KR102557289B1 - A patient-derived xenograft model of diffuse type of cancer and a method of producing thereof - Google Patents
A patient-derived xenograft model of diffuse type of cancer and a method of producing thereof Download PDFInfo
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- KR102557289B1 KR102557289B1 KR1020160010109A KR20160010109A KR102557289B1 KR 102557289 B1 KR102557289 B1 KR 102557289B1 KR 1020160010109 A KR1020160010109 A KR 1020160010109A KR 20160010109 A KR20160010109 A KR 20160010109A KR 102557289 B1 KR102557289 B1 KR 102557289B1
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Abstract
본 발명은 미만형 종양의 환자 유래 이종이식 모델 및 이의 제조방법에 관한 것이다. 본 발명에 따른 미만형 종양의 환자 유래 이종이식 모델은 미만형 암 환자에서의 암과 유전적, 생리적 및 환경적 특성이 동일한 조건을 제공하여 환자 맞춤형 항암제의 적용을 가능케 하므로, 예후가 나쁜 미만형 암 환자의 예후 증진에 크게 기여할 것으로 기대된다.The present invention relates to a patient-derived xenograft model of a diffuse tumor and a method for preparing the same. The patient-derived xenograft model of the diffuse type tumor according to the present invention provides conditions identical in genetic, physiological, and environmental characteristics to those of cancer in the diffuse type cancer patient, enabling the application of patient-specific anticancer drugs, and thus enabling the application of a patient-specific anticancer drug. It is expected to greatly contribute to improving the prognosis of cancer patients.
Description
본 발명은 미만형 종양의 환자 유래 이종이식 모델 및 이의 제조방법에 관한 것이다.The present invention relates to a patient-derived xenograft model of a diffuse tumor and a method for preparing the same.
최근 환자맞춤형 항암치료를 통해 암을 극복하고자 하는 연구가 경쟁적으로 수행되고 있다. 특히, 표적치료제는 말기암 환자의 항암제에 대한 반응률을 획기적으로 높이면서 항암제 부작용을 최소화할 수 있을 뿐만 아니라 치료제에 대한 암의 반응을 분자신호로 예측할 수 있다는 측면에서 환자 맞춤형 항암치료 연구의 핵심이라 할 수 있다. 그러나 표적치료제의 개발을 위해서는 치료제의 효능을 예측할 수 있는 전임상 자료가 필요하지만 암 치료제에 대한 일반 검사로 이용할 수 있는 효과적인 전-임상 평가 시스템이 존재하지 않는다.Recently, studies to overcome cancer through patient-specific chemotherapy are being conducted competitively. In particular, targeted therapy is the key to patient-specific anticancer treatment research in that it can dramatically increase the response rate of terminal cancer patients to anticancer drugs while minimizing the side effects of anticancer drugs, as well as predicting the cancer response to the treatment using molecular signals. can do. However, for the development of targeted therapeutics, preclinical data that can predict the efficacy of therapeutics are required, but there is no effective preclinical evaluation system that can be used as a general test for cancer therapeutics.
한편, 현재 항암제에 대한 in vitro 평가 시스템으로 불멸화된 종양세포주 및 조직으로부터 초기 종양조직을 이용한다. 불멸화된 종양조직을 이용하여 항암제 효과를 보는 것은 어려운 일은 아니지만, 환경 인자에 따라 종양조직의 분자적 특징 및 표현형이 쉽게 바뀌기 때문에 이를 이용하여 실제적으로 항암제에 적용하는데 문제점이 존재한다. 세포는 생존을 위하여 세포의 특성을 변화시키고 강한 생존력을 갖는 세포는 계대 배양시 계속 선택되기 때문에 본래의 종양의 특징과 많이 달라질 수 있다. 또한, 다양한 환자에게 일어나는 여러 암 인자를 타겟으로 하는 새로운 항암제의 개발에 적합하지 않다. 또한, 다른 시스템으로 HRDA(histoculture drug response assay)를 임상전 단계에서 환자의 암치료제의 민감도를 미리 검사하는 적으로 사용된다. 그러나 이것은 적은 양의 조직을 사용하기 때문에, 다양한 항암제의 검사가 불가능하며, 한번 쓴 샘플은 버려지므로, 주요한 암조직의 손실이 크다.On the other hand, as an in vitro evaluation system for current anticancer drugs, early tumor tissues from immortalized tumor cell lines and tissues are used. It is not difficult to see the effect of anticancer drugs using immortalized tumor tissues, but there are problems in actually applying them to anticancer drugs because the molecular characteristics and phenotypes of tumor tissues are easily changed depending on environmental factors. Since cells change their characteristics for survival and cells with strong viability are continuously selected during subculture, they may differ greatly from the characteristics of the original tumor. In addition, it is not suitable for the development of new anticancer drugs targeting various cancer factors occurring in various patients. In addition, as another system, HRDA (histoculture drug response assay) is used as an enemy to test the sensitivity of a patient's cancer treatment in advance in the preclinical stage. However, since it uses a small amount of tissue, it is impossible to test various anticancer drugs, and since the sample used once is discarded, major cancer tissue loss is great.
이러한 문제점을 해결하기 위하여, 최근 여러 제약회사와 국가 연구소에서 환자 암조직을 이용한 PDX 모델 (patient-derived xenograft)이 개발되고 있으며, 상기 모델은 화학적 민감도를 in vivo 상에서 평가하기에 적절하고, 여러 항암제 중에서 환자 개개인에 맞는 가장 적합한 치료제를 선택할 수 있는 좋은 전임상 모델이다. 또한, 암의 진행 및 전이의 과정을 이해하기 위하여, 동종 장기 내에 이식한 동물모델 또한 개발하고 있다. In order to solve this problem, several pharmaceutical companies and national research institutes have recently developed a patient-derived xenograft (PDX) model using patient cancer tissues. This model is suitable for evaluating chemical sensitivity in vivo and is suitable for various anticancer drugs. It is a good pre-clinical model to select the most appropriate treatment for each patient. In addition, in order to understand the process of cancer progression and metastasis, animal models transplanted into allogeneic organs are also being developed.
그러나 종래의 PDX 모델 제조기술은 미만형 종양에 대해서는 PDX가 만들어지지 않는 문제점이 있었다. 미만형은 종양세포의 점착력이 낮아서 명확한 종괴의 형성 없이 개별 세포들이 조직벽을 침윤하는 유형인데, 젊은 층에 많이 생기고 일반적으로 예후가 좋지 않다. However, conventional PDX model manufacturing techniques have a problem in that PDX cannot be made for diffuse tumors. Diffuse type is a type in which individual cells infiltrate the tissue wall without the formation of a clear mass due to low adhesion of tumor cells.
따라서 본 발명은 미만형 종양의 환자 유래 이종이식 모델 및 이의 제조방법에 대한 것으로, 본 발명에 의한 PDX는 미만형 종양 환자의 예후 증진에 크게 기여할 것으로 기대된다.Therefore, the present invention relates to a patient-derived xenograft model of diffuse tumor and a method for preparing the same, and PDX according to the present invention is expected to greatly contribute to improving the prognosis of patients with diffuse tumor.
본 발명은 상기와 같은 종래의 기술상의 문제점을 해결하기 위해 안출된 것으로, 미만형 종양의 환자 유래 이종이식 모델 및 이의 제조방법에 관한 것이다.The present invention has been made to solve the above problems of the prior art, and relates to a patient-derived xenograft model of a diffuse tumor and a method for preparing the same.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, numerous specific details are set forth, such as specific forms, compositions and processes, etc., in order to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, particular features, forms, compositions, or properties may be combined in one or more embodiments in any suitable way.
명세서에서 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다.Unless otherwise defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention belongs.
