CN114028541A - Application of GDF2 in preparation of medicines for improving abnormal blood vessels of tumors - Google Patents
Application of GDF2 in preparation of medicines for improving abnormal blood vessels of tumors Download PDFInfo
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- CN114028541A CN114028541A CN202110558821.7A CN202110558821A CN114028541A CN 114028541 A CN114028541 A CN 114028541A CN 202110558821 A CN202110558821 A CN 202110558821A CN 114028541 A CN114028541 A CN 114028541A
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- gdf2
- blood vessels
- liver cancer
- abnormal blood
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1841—Transforming growth factor [TGF]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides an application of GDF2 or a vector expressing GDF2 in preparing a medicament for improving abnormal blood vessels of tumors. The growth differentiation factor-2 (GDF2) can repair the abnormal blood vessels of HBV-infected liver cancer, is helpful for immune cells to treat liver cancer, provides a new treatment scheme for the normal repair of abnormal blood vessels in liver cancer, and has good application prospect in the aspect of immunotherapy of liver cancer.
Description
Technical Field
The present invention relates to the use of GDF 2.
Background
Clinically, most patients are in middle and advanced stages, and in cases of low differentiated cancer, late course of disease and relapse after radiotherapy, the relapse and metastasis often happen after the treatment of liver cancer by regular means such as surgery, radiotherapy, chemotherapy and the like. Immunocytotherapy is a fourth method of treating tumors, followed by surgery, chemotherapy, and radiation therapy. No matter which kind of treatment method is adopted, the treatment effect is inseparable from that of T cells, wherein the existence activity and the quantity of the T cells directly determine the quality of the treatment effect, and the normalization of blood vessels in the transportation and the transmission process of the T cells plays an important role in guaranteeing the activity and the quantity of the T cells.
Disclosure of Invention
It is an object of the present invention to provide a variety of uses for GDF 2.
In order to realize the purpose, the technical scheme is as follows: use of GDF2 or a vector expressing GDF2 for the preparation of a medicament for the amelioration of abnormal blood vessels in a tumor.
The invention provides an application of GDF2 or a vector expressing GDF2 in preparing a medicament for helping immune cells to kill tumors.
The invention provides the use of the combination of GDF2 and immune cells in the preparation of a medicament for the treatment of tumors.
Immune cells are a class of cells that act through the peripheral blood. GDF2 can significantly delay the growth of abnormal blood vessels in tumor and promote the normalization of abnormal blood vessels. Meanwhile, GDF2 can increase the number of immune cells by normalizing vascular transportation and enhance the capability of killing tumors, so that the medicine has more obvious treatment effect on liver cancer.
The invention provides an application of a combination of a vector expressing GDF2 and immune cells in preparing a medicament for treating tumors.
Preferably, the improvement of tumor abnormal blood vessels means inhibiting the growth of tumor abnormal blood vessels and repairing the development of tumor abnormal blood vessels to normalized blood vessels.
Preferably, the tumor is liver cancer.
Preferably, the tumor is HBV positive liver cancer.
The invention provides a medicament for treating tumors, which comprises one of GDF2 and a vector expressing GDF2, and immune cells.
Preferably, the tumor is liver cancer.
Preferably, the tumor is HBV positive liver cancer.
Preferably, the medicament further comprises a medically acceptable adjuvant or carrier.
Has the advantages that:
the invention provides multiple purposes of GDF2, the growth differentiation factor-2 (GDF2) can repair the abnormal blood vessels of the liver cancer infected by HBV, is beneficial to immune cells to treat the liver cancer, provides a new treatment scheme for the normal repair of abnormal blood vessels in the liver cancer, and has good application prospect in the aspect of immunotherapy of the liver cancer.
Drawings
FIG. 1 is a graph showing the effect of a strain of hepatocellular carcinoma cells overexpressing GDF2 on vascular endothelial homeostasis in vitro.
FIG. 2 shows the effect of GDF2 overexpression in hepatocellular carcinoma cells on vascular endothelial homeostasis.
FIG. 3 shows the effect of GDF2 overexpression in hepatocellular carcinoma cells on immune lymphocyte infiltration.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise indicated. Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Years of practical work of the inventor team shows that more than 95% of liver cancer patients are HBV positive clinically, so the experiment in the following examples shows HBV positive liver cancer as an example.
