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WO2015108195A1 - Méthode d'évaluation de la malignité d'une tumeur maligne chez un animal non humain - Google Patents

Méthode d'évaluation de la malignité d'une tumeur maligne chez un animal non humain Download PDF

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Publication number
WO2015108195A1
WO2015108195A1 PCT/JP2015/051290 JP2015051290W WO2015108195A1 WO 2015108195 A1 WO2015108195 A1 WO 2015108195A1 JP 2015051290 W JP2015051290 W JP 2015051290W WO 2015108195 A1 WO2015108195 A1 WO 2015108195A1
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tumor
cells
human animal
malignancy
antibody
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Japanese (ja)
Inventor
晋平 川原井
広郎 斑目
拓也 圓尾
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SCHOOL Corp AZABU VETERINARY MEDICINE EDUCATIONAL INSTITUTION
School Corp Azabu Veterinary Medicine Educational Inst
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SCHOOL Corp AZABU VETERINARY MEDICINE EDUCATIONAL INSTITUTION
School Corp Azabu Veterinary Medicine Educational Inst
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Priority to JP2015557918A priority Critical patent/JP6583785B2/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705

Definitions

  • the present invention relates to a method for evaluating the malignancy of a malignant tumor of a non-human animal. More specifically, the method for evaluating the malignancy of a malignant tumor of a non-human animal of the invention includes a method for predicting the prognosis of the tumor.
  • Mast cell tumors are tumors that are common in dogs and cats and often occur in the skin. In dogs, they are the most common skin tumor and the second most common in cats. .
  • Canine cutaneous mastocytoma is one of the common skin tumors, accounting for 7-21% of all skin tumors, and its biological behavior is very diverse. While there are benign cases that can be completely cured by surgical resection, there are various types of cases such as those that invade regional lymph nodes, those that recur after surgical resection, and those that cause fatal metastases Are known. Therefore, an index of malignancy of canine cutaneous mastocytoma or an index for predicting prognosis has been required.
  • Patnaik's classification method proposed by Patnaik et al. Has been used. Patnaik's classification method is based on the extent of lesion, cell density, cell morphology, fission index, stromal response, etc., well differentiated (grade I), moderately differentiated (grade II), poorly differentiated (grade) Classify as III).
  • the mitotic index is one of the most important indices (Non-patent Document 3).
  • the present inventors examined a method for more accurately evaluating the malignancy of a non-human animal malignant tumor and predicting the prognosis. That is, the present invention relates to a method for evaluating the malignancy of a malignant tumor of a non-human animal and predicting a prognosis.
  • CD34 is a transmembrane protein and is usually expressed in skeletal muscle satellite cells, gastrointestinal chahar-mediated cells, vascular endothelium, brain neuronal cell bodies, and dermal dendritic cells. CD34 is also expressed in hematopoietic stem cells, and CD34 positive cells are known as mast cell progenitors (Kawarai et al., J Vet Med Sci.
  • CD34 may have different expression depending on the degree of differentiation of tumor cells of cutaneous mastocytoma.
  • bone marrow-derived cultured mast cells obtained from CD34-deficient mice have also been reported to aggregate with each other compared to mast cells obtained from wild-type mice (Drew E, et al. , Immunity. 2005 Jan; 22 (1): 43-57.). Therefore, as a result of examining the possibility as a new prognosis or metastasis factor, the inventors have found that the level of immunostaining with an anti-CD34 antibody in a sample derived from canine cutaneous mastocytoma is not less than +2 (described later). It has been found for the first time that the prognosis is poor when the proportion of cells is approximately 20% or more.
  • the present invention includes the following (1) to (11).
  • a method for evaluating the malignancy of a tumor in a non-human animal wherein CD34 expressed in cells in a sample derived from a subject animal containing tumor cells is detected, and the CD34 against the cells present in the sample is detected. The ratio of the cell which expresses is calculated, The method of evaluating the malignancy of this tumor based on the ratio.
  • a diagnostic kit for evaluating the malignancy of a tumor of a non-human animal comprising an anti-CD34 antibody.
  • the non-human animal is a dog or a cat, and the tumor is cutaneous mastocytoma.
  • the malignancy evaluation method and prognosis prediction method of the present invention it is possible to accurately diagnose the malignancy and prognosis of tumor cells of non-human animals, particularly mastocytoma.
  • the malignancy evaluation method and prognosis prediction method of the present invention can provide a clue for determining the resection range of a tumor.