본 발명의 일 구체예에서 “암”이란, 제어되지 않은 세포성장으로 특징지어지며, 이러한 비정상적인 세포성장에 의해 종양이라고 불리는 세포 덩어리가 형성되어 주위의 조직으로 침투하고 심한 경우에는 신체의 다른 기관으로 전이되기도 하는 것을 말한다. 학문적으로는 신생물이라고 명명되기도 한다. 암은 수술, 방사선 및 화학요법으로 치료를 하더라도 많은 경우에 근본적인 치유가 되지 못하고 환자에게 고통을 주며 궁극적으로는 죽음에 이르게 하는 난치성 만성질환으로, 암의 발생요인으로는 여러 가지가 있으나, 내적 요인과 외적 요인으로 구분한다. 정상세포가 어떠한 기전을 거처 암세포로 형질전환이 되는지에 대해서는 정확하게 규명되지 않았으나, 상당수의 암이 환경요인 등 외적인자에 의해 영향을 받아 발생하는 것으로 알려져 있다. 내적 요인으로는 유전 인자, 면역학적 요인 등이 있으며, 외적 요인으로는 화학물질, 방사선, 바이러스 등이 있다. 암의 발생에 관련되는 유전자에는 종양형성유전자 (oncogenes)와 종양억제유전자 (tumor suppressor genes)가 있는데, 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 용인들에 의해 무너질 때 암이 발생하게 된다. 암은 그 발생 부위에 따라 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 피부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 나팔관암종, 항문부근암, 자궁내막암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 구분할 수 있으나, 이에 한정하는 것은 아니다.In one embodiment of the present invention, "cancer" is characterized by uncontrolled cell growth, and by such abnormal cell growth, a cell mass called a tumor is formed and penetrates into surrounding tissues and, in severe cases, into other organs of the body. It means that it can be transferred. Scientifically, it is also called neoplasia. Cancer is an intractable chronic disease that in many cases cannot be fundamentally cured even if treated with surgery, radiation, and chemotherapy, causing pain to patients and ultimately leading to death. There are many causes of cancer, but internal factors and external factors. Although it has not been precisely clarified how normal cells are transformed into cancer cells through any mechanism, it is known that a significant number of cancers are affected by external factors such as environmental factors. Internal factors include genetic factors and immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, and cancer occurs when the balance between these genes is disrupted by the internal or external factors described above. Depending on the site of occurrence, cancer is classified as oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anus. Peripheral cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, It can be divided into prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ureteric cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. It is not limited to this.
본 발명의 일 구체예에서 “미만형 암(diffuse type cancer)”이란, 종양세포의 점착력이 낮아서 명확한 종괴의 형성 없이 개별 세포들이 조직벽을 침윤하는 암 유형으로, 젊은 층에 많이 생기고 일반적으로 예후가 좋지 않다. 미만형 암은 위암 및 유방암에서 많이 발생하며, 예를 들어 위암의 경우, 로렌(Lauren) 분류법에 의해 장형(intestinal type)과 미만형(diffuse type)으로 구분할 수 있다. 조직학적 구조상 종양세포가 서로 잘 연결되어 관 모양으로 배열되어 있으며 기질(stroma)이 적은 특징을 보이는 장형에 비하여, 미만형은 조직학적 구조상 종양세포가 잘 결합되어 있지 못하여 관 모양의 구조를 보이지 않으며 종양세포가 기질 내 흩어져 분포하는 특징을 보인다. 따라서 장형에 비해 세포 밀집도가 저하되는 경향이 있으므로, 전이가 빠르고 용이하며 예후가 좋지 않다. 세포 밀집도가 낮은 이유로 미만형 암은 환자 유래 이종이식 모델(patient-derived xenograft, PDX)의 제조에 있어서도, PDX가 잘 만들어지지 않는 특징을 보인다.In one embodiment of the present invention, "diffuse type cancer" is a type of cancer in which individual cells infiltrate the tissue wall without the formation of a clear mass due to low adhesion of tumor cells, which occurs frequently in young people and generally has a poor prognosis. is not good Diffuse type cancer occurs frequently in gastric cancer and breast cancer. For example, gastric cancer can be classified into an intestinal type and a diffuse type by Lauren's classification method. Compared to the enteric type, which is characterized by a histological structure in which tumor cells are well connected to each other and arranged in a tubular shape and has less stroma, the diffuse type does not show a tubular structure because the tumor cells are not well combined in histological structure. Tumor cells are scattered and distributed throughout the matrix. Therefore, compared to the intestinal type, cell density tends to decrease, so metastasis is quick and easy, and the prognosis is poor. Due to low cell density, diffuse-type cancer shows a characteristic in which PDX is not well prepared even in the manufacture of a patient-derived xenograft (PDX).
본 발명의 일 구체예에서 “암 조직 절편”이란, 암 환자에 있어서 인체에 유익하고자 하는 목적으로 암 절개술이 필요한 경우에, 절개술 시행 후 폐기되는 암 조직으로부터 수득되는 절편을 의미한다. 상기 암 조직 절편을 이용하여 암 환자의 인체에 유익하고자 하는 목적 하에 특정 암 조직에 대한 맞춤형 치료제 개발을 할 수 있다.In one embodiment of the present invention, "cancer tissue slice" refers to a slice obtained from cancer tissue that is discarded after performing an incision when a cancer incision is necessary for the purpose of benefiting the human body in a cancer patient. A customized treatment for a specific cancer tissue can be developed for the purpose of benefiting the human body of a cancer patient by using the cancer tissue section.
본 발명의 일 구체예에서 “전이”란, 암세포가 원발장기를 떠나 다른 장기로 가는 것이다. 암이 신체의 다른 부분으로 퍼지는 것은 크게 원발암에서 암조직이 성장하여 직접적으로 주위장기를 침윤하는 것과 멀리 있는 다른 장기로 혈관이나 림프관을 따라 원격전이를 하는 것으로 나눈다. 전이는 암 발생과 관련된 유전자의 발현 억제 또는 상기 유전자의 단백질 활성 억제를 통해 조절될 수 있다.In one embodiment of the present invention, "metastasis" means that cancer cells leave the primary organ and go to other organs. The spread of cancer to other parts of the body is largely divided into cancer tissue growing from the primary cancer and directly infiltrating surrounding organs, and distant metastasis to other organs along blood vessels or lymphatic vessels. Metastasis can be regulated by inhibiting the expression of genes related to cancer development or inhibiting the protein activity of these genes.
본 발명의 일 구체예에서 “신생 혈관”이란, 혈관 내피세포가 증식하고 재구성되어 기존에 존재하는 혈관 네트워크로부터 새로운 혈관을 형성하는 세포 현상을 의미한다. 암세포가 증식 및 성장하기 위해서는 산소와 영양을 공급하는 새로운 혈관이 필요하므로, 신생혈관의 억제를 통해서 암의 전이 억제를 유도할 수 있다. In one embodiment of the present invention, “neovascularization” refers to a cellular phenomenon in which vascular endothelial cells proliferate and reconstitute to form new blood vessels from an existing vascular network. In order for cancer cells to proliferate and grow, since new blood vessels supplying oxygen and nutrients are required, suppression of cancer metastasis can be induced through suppression of new blood vessels.
본 발명의 일 구체예에서 “이종이식”이란, 종이 다른 동물의 간, 심장, 신장 등 기관, 장기, 조직, 세포 등을 이식하는 방법을 의미한다. 본 발명의 목적상 상기 이종이식은 환자로부터 분리된 암세포를 면역결핍 동물에 이식하는 방법으로 이해될 수 있으나, 특별히 이에 제한되지는 않는다.In one embodiment of the present invention, "xenotransplantation" means a method of transplanting organs, organs, tissues, cells, etc., such as the liver, heart, kidney, etc., of animals of different species. For the purpose of the present invention, the xenotransplantation may be understood as a method of transplanting cancer cells isolated from a patient into an immunodeficient animal, but is not particularly limited thereto.