Example 1 Effect of overexpression of GDF2 on vascular endothelial homeostasis and immune cell infiltration
1. Experimental Material
(1) HUVEC endothelial cells: human-derived vascular endothelial cells
(2) CIK cells: human cord blood-derived CIK cells
(3) Cancer cell: HBV negative/positive hepatoma cells (HepG2-HBV-, HepG2.2.15-HBV + and Huh6-HBV-, HB611-HBV +)
(4) Commercially available immunodeficient NCG mice.
2. Experiment grouping
(1) Control group 1: the negative control (HepG2-HBV-), i.e., the liver cancer cells, were not subjected to any treatment.
(2) Control group 2: positive control (HepG2.2.15-HBV +), i.e., hepatoma cells transfected with over-expressed empty vectors.
(3) Set of cells overexpressing GDF 2: HBV positive hepatoma cells (HepG2.2.15-HBV +) were treated with GDF2 overexpression viral transfection.
(4) CIK cell return + control 1: after the negative control group cells are inoculated, CIK cells are used for returning and treating HBV negative liver cancer cells.
(5) CIK cell return + control 2: after the positive control group cells are inoculated, CIK cells are used for returning and treating HBV positive liver cancer cells.
(6) CIK cell transfusion + over-expression GDF2 cell group: after inoculating the over-expressed GDF2 cells, using CIK cells to return and treat HBV positive hepatoma cells.
3. Cell line co-incubation and Yiwanlan assay to examine the effect of over-expression of GDF2 on endothelial cell stability
(1) Are respectively 2 × 105Numerical HBV negative/positive hepatoma cells (HepG2, HepG2.2.15 and Huh6, HB611) were plated in 6-well plates, one parallel per well. Randomized into 3 groups: negative control group 1, positive control group 2, group of cells overexpressing GDF 2. In addition, 2 is multiplied by 105Numerical endothelial cells were plated in transwell chambers (0.4um) for culture.
(2) When the cell flat layer in the 6-well plate and chamber grew full: we embedded the chambers separately into the corresponding 6-well plates and performed a 96h co-incubation.
(3) The cell state was observed once a day while cell culture broth was replenished.
(4) And after 96h, adding an avalanin dye into the small chamber, standing for 90min, and respectively sucking the culture medium of the small chamber and the culture medium of the corresponding hole to perform the detection of avalanin permeation.
4. The immunodeficiency NCG mouse subcutaneous tumor formation experiment detects the influence of CIK cell reinfusion or/and over-expression GDF2 on HBV positive liver cancer cell transplantation tumor
(1) Are respectively 2.5 × 106Numerical HBV negative/positive liver cancer cells (HepG2 or HepG2.2.15) were implanted subcutaneously in axilla of 20 NCG mice aged 4 weeks. Randomized into 6 groups: negative control group 1, positive control group 2, over-expression GDF2 cell group, CIK cell feedback + control group 1, CIK cell feedback + control group 2, and CIK cell feedback + over-expression GDF2 cell group.
(2) When the size of subcutaneous tumor reaches 100-200 mm3The method comprises the following steps: CIK cell Return + 1X 10 administration of CIK cells to the tail vein of each mouse of control group 1 every three days7One/one 1 time, during which IL-2 was administered intraperitoneally daily (10000U/one/day); CIK cell Return + control group 2 Each mouse was given 1X 10 CIK cells every three days of tail vein7One/one 1 time, during which IL-2 (10000U/one/day) was administered intraperitoneally every day; CIK cell transfusion + administration of 1X 10 CIK cells to the tail vein of each mouse overexpressing GDF2 cell group every three days7One/one 1 time, during which IL-2 was administered intraperitoneally daily (10000U/one/day).
(3) After 2 weeks, the mice were sacrificed by cervical dislocation, tumor tissue was excised, immunohistochemistry was performed to detect the infiltration of CIK marker (CD3), tumor growth and weight, and immunofluorescence of vascular associated factors (CD31, NG2, α -SMA) was finally performed.
5. Results of the experiment
The result is shown in fig. 1, after the GDF2 is over-expressed, the damage of HBV negative/positive liver cancer cells to the stability of endothelial cells can be resisted, which shows that the expression of GDF2 has a significant inhibition effect on the damage of the stability of vascular endothelial cells caused by HBV negative/positive liver cancer.
In addition, as shown in fig. 2, immunofluorescence assay results showed that the over-expression of GDF2 significantly recruited pericytes and promoted abnormal blood vessel growth toward normalization, indicating the significance of GDF2 for normalization of blood vessels.