  • the present invention Until now, unless surgery was performed, malignancy or prognosis could not be determined, and it was necessary to consider the indication of chemotherapy in all cases. According to the present invention, the possibility of metastasis can be predicted without performing image diagnosis, and chemotherapy can be started in accordance with the results of the present invention. That is, it is possible to perform appropriate chemotherapy for necessary cases. In this respect, the present invention also exerts an effect that it is not necessary to perform unnecessary chemotherapy for a negative case.
  • FIG. 1 is an ROC curve for canine mastocytoma.
  • FIG. 2 is a diagram showing the relationship between Patnaik grade and CD34 staining according to the present invention.
  • FIG. 3 shows the results of immunostaining of cells derived from canine mastocytoma with anti-CD34 antibody. Refer to the text of the specification for staining 1+, 2+ and staining 3+.
  • FIG. 4 shows the log rank test results regarding the presence or absence of metastasis of mastocytoma in dogs and the number of days of survival.
  • FIG. 5 shows the log rank test results regarding the staining ability of CD34 antibody-derived cells of canine mastocytoma-derived cells and the survival days.
  • the present invention is a method for evaluating the malignancy of a tumor cell, predicting the prognosis, or the presence of metastasis using the expression level of CD34 expressed in the tumor cell as an index. That is, one of the embodiments of the present invention is a method for evaluating the malignancy of a tumor in a non-human animal or predicting prognosis, and is expressed in cells in a sample derived from a target animal including tumor cells. When the expression of CD34 is detected and the number of cells expressing CD34 is a certain percentage or more of the total number of cells present in the sample, it is judged that the tumor has a high malignancy or a poor prognosis Is the method.
  • “high malignancy” means that the prognosis thereafter is poor, and the malignancy obtained using the tumor malignancy evaluation method of the present invention is determined by surgical operation of the tumor. This is effective in determining the range of resection, and the choice of treatment methods such as the necessity of pre- or post-operative adjuvant therapy or medical therapy (such as chemotherapy using chemotherapeutic agents or molecular targeted drugs). Accordingly, the use of the present invention to determine the therapeutic range and method of treatment of the tumor naturally falls within the scope of the present invention within the scope of the present invention.
  • “prognosis” has the same meaning as used in the medical field and is not particularly limited.
  • a view regarding an expected medical condition (health condition), a future of illness / wound It is a state.
  • the prognostic evaluation or prognosis includes, for example, grade diagnosis of cancer, malignancy diagnosis, prediction of the presence or absence of metastasis in the future, presence or absence of deterioration of symptoms after surgery Predictions can be mentioned.
  • the poor prognosis refers to, for example, a case where there is a possibility that the survival rate is shortened, the risk of recurrence is increased, and / or the tumor has metastasized to another site.
  • the tumor cells in the present invention are cells that originate from cells expressing CD34, such as cells derived from hair follicle stem cells, mast cells, vascular endothelial cells, fibroblasts, and Langerhans cells. Particularly preferred are mastocytoma cells.
  • the non-human animal that is the subject of the prognostic evaluation method of the present invention is not particularly limited, and examples thereof include dogs, cats, ferrets, and the like.
  • CD34 is a 110 kDa single-chain transmembrane phosphorylated glycoprotein, but when described herein as “CD34”, it refers to a protein.
  • Nucleic acid Information such as the amino acid sequence and nucleic acid sequence of CD34 has already been disclosed in public databases, and can be easily obtained by those skilled in the art.
  • the canine CD34 amino acid sequence and nucleic acid sequence are SEQ ID NOs: 1 and 2, respectively
  • the feline CD34 amino acid sequence and nucleic acid sequence are SEQ ID NOs: 3 and 4, respectively.
  • a preferred embodiment of the present invention includes the step of detecting CD34.
  • means for collecting a sample of tumor cells from the animal to be diagnosed may be any method easily selected by those skilled in the art, for example, a needle biopsy for obtaining a cell sample using a puncture needle, or a surgical incision. It can be carried out by a method such as an incision biopsy to obtain an affected tissue piece.
  • the expression state of CD34 in a diagnostic sample containing tumor cells can be carried out by a method that can be easily selected by those skilled in the art.
  • a tissue specimen or cytological specimen can be prepared and examined.
  • the tissue specimen or cell specimen may be produced using any known method.