본 발명의 일 구체예에서 “면역 결핍 마우스”란, 암이 발병될 수 있도록 면역시스템을 구성하는 일부 구성요소를 유전자 수준에서 인위적으로 손상시켜서 정상적인 면역시스템이 구현되지 않도록 조작하여 제조된 동물모델을 의미한다. 상기 면역 결핍 마우스를 포함하는 면역 결핍 동물로는 신경계가 형성된 동물을 사용할 수 있는데, 바람직하게는 면역 결핍 포유동물을 사용할 수 있고, 보다 바람직하게는 면역 결핍되도록 조작된 마우스, 랫트, 햄스터, 기니어피그 등의 면역 결핍 설치류가 될 수 있으며, 가장 바람직하게는 누드 마우스, NOD(non-obese diabetic) 마우스, SCID(Severe combined immunodeficiency) 마우스, NOD-SCID 마우스, NOG(NOD/shi-SCID/IL2Rnull) 마우스 등이 될 수 있으나, 특별히 이에 제한되지는 않는다.In one embodiment of the present invention, "immune deficient mouse" is an animal model manufactured by artificially damaging some components constituting the immune system at the genetic level so that cancer can develop so that a normal immune system is not implemented. it means. As the immune-deficient animal including the immune-deficient mouse, an animal with a formed nervous system may be used, preferably an immune-deficient mammal, and more preferably, a mouse, rat, hamster, or guinea engineered to be immune-deficient. It may be an immunodeficient rodent such as a pig, most preferably a nude mouse, a non-obese diabetic (NOD) mouse, a severe combined immunodeficiency (SCID) mouse, a NOD-SCID mouse, or a NOG (NOD/shi-SCID/IL2Rnull) It may be a mouse or the like, but is not particularly limited thereto.
본 발명의 일 구체예에서 “환자 유래 이종이식 동물(patient-derived xenograft, PDX)”이란, 환자 유래 암세포 또는 암 조직을 면역결핍 동물에 이종이식하여 제작된 암 환자 맞춤형 동물모델로서, 암 환자에서 암과 형태학적 환경이 동일 또는 유사하고, 유전학적 환경이 동일 또는 유사하며, 암의 마커 단백질의 발현특성이 동일하여, 암 환자의 유전적, 생리적 및 환경적 특성을 그대로 반영한 조건을 제공할 수 있다. 따라서, 환자 유래 이종이식 동물모델에서 항암 효과가 있다고 판단된 항암제 후보물질을 암세포 또는 암 조직 제공 암 환자에게 처리하면, 이들 항암제 후보물질을 환자에게 처리한 것과 동일한 효과를 확인할 수 있으므로, 상기 환자 유래 이종이식 동물 모델을 이용하면 항암제가 실제로 환자에게 적절한 효과를 나타낼 수 있는지에 대하여 확인할 수 있다는 장점을 가진다.In one embodiment of the present invention, "patient-derived xenograft (PDX)" is a cancer patient-specific animal model produced by xenotransplanting patient-derived cancer cells or cancer tissues into immunodeficient animals. The morphological environment is the same as or similar to that of cancer, the genetic environment is the same or similar, and the expression characteristics of cancer marker proteins are the same, so conditions reflecting the genetic, physiological and environmental characteristics of cancer patients as they are can be provided. there is. Therefore, when an anticancer drug candidate, which is determined to have an anticancer effect in a patient-derived xenograft animal model, is treated with cancer cells or cancer tissue-provided cancer patients, the same effect as that of treating the patient with these anticancer drug candidates can be confirmed. Using a xenotransplantation animal model has the advantage of being able to confirm whether an anticancer drug can actually exhibit an appropriate effect on a patient.
본 발명의 일 구체예에서 “세포외기질(extracellular matrix, ECM)”이란, 조직내 또는 세포외의 공간을 채우고 있는 생체고분자의 복잡한 집합체이다. 결합조직에 다량으로 존재하는데, 소량이라면 모든 조직에 존재하며, 기저막은 세포외기질의 일종이다. 세포에 의해 합성되고 세포외에 분비, 축적된 분자로 구성되어 있다. 구성분자로서는 교원질, 탄력소 등의 섬유성단백질, 프로테오글리칸, 글리코사미노글리칸이라는 복합단백질, 피브로넥틴, 라미닌, 비트로넥틴 등의 세포부착성 당단백질이 있다. 현재는 교원질이나 탄력소에도 세포부착 활성이 있는 것으로 알려져 있다(Nat Rev Cancer. 2014 Jun;14(6):430-9.).In one embodiment of the present invention, "extracellular matrix (ECM)" is a complex assembly of biopolymers that fills the space within tissues or extracellular space. It exists in large amounts in connective tissue, but if it is small, it is present in all tissues, and the basement membrane is a kind of extracellular matrix. It is composed of molecules synthesized by cells and secreted and accumulated extracellularly. As constituent molecules, there are fibrous proteins such as collagen and elastin, complex proteins such as proteoglycan and glycosaminoglycan, and cell adhesion glycoproteins such as fibronectin, laminin, and vitronectin. Currently, it is known that collagen or elastin also has cell adhesion activity (Nat Rev Cancer. 2014 Jun; 14(6):430-9.).
세포외기질은 골격, 치아, 힘줄, 피부 등에 많이 포함되어 있는 것에서도 알 수 있는 것과 같이 조직의 지지와 결합, 물리적 경계, 힘의 흡수, 탄성요소라는 물리적 역할이 있다. 최근에는 세포증식, 세포이동, 세포내 대사, 세포분화, 세포의 형태 등을 세포의 외부에서 조절하는 생리화학적 역할에도 세포외기질이 관여하는 것으로 알려져 있다. 예를 들어, 발생, 가령(加齡), 암의 전이, 조직구축, 창상치료, 생체방어 등의 현상에도 세포외기질이 기능하고 있다. 세포기능의 조절기구에 대해서는 분자 수준에서의 해석이 진행되어, 인테그린을 대표하는 세포외기질수용체가 세포질막 표면 상에 존재함이 알려졌다. 세포외기질(특히 접착단백질)은 인테그린을 개재하며 세포의 정보를 세포 내에 전달한다.As can be seen from the fact that the extracellular matrix is included in a lot of skeletons, teeth, tendons, and skin, there are physical roles such as tissue support and bonding, physical boundaries, force absorption, and elastic elements. Recently, it is known that the extracellular matrix is also involved in the physiochemical role of regulating cell proliferation, cell migration, intracellular metabolism, cell differentiation, and cell morphology from the outside of the cell. For example, the extracellular matrix also functions in phenomena such as development, aging, cancer metastasis, tissue construction, wound healing, and biological defense. As for the regulatory mechanisms of cellular functions, analysis at the molecular level has been conducted, and it has been known that extracellular matrix receptors representing integrins exist on the surface of the cytoplasmic membrane. Extracellular matrix (particularly adhesive proteins) transmits cell information into cells through integrins.
본 발명의 일 구체예에서 “마트리젤”이란, 인위적으로 합성된 세포외기질로써 상업적으로 판매되는 것이며, 라미닌, 콜라겐 타입 IV, 헤파린 황산염 프로테오클리칸 및 엔탁틴/니도겐을 포함하여 구성되나, 이에 한정하는 것은 아니다.In one embodiment of the present invention, “Matrigel” is an artificially synthesized extracellular matrix that is commercially sold and is composed of laminin, collagen type IV, heparin sulfate proteoglycan, and entactin/nidogen. , but is not limited thereto.