More importantly, as shown in fig. 3, immunohistochemical results show that over-expression of GDF2 promotes CIK cells to enter the tumor.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
- Use of GDF2 or a vector expressing GDF2 in the manufacture of a medicament for ameliorating abnormal blood vessels in a tumor.
- Use of GDF2 or a vector expressing GDF2 in the manufacture of a medicament for use in the killing of tumours by immune cells.
- Use of a combination of GDF2 and immune cells in the manufacture of a medicament for the treatment of a tumour.
- 4. Use of a vector expressing GDF2 in combination with an immune cell in the preparation of a medicament for the treatment of a tumour.
- 5. The use according to claim 1, wherein the improvement of abnormal blood vessels in tumor is the inhibition of the growth of abnormal blood vessels in tumor, and the repair of abnormal blood vessels in tumor to the development of normal blood vessels.
- 6. The use according to any one of claims 1 to 4, wherein the tumor is liver cancer.
- 7. The use according to any one of claims 1 to 4, wherein the tumor is HBV positive liver cancer.
- 8. A medicament for treating a tumour, the medicament comprising one of GDF2 and a vector expressing GDF2, and an immune cell.
- 9. The medicament of claim 8, wherein the tumor is liver cancer.
- 10. The medicament of claim 8, further comprising a pharmaceutically acceptable adjuvant or carrier.
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Citations (5)
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|---|---|---|---|---|
| CN105963695A (en) * | 2008-05-02 | 2016-09-28 | 阿塞勒隆制药公司 | Methods and compositions based on ALK1 antagonists for modulating angiogenesis and pericyte coverage |
| CN106994181A (en) * | 2017-03-10 | 2017-08-01 | 上海交通大学医学院附属第九人民医院 | BMP9 is preparing the application in delaying hepatic fibrosis medicines |
| CN108348575A (en) * | 2015-09-01 | 2018-07-31 | 日东制药株式会社 | Pharmaceutical composition for preventing and treating cancer or angiogenesis-associated diseases contains the fusion protein as active ingredient, which has merged tumour penetrating peptide and anti-angiogenic agent |
| CN109692182A (en) * | 2019-01-15 | 2019-04-30 | 新乡医学院 | Taraxacum Polysaccharides inhibit the application in liver cancer cells angiogenesis drug in preparation |
| US20190137495A1 (en) * | 2017-06-04 | 2019-05-09 | Rappaport Family Institute for Research in the Me dical Sciences | Method of Predicting Personalized Response to Cancer Therapy, Method of Treating Cancer, and Kit Therefor |
-
2021
- 2021-05-21 CN CN202110558821.7A patent/CN114028541A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105963695A (en) * | 2008-05-02 | 2016-09-28 | 阿塞勒隆制药公司 | Methods and compositions based on ALK1 antagonists for modulating angiogenesis and pericyte coverage |
| CN108348575A (en) * | 2015-09-01 | 2018-07-31 | 日东制药株式会社 | Pharmaceutical composition for preventing and treating cancer or angiogenesis-associated diseases contains the fusion protein as active ingredient, which has merged tumour penetrating peptide and anti-angiogenic agent |
| CN106994181A (en) * | 2017-03-10 | 2017-08-01 | 上海交通大学医学院附属第九人民医院 | BMP9 is preparing the application in delaying hepatic fibrosis medicines |
| US20190137495A1 (en) * | 2017-06-04 | 2019-05-09 | Rappaport Family Institute for Research in the Me dical Sciences | Method of Predicting Personalized Response to Cancer Therapy, Method of Treating Cancer, and Kit Therefor |
| CN109692182A (en) * | 2019-01-15 | 2019-04-30 | 新乡医学院 | Taraxacum Polysaccharides inhibit the application in liver cancer cells angiogenesis drug in preparation |
Non-Patent Citations (4)
| Title |
|---|
| JAE WOO JUNG等: "Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population", 《ONCOTARGET》 * |
| MARIE OUARNÉ等: "BMP9, but not BMP10, acts as a quiescence factor on tumor growth, vessel normalization and metastasis in a mouse model of breast cancer", 《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》 * |
| WEI LIU等: "Highly expressed BMP9/GDF2 in postnatal mouse liver and lungs may account for its pleiotropic effects on stem cell differentiation, angiogenesis, tumor growth and metabolism", 《GENES & DISEASES》 * |
| 马翠: "BMP9与肝脏疾病的研究进展", 《中国药理学通报》 * |
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