10 5 per mouse) were placed in the right frontal lobe of the mouse with a guide-screw system. was used and implanted at a depth of 4.5 mm. If the animal's body weight decreased by 15% or more from the maximum during the test period, euthanasia was performed.
- the tissue was prepared as a paraffin block, and a slide was prepared by cutting it into a 5- ⁇ m thickness using a microtome.
- Antigen retrieval and antibody attachment were performed using an automated device (Discovery XT), and peroxidase / DAB staining was performed to observe the invasion marker Zeb1.
- the results are shown in Figs. 6a to 6c.
- TS+vMSLC As a result of confirming the survival rate and tumor formation of mice in vivo, significant brain cancer formation was observed in the TS+vMSLC experimental group, and the expression of Zeb1, an invasion marker, increased in the order of control (TS) ⁇ tMSLC ⁇ vMSLC.
- glioblastoma Compared to other brain cancers, glioblastoma is the most malignant, highly invasive, and has a very poor prognosis as it exhibits an aggressive variant. If not treated promptly, glioblastoma can have fatal consequences within a few weeks. However, due to the unique characteristics of the brain that it is difficult for a therapeutic drug to be delivered to a target brain region due to the brain blood barrier, there is no special treatment other than radiation therapy to date. Since the animal model according to the present invention implements a characteristic of strong invasiveness among brain cancers such as glioblastoma, it is expected that it can be actively used for the development of therapeutic agents for invasive brain cancer.
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Abstract
La présente invention concerne un modèle animal de cancer invasif du cerveau et son procédé de production. Un modèle animal de cancer invasif du cerveau de la présente invention met en œuvre l'invasivité élevée du cancer du cerveau tel que le glioblastome, et ainsi est prévu pour être activement utilisé dans le développement d'agents thérapeutiques contre le cancer invasif du cerveau, tel que dans le criblage de substances candidates qui inhibent l'invasion des cellules du cancer du cerveau ou le criblage de substances candidates qui inhibent la métastase du cancer du cerveau causée par l'invasion des cellules du cancer du cerveau.
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| AURéLIE TCHOGHANDJIAN; NATHALIE BAEZA-KALLEE; CHRISTOPHE BECLIN; PHILIPPE METELLUS; CAROLE COLIN; FRANçOIS DUCRAY; JOSé ADéLAÃ: "Cortical and Subventricular Zone Glioblastoma-Derived Stem-Like Cells Display Different Molecular Profiles and Differential In Vitro and In Vivo Properties", ANNALS OF SURGICAL ONCOLOGY, vol. 19, no. 3, 12 October 2011 (2011-10-12), Ne , pages 608 - 619, XP035092683, ISSN: 1534-4681, DOI: 10.1245/s10434-011-2093-5 * |
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| LIM EUN-JUNG, KIM SEUNGMO, OH YOONJEE, SUH YONGJOON, KAUSHIK NEHA, LEE JI-HYUN, LEE HAE-JUNE, KIM MIN-JUNG, PARK MYUNG-JIN, KIM RA: "Crosstalk between GBM cells and mesenchymal stemlike cells promotes the invasiveness of GBM through the C5a/p38/ZEB1 axis", NEURO-ONCOLOGY, vol. 22, no. 10, 14 October 2020 (2020-10-14), US , pages 1452 - 1462, XP055960407, ISSN: 1522-8517, DOI: 10.1093/neuonc/noaa064 * |
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