본 발명의 일 구체예에서 “진단”이란, 병리 상태의 존재 또는 특징을 확인하는 것을 의미하며, 본 발명의 목적상 진단은 암의 발병 유무 및 전이 여부를 확인하는 것이다. 암 발병 또는 전이 의심 환자로부터의 조직의 육안적 또는 세포학적 확인으로 암을 진단할 수 있으며, 암 발병 또는 전이 의심 조직의 검체(임상적으로는 세포, 혈액, 수액, 흉수, 복수, 관절액, 농(膿), 분비액, 담,인두점액, 요(尿), 담즙, 대변등) 내에 포함되어 있는 암 대응 항체를 이용하는 방법, 상기 검체 내 암 관련 단백질을 직접 검출하는 방법 또는 암 관련 단백질을 코딩하는 핵산을 직접 검출하는 방법으로 암을 진단할 수 있다. 항원-항체 결합 또는 암 관련 단백질을 직접 검출하는 방법을 이용한 진단적 수단으로는 웨스턴 블랏, ELISA(enzyme linked immunosorbent assay), 방사선면역분석(RIA: Radioimmunoassay), 방사 면역 확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역 확산법, 로케트(rocket) 면역전기영동, 조직면역 염색, 면역침전 분석법(Immunoprecipitation Assay), 보체 고정 분석법(Complement Fixation Assay), 유세포분석(Fluorescence Activated Cell Sorter, FACS), 단백질 칩(protein chip) 등이 있으나, 이에 제한되는 것은 아니며, 암 관련 단백질을 코딩하는 핵산을 직접 검출하는 방법으로는 역전사 중합효소반응(RT-PCR), 경쟁적 역전사 중합효소반응(Competitive RT-PCR), 실시간 역전사 중합효소반응(Real-time RT-PCR), RNase 보호 분석법(RPA; RNase protection assay), 노던 블랏팅(Northern blotting) 또는 DNA 칩 등이 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, “diagnosis” means confirming the presence or characteristics of a pathological state, and for the purpose of the present invention, diagnosis is to determine whether cancer has developed or metastasized. Cancer can be diagnosed by macroscopic or cytological confirmation of tissue from a patient suspected of having cancer or metastasis, and samples of tissues suspected of having cancer or metastasis (clinically, cells, blood, fluid, pleural fluid, ascites, joint fluid, pus) (膿), secretion fluid, bile, pharyngeal mucus, urine, bile, stool, etc.), a method using a cancer-fighting antibody contained in the sample, a method of directly detecting a cancer-related protein in the sample, or a method encoding a cancer-related protein Cancer can be diagnosed by directly detecting nucleic acids. Diagnostic methods using antigen-antibody binding or direct detection of cancer-related proteins include Western blot, ELISA (enzyme linked immunosorbent assay), RIA (Radioimmunoassay), radioimmunodiffusion, and Ouktero. Ouchterlony immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, flow cytometry (Fluorescence Activated Cell Sorter, FACS), protein chip ( protein chip), but is not limited thereto. Methods for directly detecting nucleic acids encoding cancer-related proteins include RT-PCR, competitive RT-PCR, and real-time Reverse transcription polymerase reaction (Real-time RT-PCR), RNase protection assay (RPA; RNase protection assay), Northern blotting, or DNA chip, but is not limited thereto.
본 발명의 일 구체예에서 “스크리닝”이란, 여러 물질로 이루어진 후보군으로부터 목적으로 하는 어떤 특정한 성질을 갖는 물질을 특정한 조작 또는 평가 방법으로 선별하는 것이다. 본 발명의 목적상, 본 발명의 스크리닝은, 본 발명에 의한 환자 유래 이종이식 동물 모델에 항암 후보물질을 처리하고 상기 항암 후보물질에 의하여 암 조직의 크기가 감소하거나 전이가 억제됐을 경우에 후보물질을 암 치료제 또는 암 전이 억제제로 결정하는 것이다.In one embodiment of the present invention, "screening" is to select a substance having a specific target property from a candidate group composed of various substances by a specific manipulation or evaluation method. For the purpose of the present invention, the screening of the present invention is performed when an anticancer candidate is treated with a patient-derived xenograft animal model according to the present invention, and the size of cancer tissue is reduced or metastasis is suppressed by the anticancer candidate. to be determined as a cancer therapeutic agent or cancer metastasis inhibitor.
본 발명의 일 구체예에서 “항암제 후보물질”이란, 종양조직의 성장 또는 전이에 대하여 억제 활성을 가지는지 여부를 검사하기 위하여 스크리닝에서 이용되는 미지의 물질을 의미한다. 상기 후보물질은 화학물질, 펩타이드, 단백질, 항체 및 천연 추출물을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 스크리닝 방법에 의해 분석되는 후보물질은 단일 화합물 또는 화합물들의 혼합물(예컨대, 천연 추출물 또는 세포 또는 조직 배양물)이다. 후보물질은 합성 또는 천연 화합물의 라이브러리로부터 얻을 수 있다. 이러한 화합물의 라이브러리를 얻는 방법은 당업계에 공지되어 있다. 합성 화합물 라이브러리는 Maybridge Chemical Co.(UK), Comgenex(USA), Brandon Associates(USA),Microsource(USA) 및 Sigma-Aldrich(USA)에서 상업적으로 구입 가능하며, 천연 화합물의 라이브러리는 Pan Laboratories(USA) 및 MycoSearch(USA)에서 상업적으로 구입 가능하나, 이에 한정하는 것은 아니다. 후보물질은 당업계에 공지된 다양한 조합 라이브러리 방법에 의해 얻을 수 있으며, 예를 들어, 생물학적 라이브러리, 공간 어드레서블 패러럴 고상 또는 액상 라이브러리(spatially addressable parallel solid phase or solution phase libraries), 디컨볼루션이 요구되는 합성 라이브러리 방법, 1-비드 1-화합물 라이브러리 방법, 그리고 친화성 크로마토그래피 선별을 이용하는 합성 라이브러리 방법에 의해 얻을 수 있다. 분자 라이브러리의 합성 방법은, DeWitt et al., Proc. Natl.Acad. Sci. U.S.A. 90, 6909, 1993; Erb et al. Proc. Natl. Acad. Sci.In one embodiment of the present invention, "anti-cancer drug candidate" means an unknown substance used in screening to test whether or not it has inhibitory activity against the growth or metastasis of tumor tissue. The candidate substances include, but are not limited to, chemicals, peptides, proteins, antibodies, and natural extracts. Candidates analyzed by the screening methods of the present invention are single compounds or mixtures of compounds (eg, natural extracts or cell or tissue cultures). Candidates can be obtained from libraries of synthetic or natural compounds. Methods of obtaining libraries of such compounds are known in the art. Synthetic compound libraries are commercially available from Maybridge Chemical Co. (UK), Comgenex (USA), Brandon Associates (USA), Microsource (USA) and Sigma-Aldrich (USA), and libraries of natural compounds are available from Pan Laboratories (USA). ) and commercially available from MycoSearch (USA), but is not limited thereto. Candidates can be obtained by various combinatorial library methods known in the art, for example, biological libraries, spatially addressable parallel solid phase or solution phase libraries, and deconvolution. It can be obtained by the required synthetic library method, the 1-bead 1-compound library method, and the synthetic library method using affinity chromatography screening. Methods for synthesizing molecular libraries are described in DeWitt et al., Proc. Natl. Acad. Sci. U.S.A. 90, 6909, 1993; Erb et al. Proc. Natl. Acad. Sci.
U.S.A. 91, 11422, 1994; Zuckermann et al., J. Med. Chem. 37, 2678, 1994; Cho et al., Science 261, 1303, 1993; Carell et al., Angew. Chem. Int. Ed. Engl. 33, 2059, 1994; Carell et al., Angew. Chem. Int. Ed. Engl. 33, 2061; Gallop et al., J.Med. Chem. 37, 1233, 1994 등에 개시되어 있다. U.S.A. 91, 11422, 1994; Zuckermann et al., J. Med. Chem. 37, 2678, 1994; Cho et al., Science 261, 1303, 1993; Carell et al., Angew. Chem. Int. Ed. Engl. 33, 2059, 1994; Carell et al., Angew. Chem. Int. Ed. Engl. 33, 2061; Gallop et al., J. Med. Chem. 37, 1233, 1994 and the like.
현재 항암 후보물질은 생화학적인 작용 기전에 따라 하기 6개의 범주로 구분하고 있다.Currently, anticancer candidates are classified into the following six categories according to their biochemical mechanism of action.