  • the collected tissue or the like can be fixed with formalin or the like, and after paraffin embedding treatment, a section can be prepared and immunohistochemical staining can be performed to examine the expression level of CD34.
  • it can also implement by Liquid Based Cytology (LBC: Liquefaction cytology) which is one method of cytodiagnosis.
  • LBC Liquid Based Cytology
  • an antibody against CD34 can be used to detect CD34 expressed in collected tissues or cells by an immunohistochemical technique.
  • anti-CD34 antibody any one of an antibody prepared by a person who carries out the present invention or a commercially available antibody (for example, SANTARUCRUZ BIOTECHNOLOGY, # sc-7045) can be used. Or a polyclonal antibody may be sufficient.
  • the antibody does not have to be a complete antibody, and may be a fragment containing a CDR region or the like, or may be prepared by genetic engineering.
  • the antibody fragment may be any fragment that binds to CD34 expressed on cells and can be used for immunohistochemical staining.
  • DAB diaminobenzidine
  • ACE aminomethylcarbazole
  • BCIP / NBT 5-bromo-4-chloro-3-indoxyl Phosphate / nitro blue tetrazolium chloride
  • a tissue or cell specimen stained at a low magnification is observed with a microscope, a region having the strongest staining intensity is selected, and then the region is observed under a high-magnification visual field to select 100 cells to be observed.
  • the staining intensity of each of the selected 100 cells is classified into the following four (see also FIG. 1). 0: Cells that are not stained or are slightly stained as much as the background. 1+: Cells that are indistinguishable from 0 at a low magnification, but are light and stainable at a high magnification. 2+: Cells whose staining property can be confirmed at a low magnification and completely stained at a high magnification. 3+: Cells that are completely stained at low magnification.
  • Cells having a staining ability of 2+ or more with respect to 100 selected cells are determined as “cells expressing CD34”, and the ratio is calculated.
  • the ratio is 10% or more, 15% or more, more preferably 20% or more.
  • the above four levels of staining may be evaluated by quantifying and digitizing the staining intensity obtained from the image.
  • a high-magnification field image (200 to 400 times) of a main tumor cell group stained on a microscope is photographed, and the color stained with CD34 expression positive in the photographed image is displayed as a bioimaging analysis system (Lumina Vision, Mitani Corp.) and divide it into red, green, and blue RGB colors.
  • the stained positive area on the photographed image is obtained by subtracting the negative area that is non-specifically stained with the negative antibody, and the ROC curve is obtained by statistical analysis between the positive area and the metastasis and survival results to cut off.
  • a value can be set and a cutoff value or higher can be determined as positive.
  • CD34 mRNA expressed in tumor cells in a sample may be detected by a so-called hybridization method to monitor the expression status of CD34.
  • hybridization methods include in situ hybridization methods (see, for example, Pascucci et al., Vet Dermatol. 2006 Aug; 17 (4): 244-51).
  • Labeled probes complementary to CD34 mRNA such as radioactively labeled probes, digoxigenin (DIG) probes, fluorescently labeled (FITC, RITC, etc.) probes, etc. Can be used to detect the amount of CD34 mRNA in a sample section or specimen.
  • Evaluation of the amount of mRNA of CD34 in the sample is performed by observing the signal obtained from the labeled probe under a microscope, classifying the observed cells into four stages as described above [0019] based on the signal intensity from the label, The ratio of cells having a signal intensity of 2+ or more can be calculated and used as an indicator of prognosis.
  • the amount of CD34 mRNA expressed in a sample is detected by quantitative RT-PCR (real time PCR) as a method for detecting the level of CD34 expressed in tumor cells in the sample. May be.
  • Another embodiment of the present invention is a kit for evaluating malignancy of a tumor cell that develops in a non-human animal such as a dog or a cat, for example, a mastocytoma, or a prognosis diagnostic kit.
  • the present invention provides a method for evaluating the malignancy of a tumor cell and predicting the prognosis using the expression level of CD34 in the tumor cell as an index. Therefore, the probe or primer used to measure the expression level of anti-CD34 antibody or CD34 mRNA used to measure the expression level of CD34 in tumor cells contained in the sample is the prognosis of non-human animals. This application is disclosed for the first time in the present invention.
  • the diagnostic kit for prognosis of tumor cells of the present invention includes a probe for detecting CD34 expressed in cells as an essential component thereof, for example, an anti-CD34 antibody, a probe for detecting CD34 mRNA. It is.