(1) 알킬화제(alkylating agents): 어떤 화합물에 알킬기 R-CH2를 도입할 능력을 갖춘, 반응성이 대단히 높은 물질로 세포에 작용시키면 대부분은 DNA의 구아닌의 N7과 반응하여 DNA구조를 변형시키고, 사슬절단[鎖切斷]을 일으켜 항암효과 및 세포독효과를 나타낸다. 여기에 속하는 약물로는, ① 나이트로젠머스터드계(系): 나이트로젠 머스타드·클로람부실·멜팔란·사이클로포스파마이드 등 ② 에틸렌이민계: 싸이오테파 ③ 알킬설포네이트계: 부설판 ④ 트라이아진계·하이드라진계: DTIC(다카바진)·프로카바진 ⑤ 나이트로소요소계: BCNU, CCNU, 메틸-CCNU 등이 있다. (1) Alkylating agents: A highly reactive substance that has the ability to introduce an alkyl group R-CH2 into a compound. When applied to cells, most of them react with N7 of guanine in DNA to modify the DNA structure and chain. It causes cutting [鎖切斷] to show anticancer and cytotoxic effects. Drugs belonging to this category include: ① Nitrogen mustard class: Nitrogen mustard · Chlorambucil · Melphalan · Cyclophosphamide, etc. ② Ethyleneimine class: Thiotepa ③ Alkyl sulfonate class: Busulfan ④ Tri Azine/hydrazine: DTIC (dacarbazine)/procarbazine ⑤ Nitro element urea: BCNU, CCNU, methyl-CCNU, etc.
(2) 대사길항제(代謝拮抗劑: antimetabolites): 이 군(群)에 속하는 약물은 암세포의 증식에 필요한 대사과정을 저해하는 작용을 가진 것으로 ① 엽산유도체: 메소트렉세이트(MTX) ② 퓨린 유도체: 6-메르캅토퓨린(6-MP), 6-싸이오구아닌 ③ 피리미딘 유도체: 5-플루오로우라실, 시타라빈 등이 있다. (2) Metabolites (Antimetabolites): Drugs belonging to this group have the effect of inhibiting metabolic processes necessary for the proliferation of cancer cells. ① Folic acid derivatives: methotrexate (MTX) ② Purine derivatives: 6-Mercaptopurine (6-MP), 6-thioguanine ③ Pyrimidine derivatives: 5-fluorouracil, cytarabine, etc.
(3) 항생물질(抗生物質: antibiotics): 세균에서 생산되는 항생물질 가운데 항암작용을 나타내는 것으로는 아드리아마이신, 다우노루비신, 블레오마이신, 미토마이신-C, 악티노마이신-D 등이 있다. (3) Antibiotics: Antibiotics produced by bacteria include adriamycin, daunorubicin, bleomycin, mitomycin-C, and actinomycin-D that exhibit anticancer activity.
(4) 유사분열억제제(有絲分裂抑制劑: vinca alkaloid): 이들 약물은 분열시기 특이성 약물로서 유사분열 시기 중 중기(metaphase)에서 세포분열을 중지시킨다. 빈크리스틴, 빈블라스틴, VP-16-213 및 VM-26이 있다. (4) Mitotic inhibitors (vinca alkaloids): These drugs are mitotic phase-specific drugs that stop cell division in the metaphase of the mitotic phase. vincristine, vinblastine, VP-16-213 and VM-26.
(5) 호르몬제: 어떤 종류의 암은 호르몬을 투여함으로써 치료효과를 볼 수 있는데, 남성호르몬을 사용하는 경우는 유방암, 여성호르몬은 전립선암, 프로게스테론은 자궁내막암에 효과가 있으며, 부신피질호르몬은 급성림프성 백혈병이나 림프종(腫)의 치료에 사용하고 있고, 유방암에 대해서는 항여성 호르몬제인 타목시펜이 쓰이고 있다. (5) Hormone drugs: Some types of cancer can be treated by administering hormones. Male hormones are effective for breast cancer, female hormones for prostate cancer, and progesterone for endometrial cancer. is used for the treatment of acute lymphocytic leukemia or lymphoma, and the anti-female hormone tamoxifen is used for breast cancer.
(6) 기타: 시스플라틴, L-아스파라지네이스, o,p-DDD 등이 있다. 이상과 같이 현재 암치료에 사용되고 있는 항암제는 40여 종으로서 각각의 약제마다 그 항암범위에는 큰 차이가 있다.(6) Others: Cisplatin, L-asparaginase, o,p-DDD, etc. As described above, about 40 anticancer drugs are currently used for cancer treatment, and each drug has a large difference in its anticancer range.
본 발명의 일 구체예에서 “투여”란, 어떠한 적절한 방법으로 환자에게 본 발명의 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 경구 투여, 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피내 투여, 비내 투여, 폐내 투여, 직장내 투여, 강내 투여, 복강 내 투여, 경막 내 투여가 이루어질 수 있으나, 이에 제한되지는 않는다. 본 발명에서 유효량은 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료 기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 성인의 경우, 상기 치료용 약학조성물을 1회 50ml~500ml의 양으로 체내에 투여 가능하며, 화합물일 경우 0.1ng/kg-10㎎/kg, 상기 단백질에 대한 모노클로날 항체일 경우 0.1ng/kg-10㎎/kg의 용량으로 투여될 수 있다. 투여간격은 1일 1회 내지 12회일 수 있으며, 1일 12회 투여할 경우에는 2시간마다 1회씩 투여할 수 있다. 또한 항체 또는 siRNA를 포함한 항암 목적의 펩타이드 또는 핵산들은 목적하고자 하는 암의 치료를 위해 단독 또는 당업계에 공지된 다른 치료법 예를 들어 화학요법제, 방사선 및 수술과 같이 투여될 수 있다. 또한 본 발명의 펩타이드들 및 핵산들은 면역 반응을 증진하기 위하여 고안된 다른 치료, 예를 들어 당업계에 주지된 것과 같은 어쥬번트 또는 사이토카인(또는 사이토카인을 코딩하는 핵산)과 혼합하여 투여될 수 있다. 바이오리스틱(biolistic) 전달 또는 생체 외(ex vivo) 처리와 같은 다른 표준 전달 방법들이 사용될 수도 있다. 생체 외 처리에서 예를 들어 항원제시 세포들(APCs), 수지상세포들, 말초혈액 단핵구 세포들, 또는 골수세포들을 환자 또는 적당한 공여자로부터 얻어서 본 면역 조성물로 생체 외에서 활성화된 후 그 환자에게 투여될 수 있다.In one embodiment of the present invention, "administration" means introducing the composition of the present invention to a patient by any suitable method, and the administration route of the composition of the present invention is through any general route as long as it can reach the target tissue. can be administered. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, intrarectal administration, intracavity administration, intraperitoneal administration, intrathecal administration may be performed, but are not limited thereto. don't In the present invention, the effective amount is the type of disease, the severity of the disease, the type and amount of the active ingredient and other ingredients contained in the composition, the type of formulation and the patient's age, weight, general health condition, sex and diet, administration time, administration route And it can be adjusted according to various factors including the secretion rate of the composition, the treatment period, and drugs used simultaneously. In the case of adults, the therapeutic pharmaceutical composition can be administered to the body in an amount of 50 ml to 500 ml once, and in the case of a compound, 0.1 ng / kg-10 mg / kg, in the case of a monoclonal antibody to the protein, 0.1 ng / It may be administered at a dose of kg-10 mg/kg. The administration interval may be 1 to 12 times a day, and in the case of administration 12 times a day, it may be administered once every 2 hours. In addition, anti-cancer peptides or nucleic acids, including antibodies or siRNA, may be administered alone or with other therapies known in the art, such as chemotherapeutic agents, radiation, and surgery, for the treatment of desired cancer. In addition, the peptides and nucleic acids of the present invention can be administered in admixture with other treatments designed to enhance the immune response, such as adjuvants or cytokines (or nucleic acids encoding cytokines), such as those well known in the art. . Other standard delivery methods may also be used, such as biolistic delivery or ex vivo treatment. In ex vivo treatment, for example, antigen presenting cells (APCs), dendritic cells, peripheral blood mononuclear cells, or bone marrow cells can be obtained from a patient or a suitable donor, activated ex vivo with the present immune composition, and then administered to the patient. there is.
본 발명의 일 구체예에서, 목적하는 환자의 종양이 환자 유래 이종이식 동물 모델이 제조되지 않는 종양일 경우에, 목적하는 환자의 종양으로부터 세포를 분리하는 단계, 상기 세포와 미만형 종양으로부터 분리한 세포외기질을 결합하여 결합체를 준비하는 단계, 및 상기 결합체를 면역 결핍 마우스에 이식하는 단계를 포함하는 환자 유래 이종이식 동물 모델 제조방법을 제공하고, 상기 종양은 위암 또는 유방암 종양인 환자 유래 이종이식 동물 모델 제조방법을 제공하며, 상기 세포외기질은 탈세포한 세포외기질을 분쇄한 후 액상화하는 것인 환자 유래 이종이식 동물 모델 제조방법을 제공하며, 상기 탈세포는 0.1 내지 5 중량% Triton X-100과 0.01 내지 1 중량% NH4OH를 포함하는 용액으로 수행하는 환자 유래 이종이식 동물 모델 제조방법을 제공하며, 상기 분쇄는 동결건조 후 분쇄하는 것인 환자 유래 이종이식 동물 모델 제조방법을 제공하며, 상기 액상화는 0.01 내지 1 중량% 펩신을 포함하는 용액에 용해하는 것인 환자 유래 이종이식 동물 모델 제조방법을 제공하며, 상기 면역 결핍 마우스는 T세포, B세포 및 자연살해세포(NK세포) 결핍인 환자 유래 이종이식 동물 모델 제조방법을 제공하며, 상기 면역 결핍 마우스는 누드마우스인 환자 유래 이종이식 동물 모델 제조방법을 제공한다.In one embodiment of the present invention, when the tumor of the patient of interest is a tumor for which a patient-derived xenograft animal model is not prepared, isolating cells from the tumor of the patient of interest, separating the cells from the diffuse tumor Provided is a method for preparing a patient-derived xenograft animal model comprising preparing a conjugate by combining an extracellular matrix, and transplanting the conjugate into an immunodeficient mouse, wherein the tumor is a patient-derived xenograft of gastric cancer or breast cancer. A method for manufacturing an animal model is provided, wherein the extracellular matrix is liquefied after crushing the decellularized extracellular matrix, and the decellularization is 0.1 to 5% by weight Triton X Provides a method for preparing a patient-derived xenograft animal model performed with a solution containing -100 and 0.01 to 1% by weight NH 4 OH, wherein the pulverization is lyophilized and then pulverized. And, the liquefaction provides a method for preparing a patient-derived xenograft animal model in which the liquefaction is dissolved in a solution containing 0.01 to 1 wt% pepsin, and the immune-deficient mouse is T cells, B cells and natural killer cells (NK cells) Provided is a method for preparing a patient-derived xenograft animal model that is deficient, and wherein the immune-deficient mouse is a nude mouse.
본 발명의 다른 구체예에서, 미만형 종양으로부터 분리한 세포외기질을 포함하는 환자 유래 이종이식 동물 모델을 제공하고, 상기 동물 모델은 목적하는 환자의 종양으로부터 분리된 세포를 포함하는 환자 유래 이종이식 동물 모델을 제공하며, 상기 종양은 위암 또는 유방암 종양인 환자 유래 이종이식 동물 모델을 제공하며, 상기 세포외기질은 탈세포한 세포외기질을 분쇄한 후 액상화하는 것인 환자 유래 이종이식 동물 모델을 제공하며, 상기 동물은 면역 결핍 마우스인 환자 유래 이종이식 동물 모델을 제공하며, 상기 면역 결핍 마우스는 T세포, B세포 및 자연살해세포(NK세포) 결핍인 환자 유래 이종이식 동물 모델을 제공한다.In another embodiment of the present invention, a patient-derived xenograft animal model comprising extracellular matrix isolated from a diffuse tumor is provided, wherein the animal model is a patient-derived xenograft comprising cells isolated from a target patient's tumor. An animal model is provided, and a patient-derived xenograft animal model in which the tumor is a gastric or breast cancer tumor is provided, and the extracellular matrix is a patient-derived xenograft animal model in which the decellularized extracellular matrix is pulverized and then liquefied. Provided is a patient-derived xenograft animal model in which the animal is an immunodeficient mouse, and a patient-derived xenograft animal model in which the immunodeficient mouse is deficient in T cells, B cells, and natural killer cells (NK cells).
본 발명의 또 다른 구체예에서, 상기의 어느 하나의 동물 모델에 항암 후보물질을 처리하는 단계 및 상기 항암 후보물질에 의하여 암 조직의 크기가 감소하거나 전이가 억제됐을 경우에 후보물질을 암 치료제 또는 암 전이 억제제로 결정하는 단계를 포함하는 항암 후보물질의 스크리닝 방법을 제공하고, 상기 스크리닝 방법은 항암 후보물질이 처리된 동물 모델의 예후를 확인하는 단계를 추가로 포함하는 항암 후보물질의 스크리닝 방법을 제공한다.In another embodiment of the present invention, the step of treating any one of the above animal models with an anticancer candidate, and when the size of cancer tissue is reduced or metastasis is inhibited by the anticancer candidate, the candidate is treated as a cancer drug or It provides a method for screening an anti-cancer candidate including the step of determining a cancer metastasis inhibitor, wherein the screening method further comprises the step of confirming the prognosis of an animal model treated with the anti-cancer candidate. to provide.
본 발명의 또 다른 구체예에서, 상기의 어느 하나의 동물 모델에 항암 후보물질을 처리하는 단계 및 상기 항암 후보물질에 의하여 암 조직의 크기가 감소하거나 전이가 억제됐을 경우에 후보물질을 목적하는 환자의 암 치료제 또는 암 전이 억제제로 선택하는 단계를 포함하는, 환자 맞춤형 암 치료방법의 선택을 위한 정보제공 방법을 제공하고, 상기 암 치료방법의 선택은 화학적 요법, 방사선 요법, 외과적 요법, 면역세포치료법 또는 이들의 조합인 것을 특징으로 하는 환자 맞춤형 암 치료방법의 선택을 위한 정보제공 방법을 제공한다.In another embodiment of the present invention, the step of treating any one of the above animal models with an anticancer candidate, and a patient who desires the candidate when the size of cancer tissue is reduced or metastasis is inhibited by the anticancer candidate Provides a method for providing information for selecting a patient-specific cancer treatment method, including the step of selecting a cancer treatment agent or cancer metastasis inhibitor of cancer treatment, wherein the selection of the cancer treatment method is chemotherapy, radiation therapy, surgical therapy, immune cells Provided is a method of providing information for selection of a patient-specific cancer treatment method, characterized in that the treatment or a combination thereof.
이하 상기 본 발명을 단계별로 상세히 설명한다.Hereinafter, the present invention will be described in detail step by step.
환자 유래 종양조직 이종이식 동물 모델은 암 환자에서의 암과 유전적, 생리적 및 환경적 특성이 동일한 조건을 제공할 수 있다. 따라서, 환자 유래 이종이식 동물모델에서 항암 효과가 있다고 판단된 항암제 후보물질을 암세포 또는 암 조직 제공 암 환자에게 처리하면, 이들 항암제 후보물질을 환자에게 처리한 것과 동일한 효과를 확인할 수 있으므로, 암 환자의 표적 항암제 후보물질 스크리닝 및 암 치료에 크게 활용된다. 본 발명에 따른 미만형 종양의 환자 유래 이종이식 모델은 예후가 나쁜 미만형 암 환자의 예후 증진에 크게 기여할 것으로 기대된다.A patient-derived tumor tissue xenograft animal model can provide conditions with the same genetic, physiological, and environmental characteristics as cancer in a cancer patient. Therefore, when an anticancer drug candidate, which is determined to have an anticancer effect in a patient-derived xenograft animal model, is treated with cancer cells or cancer tissue-provided cancer patients, the same effect as that of treating the patient with these anticancer drug candidates can be confirmed. It is widely used for screening target anticancer drug candidates and cancer treatment. The patient-derived xenograft model of the diffuse type tumor according to the present invention is expected to greatly contribute to improving the prognosis of diffuse type cancer patients with poor prognosis.