  • a fixing agent such as formalin necessary for immunostaining a tissue or cells to be diagnosed, immunohistochemical staining or quantitative RT-PCR is performed.
  • it may contain a chromogenic substrate, a buffer and the like.
  • Experimental method 1-1 Test animals Visited the department of oncology at Azabu University Hospital between 2007 and 2011. After surgical removal, the tumor was removed and submitted to the pathology laboratory of the hospital to be diagnosed with mastocytoma. Fifteen cases were included. Information about the clinical course, date of collection, age, sex, dog breed, body weight, distribution and number of mass lesions, location of mass, and surgical margin for each case can be obtained from the histopathology request form. It was. Information about the cases is summarized in Table 1.
  • the embedded tissue is sliced to 3-5 ⁇ m and then slide glass (MICRO SLIDE GLASS pre-clean water drainage, code S-7224, Matsunami Glass Industry) (MICRO SLIDE GLASS water edge polishing frost, code S-8215, Matsunami Glass Industry) ) To obtain tissue sections, and immunohistochemical staining was performed.
  • Hematoxylin and eosin (HE) staining Tissue sections were deparaffinized (xylene I for 7 minutes, xylene II for 7 minutes, 99% alcohol I for 5 minutes, 99% alcohol II for 10 minutes, 80% alcohol for 7 minutes And 70% alcohol for 7 minutes) and passed through distilled water 10 times. Subsequently, the mixture was passed through a hematoxylin solution (Tissue Tech Hematoxylin 3G, code 8656, Sakura Finetech Japan) for 3 minutes, washed with running water for 30 minutes, and distilled water 10 times.
  • a hematoxylin solution Tissue Tech Hematoxylin 3G, code 8656, Sakura Finetech Japan
  • eosin liquid Tissue Tech eosin, code 8659 Sakura Finetech Japan
  • color separation and dehydration treatment 70% alcohol, 80% alcohol, 90% alcohol, 95% alcohol, each several times, 99% Alcohol I, 99% Alcohol II, 99% Alcohol III, 99% Alcohol IV for 5 minutes each
  • thorough treatment xylene I for 7 minutes, xylene II for 7 minutes, xylene III for 10 minutes
  • Encapsulant (NEW M • X, code FX00500, Matsunami Glass Industry Co., Ltd. was used.
  • Antigen activation treatment was performed using a pressure kettle (Tifar krypsocler, model P4310731, Group Cebu Japan), and the sections were immersed in the antigen activation solution (Dako REALTM Target Retrieval Solution, code S2031, Dako) and pressurized for 5 minutes. . After the pressure treatment, the mixture was cooled at room temperature for 20 minutes, and then washed with PBS.
  • the primary antibody is an anti-human CD34 goat polyclonal antibody that is known to cross-react with dogs immunohistochemically (sc-7045, SANTA CRUZ; Jennings et al., Vet Pathol., 49: 532-537, 2012) Was used. After flowing blocking serum, the primary antibody was added dropwise and reacted at a concentration of 1: 100 overnight at 4 ° C. (about 12 hours).
  • goat IgG PURIFIED GOAT IgG, code PCP001, AbD SEROTEC
  • KITPBS KITPBS was washed to remove excess water.
  • a histofine biotin-labeled anti-goat IgG antibody code 416022, Nichirei
  • the secondary antibody was reacted at room temperature for 10 minutes.
  • histofine peroxidase-labeled streptavidin code 426062, Nichirei
  • PBS was washed to remove excess water.
  • a simple stain DAB solution (code 415172, Nichirei) was added dropwise, and color development was performed for 7 minutes under a microscope. After stopping color development with distilled water, counterstaining was performed with Mayer's hematoxylin (code 30002, Muto Chemical) for 30 seconds, washed with running water for 30 minutes, and passed through distilled water 10 times. Then, dehydration treatment (70% alcohol, 80% alcohol, 90% alcohol, 99% alcohol I, 99% alcohol II, 99% alcohol III each for 7 minutes) and clearing treatment (xylene I, xylene II, xylene III each 7 minutes) and sealed with M ⁇ X.