도 1은 본 발명의 일 실시예에 따른, 목적하는 환자의 병변 조직으로부터 세포외기질 용액을 준비하는 방법을 나태낸 모식도이다.
도 2는 본 발명의 일 실시예에 따른, 본 발명의 미만형 종양의 환자 유래 이종이식 모델을 제조하는 방법을 나타낸 모식도이다.
도 3은 본 발명의 일 실시예에 따른, 장형 또는 미만형 위암 조직에 마트리젤 또는 미만형 위암의 세포외기질을 결합하여 적용한 환자 유래 이종이식 모델의 제조 결과를 나타낸 도이다.1 is a schematic diagram showing a method for preparing an extracellular matrix solution from a target patient's lesion tissue according to an embodiment of the present invention.
2 is a schematic diagram showing a method for preparing a patient-derived xenograft model of a diffuse tumor of the present invention according to an embodiment of the present invention.
FIG. 3 is a view showing the results of manufacturing a patient-derived xenograft model obtained by combining Matrigel or diffuse-type gastric cancer extracellular matrix with intestinal-type or diffuse-type gastric cancer tissue according to an embodiment of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example 1: 종양세포 및 1: tumor cells and 세포외기질의extracellular matrix 준비 preparation
실시예Example 1-1. 장형 또는 미만형 종양세포의 준비 1-1. Preparation of intestinal or diffuse tumor cells
국내의 대학병원(연세세브란스병원)으로부터 위암 환자의 병변 조직을 제공받아, Lauren 분류상 장형 (intestinal type) 또는 미만형(diffuse type)으로 분류하였다. 각 조직을 3 종류의 항생제(penicillin+streptomycin+gentamycin)와 항진균제 (amphotericin B)가 들어있는 배지에 넣어 소독한 후, PBS로 3회 세척하고 작은 절편으로 세절하였다. 세절한 조직을 콜라겐 분해효소 1A(collagenase 1A) 용액과 함께 37℃ 배양기에서 1 내지 1.5 시간 동안 반응시켜 녹인 후, 70um 여과기를 이용하여 걸러주었다. 이 후, 원심분리 (1200rpm, 5분)를 통하여 종양세포를 획득하였고, 방사선을 조사한 배양보조세포(feeder cell)과 ROCK(Rho-associated protein kinase) 억제제가 들어 있는 F-배양액을 이용한 일차배양법으로 종양세포를 준비하였다. Lesion tissues of gastric cancer patients were provided from a domestic university hospital (Yonsei Severance Hospital), and classified as intestinal type or diffuse type according to Lauren classification. Each tissue was sterilized in a medium containing three types of antibiotics (penicillin+streptomycin+gentamycin) and an antifungal agent (amphotericin B), washed three times with PBS, and cut into small sections. The cut tissue was dissolved by reacting with a collagenase 1A solution in a 37° C. incubator for 1 to 1.5 hours, and then filtered using a 70um filter. After that, tumor cells were obtained through centrifugation (1200 rpm, 5 minutes), and primary culture using F-culture medium containing irradiated feeder cells and ROCK (Rho-associated protein kinase) inhibitors Tumor cells were prepared.
실시예Example 1-2. 장형 또는 미만형 종양으로부터 1-2. from intestinal or diffuse tumors 세포외기질extracellular matrix 준비 preparation
국내의 대학병원(연세세브란스병원)으로부터 위암 환자의 병변 조직을 제공받아, Lauren 분류상 장형(intestinal type) 또는 미만형(diffuse type)으로 분류하였다. 각 조직을 3 종류의 항생제(penicillin+streptomycin+gentamycin)와 항진균제 (amphotericin B)가 들어있는 배지에 넣어 소독한 후, PBS로 4℃에서 12 내지 24 시간 동안 세척하였다. 세척이 끝난 조직은 탈세포화용액인 1 중량% Triton X-100과 0.1 중량% NH4OH 혼합액에 넣어 상온에서 1 내지 3일 동안 교반하여 종양세포와 기질 내 세포를 모두 제거하였다. 탈세포 완료 후 남은 세포외기질 (extracellular matrix, ECM)은 PBS로 10회 (12시간 이상) 세척하여 동결건조하였다. 동결건조가 끝난 세포외 기질은 막자와 막자사발을 이용하여 분쇄한 후 0.1 중량% 펩신용액에 녹여 액상화하여 준비하였다. 상기 위암 환자의 병변 조직으로부터 세포외기질 용액을 준비하는 방법을 도 1에 나타내었다.Lesion tissues of gastric cancer patients were provided from a domestic university hospital (Yonsei Severance Hospital), and were classified as intestinal type or diffuse type according to Lauren classification. Each tissue was sterilized in a medium containing three types of antibiotics (penicillin+streptomycin+gentamycin) and an antifungal agent (amphotericin B), and then washed with PBS at 4°C for 12 to 24 hours. The washed tissue was put in a mixture of 1 wt% Triton X-100 and 0.1 wt% NH 4 OH, which is a decellularization solution, and stirred at room temperature for 1 to 3 days to remove both tumor cells and cells in the matrix. After completion of decellularization, the remaining extracellular matrix (ECM) was washed with PBS 10 times (over 12 hours) and lyophilized. After lyophilization, the extracellular matrix was pulverized using a mortar and pestle, and then dissolved in 0.1 wt% pepsin solution to prepare liquefaction. A method for preparing an extracellular matrix solution from the lesion tissue of the gastric cancer patient is shown in FIG. 1 .
실시예Example 2: 장형 또는 미만형 종양 2: enteric or diffuse tumor PDXPDX 제조 및 결과 확인 Manufacturing and results confirmation
실시예Example 2-1. 장형 또는 미만형 종양 2-1. Intestinal or diffuse tumors PDXPDX 제조 manufacturing
실시예 1에서 준비한 장형 또는 미만형 종양세포 및 세포외기질을 표 1과 같은 조합으로 결합하였다. 종양세포는 액상화된 장형 또는 미만형 세포외기질에 섞은 후 누드 마우스 등쪽 피하에 이식하였다. 장형 또는 미만형 종양 유래 세포외기질의 대조군으로는 시판되는 마트리젤(Corning® Matrigel® Matrix, Corning®)을 사용하였다.The intestinal or diffuse tumor cells prepared in Example 1 and the extracellular matrix were combined in the combination shown in Table 1. Tumor cells were mixed with liquefied enteric or diffuse extracellular matrix, and then transplanted under the skin of the back of nude mice. A commercially available Matrigel (Corning® Matrigel® Matrix, Corning®) was used as a control for the intestinal or diffuse tumor-derived extracellular matrix.
상기 제조예 1 내지 6을 누드 마우스의 등쪽 피하에 이식하였다. 상기 PDX 제조 과정의 모식도를 도 2에 나타내었다.Preparation Examples 1 to 6 were implanted subcutaneously on the dorsal side of nude mice. A schematic diagram of the PDX manufacturing process is shown in FIG. 2 .
실시예Example 2-2. 장형 또는 미만형 종양 2-2. Intestinal or diffuse tumors PDXPDX 제조결과 확인 Manufacturing result confirmation
실시예 2-1의 제조예 1 내지 6을 누드 마우스에 이식하고 40일 후, PDX 제조 결과를 관찰하였다. 그 결과를 도 3에 나타내었다. 도 3에서와 같이, 장형 종양 유래 종양세포를 마트리젤 또는 미만형 종양 유래 세포외기질과 결합하여 누드 마우스에 이식하였을 경우(제조예 1 및 2)에는 양쪽 모두에서 종양을 잘 형성하였다. 그러나 미만형 종양 유래 종양세포를 마트리젤 또는 미만형 종양 유래 세포외기질과 결합하여 누드 마우스에 이식하였을 경우(제조예 4 및 5)에는 미만형 종양 유래 세포외기질과 결합한 제조예 5에서만 종양이 형성되었다. Preparation Examples 1 to 6 of Example 2-1 were transplanted into nude mice, and 40 days later, PDX production results were observed. The results are shown in Figure 3. As shown in FIG. 3, when tumor cells derived from intestinal tumors were combined with Matrigel or diffuse tumor-derived extracellular matrix and transplanted into nude mice (Preparation Examples 1 and 2), tumors were well formed in both cases. However, when the tumor cells derived from the diffuse tumor were transplanted into nude mice in combination with Matrigel or the diffuse tumor-derived extracellular matrix (Preparation Examples 4 and 5), only in Preparation Example 5 combined with the diffuse-type tumor-derived extracellular matrix, tumors were formed. was formed
상기 결과와 같이, 장형 종양 유래 종양세포는 마트리젤과 결합 시에도 PDX 종양이 잘 형성되었으나(제조예 1), 미만형 종양 유래 종양세포는 마트리젤과 결합 시 종양이 형성되지 않았다(제조예 4). 그러나 미만형 종양 유래 종양세포를 미만형 종양 유래 세포외기질과 결합 시에는 종양이 잘 형성되었다(제조예 5). 따라서, 미만형 종양 유래 종양세포의 PDX 제조에 있어서 미만형 종양 유래 세포외기질을 결합하여 이식하는 것이 중요하다는 것을 알 수 있었다. As shown in the above results, PDX tumors were well formed in intestinal tumor-derived tumor cells even when combined with Matrigel (Preparation Example 1), but no tumors were formed in diffuse-type tumor-derived tumor cells when combined with Matrigel (Preparation Example 4 ). However, when the tumor cells derived from the diffuse tumor were combined with the extracellular matrix derived from the diffuse tumor, the tumor was well formed (Preparation Example 5). Therefore, it was found that it is important to combine and transplant the diffuse-type tumor-derived extracellular matrix in PDX production of the diffuse-type tumor-derived tumor cells.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.Having described specific parts of the present invention in detail above, it is clear that these specific descriptions are only preferred embodiments for those skilled in the art, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.
Claims (18)
목적하는 환자의 종양으로부터 세포를 분리하는 단계;
상기 세포와 미만형 종양으로부터 분리한 세포외기질을 결합하여 결합체를 준비하는 단계; 및
상기 결합체를 면역 결핍 마우스에 이식하는 단계를 포함하는 환자 유래 이종이식 동물 모델 제조방법으로서,
상기 세포외기질은 탈세포한 세포외기질인 것이고,
상기 탈세포는 0.1 내지 5 중량% Triton X-100과 0.01 내지 1 중량% NH4OH를 포함하는 용액으로 수행하는 것인, 환자 유래 이종이식 동물 모델 제조방법.
If the tumor of the patient of interest is a tumor for which a patient-derived xenograft animal model is not prepared,
isolating cells from a tumor of a patient of interest;
preparing a conjugate by combining the cells and the extracellular matrix isolated from the diffuse tumor; and
A method for preparing a patient-derived xenograft animal model comprising the step of transplanting the conjugate to an immune deficient mouse,
The extracellular matrix is a decellularized extracellular matrix,
The decellularization is performed with a solution containing 0.1 to 5% by weight of Triton X-100 and 0.01 to 1% by weight of NH 4 OH, a patient-derived xenograft animal model manufacturing method.
상기 종양은 위암 또는 유방암 종양인, 환자 유래 이종이식 동물 모델 제조방법.
According to claim 1,
The tumor is a gastric cancer or breast cancer tumor, a method for producing a patient-derived xenograft animal model.
상기 세포외기질은 탈세포한 세포외기질을 분쇄한 후 액상화하는 것인, 환자 유래 이종이식 동물 모델 제조방법.
According to claim 1,
The method for preparing a patient-derived xenograft animal model, wherein the extracellular matrix is liquefied after crushing the decellularized extracellular matrix.
상기 분쇄는 동결건조 후 분쇄하는 것인, 환자 유래 이종이식 동물 모델 제조방법.
According to claim 3,
The pulverization is a method for producing a patient-derived xenograft animal model, which is pulverized after lyophilization.
상기 액상화는 0.01 내지 1 중량% 펩신을 포함하는 용액에 용해하는 것인, 환자 유래 이종이식 동물 모델 제조방법.
According to claim 3,
The liquefaction is to dissolve in a solution containing 0.01 to 1% by weight pepsin, a method for producing a patient-derived xenograft animal model.
상기 면역 결핍 마우스는 T세포, B세포 및 자연살해세포(NK세포) 결핍인, 환자 유래 이종이식 동물 모델 제조방법.
According to claim 1,
The immunodeficient mouse is a method for producing a patient-derived xenograft animal model that is deficient in T cells, B cells and natural killer cells (NK cells).
상기 면역 결핍 마우스는 누드마우스인, 환자 유래 이종이식 동물 모델 제조방법.
According to claim 7,
The immunodeficient mouse is a nude mouse, a method for producing a patient-derived xenograft animal model.
A patient-derived xenograft animal model prepared by the method of claim 1.
상기 종양은 위암 또는 유방암 종양인, 환자 유래 이종이식 동물 모델.
According to claim 9,
The tumor is a gastric or breast cancer tumor, a patient-derived xenograft animal model.
상기 세포외기질은 탈세포한 세포외기질을 분쇄한 후 액상화하는 것인, 환자 유래 이종이식 동물 모델.
According to claim 9,
The extracellular matrix is a patient-derived xenograft animal model that is liquefied after crushing the decellularized extracellular matrix.
상기 동물은 면역 결핍 마우스인, 환자 유래 이종이식 동물 모델.
According to claim 9,
A patient-derived xenograft animal model, wherein the animal is an immunodeficient mouse.
상기 면역 결핍 마우스는 T세포, B세포 및 자연살해세포(NK세포) 결핍인, 환자 유래 이종이식 동물 모델.
According to claim 13,
The immunodeficient mouse is a patient-derived xenograft animal model that is deficient in T cells, B cells, and natural killer cells (NK cells).
(b) 상기 항암 후보물질에 의하여 암 조직의 크기가 감소하거나 전이가 억제됐을 경우에 후보물질을 암 치료제 또는 암 전이 억제제로 결정하는 단계를 포함하는, 항암 후보물질의 스크리닝 방법.
(a) treating the animal model of claim 9 with an anticancer candidate; and
(b) a method for screening an anticancer candidate, comprising the step of determining the candidate as a cancer treatment agent or cancer metastasis inhibitor when the size of cancer tissue is reduced or metastasis is inhibited by the anticancer candidate.
상기 스크리닝 방법은 항암 후보물질이 처리된 동물 모델의 예후를 확인하는 단계를 추가로 포함하는, 항암 후보물질의 스크리닝 방법.
According to claim 15,
The screening method further comprises the step of confirming the prognosis of the animal model treated with the anti-cancer candidate, anti-cancer candidate screening method.
(b) 상기 항암 후보물질에 의하여 암 조직의 크기가 감소하거나 전이가 억제됐을 경우에 후보물질을 목적하는 환자의 암 치료제 또는 암 전이 억제제로 선택하는 단계를 포함하는, 환자 맞춤형 암 치료방법의 선택을 위한 정보제공 방법.
(a) treating the animal model of claim 9 with an anticancer candidate; and
(b) selection of a patient-specific cancer treatment method comprising the step of selecting the candidate substance as a cancer treatment agent or cancer metastasis inhibitor for the patient when the size of cancer tissue is reduced or metastasis is inhibited by the anticancer candidate substance How to provide information for
상기 암 치료방법의 선택은 화학적 요법, 방사선 요법, 외과적 요법, 면역세포치료법 또는 이들의 조합인 것을 특징으로 하는, 환자 맞춤형 암 치료방법의 선택을 위한 정보제공 방법.
According to claim 17,
The method of providing information for selection of a patient-specific cancer treatment method, characterized in that the selection of the cancer treatment method is chemotherapy, radiation therapy, surgical therapy, immune cell therapy or a combination thereof.
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| JP2011135818A (en) | 2009-12-28 | 2011-07-14 | Tohoku Univ | Method for preparing model animal for human uterus myoma |
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| KR101327533B1 (en) * | 2012-12-11 | 2013-11-08 | 사회복지법인 삼성생명공익재단 | Novel screening system for personalized anti-cancer agents |
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