  • dehydration treatment (70% alcohol, 80% alcohol, 90% alcohol, 99% alcohol I, 99% alcohol II, 99% alcohol III each for 7 minutes
  • clearing treatment xylene I, xylene II, xylene III each 7 minutes
  • Histopathological evaluation (1) HE staining Grade sections of each case diagnosed as cutaneous mastocytoma were classified according to Patnaik's report (Patnaik et al., Vet Pathol., 21: 469-474, 1984). It was. Observations include tumor invasion site, cell density, morphology of cells and nuclei, cell borders, presence or absence of cytoplasmic granules, fission image in high magnification field, presence or absence of eosinophil infiltration, degree of sweat gland, lymphatic vessel dilation Interstitial reactions including presence and extent, presence or absence of collagen fiber degeneration, necrosis, edema and bleeding were performed.
  • the epidermis When evaluating the site of tumor invasion, the epidermis is a layer composed of stratified squamous epithelial cells with a keratinized layer, and the dermis is a dense fiber in the epidermis where hair follicles, sebaceous glands, sweat glands, lymphatic vessels, etc. are observed Sexual connective tissue and subcutaneous tissue were fibrillar connective tissue including adipose tissue. Furthermore, the dermis was divided into three layers, the layer from the epidermis to the region where the appendages were present was the shallow layer, the region where the appendages were present was the middle layer, and the layers below the middle layer were the deep layers. For the subcutaneous tissue, the upper layer close to the dermis was the shallow layer, and the lower layer close to the muscle layer was the deep layer.
  • 1+ Indistinguishable from 0 at low magnification, but light and highly stainable at high magnification.
  • the prognosis of grade 3 mastocytoma is poor, but when the resection margin is sufficient, the prognosis may be good. Therefore, the Patnaik grade classification alone may be insufficient as a prognostic indicator.
  • the present invention provides a method for evaluating the grade of malignancy of a non-human animal tumor, a method for determining a prognosis, and a kit suitable for use of the method.
  • the method of the present invention that makes it possible to appropriately determine the prognosis of tumors in non-human animals, particularly pet animals such as dogs and cats, is highly expected to be put to practical use in the field of animal medicine.

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Abstract

La présente invention concerne une méthode d'évaluation de la malignité d'une tumeur maligne chez un animal non humain et une composition destinée à être utilisée pour ladite évaluation. La méthode d'évaluation de la malignité d'une tumeur chez un animal non humain consiste à : détecter l'antigène CD34 qui est exprimé dans des cellules d'un échantillon contenant des cellules tumorales dérivé de l'animal sujet ; et, lorsque le rapport de cellules exprimant l'antigène CD34 à la totalité des cellules dans l'échantillon est supérieur ou égal à un niveau prédéfini, évaluer la tumeur comme étant maligne. L'invention concerne également un kit de diagnostic permettant d'évaluer la malignité d'une tumeur chez un animal non humain, ledit kit comprenant un anticorps anti-CD34.
PCT/JP2015/051290 2014-01-20 2015-01-20 Méthode d'évaluation de la malignité d'une tumeur maligne chez un animal non humain Ceased WO2015108195A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023029785A1 (fr) * 2021-09-01 2023-03-09 致慧医疗科技(上海)有限公司 Système et procédé d'évaluation de la malignité tumorale sur la base de l'intensité de charge de surface de cellules cancéreuses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005100999A2 (fr) * 2004-04-08 2005-10-27 Cornell Research Foundation, Inc. Analyse de cycle cellulaire fonctionnel immunohistochimique comme indicateur de pronostic pour le cancer
JP2007263958A (ja) * 2006-02-28 2007-10-11 Nippon Medical Soken:Kk 血液細胞の分類法および診断ならびにそれを利用したテイラーメード治療および予防
WO2013056217A1 (fr) * 2011-10-14 2013-04-18 The Ohio State University Méthodes et matériaux relatifs au cancer des ovaires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005100999A2 (fr) * 2004-04-08 2005-10-27 Cornell Research Foundation, Inc. Analyse de cycle cellulaire fonctionnel immunohistochimique comme indicateur de pronostic pour le cancer
JP2007263958A (ja) * 2006-02-28 2007-10-11 Nippon Medical Soken:Kk 血液細胞の分類法および診断ならびにそれを利用したテイラーメード治療および予防
WO2013056217A1 (fr) * 2011-10-14 2013-04-18 The Ohio State University Méthodes et matériaux relatifs au cancer des ovaires

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023029785A1 (fr) * 2021-09-01 2023-03-09 致慧医疗科技(上海)有限公司 Système et procédé d'évaluation de la malignité tumorale sur la base de l'intensité de charge de surface de cellules cancéreuses

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