类器官技术在肿瘤研究中的应用与展望
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摘要
背景:作为一类新型的体外模型,类器官能用于研究正常组织器官的生理特性,也能稳定地维持肿瘤细胞在体内的特征,同时可应用于抗肿瘤药物筛选和个性化治疗。目的:简述类器官技术的发展历程及现状,综述其在肿瘤研究中的应用。方法:第一作者以"类器官,肿瘤研究,3D培养,干细胞;Organoid,Three-dimensional culture,Cancer research,Stemcell"为关键词,检索2013年5月至2018年5月期间收录在CNKI、PubMed数据库中的相关文献,文献类型包括临床研究、基础研究及综述类文章,排除与文章研究目的无关及重复性的文献,最终纳入47篇文献进行综述。结果与结论:肿瘤类器官为癌症研究和治疗提供了可靠的模型,特别是为个性化癌症治疗开辟了新的视野。肿瘤来源的类器官是源自组织或肿瘤特异性干细胞的三维组织细胞簇,它可模拟体内肿瘤特征及肿瘤细胞异质性。目前,科研人员通过优化各种培养条件成功产生了许多肿瘤类器官,包括结肠癌、前列腺癌、胃癌、乳腺癌和胰腺癌、宫内膜/卵巢癌、子宫癌肉瘤、尿路上皮癌和肾癌等。但类器官培养具有明显的局限性,其中之一就是该模型中神经、血管及免疫细胞缺乏,这就使其不能完全表现出器官的全部特征,对于疾病过程的模拟也只能是部分重现。
BACKGROUND: As a new kind of model in vitro, the organoid allows the in vitro long-term culture of patient-derived cancer cells that faithfully recapitulate the in vivo phenotype. This technology facilitates antineoplastic drug screening and personalized therapies. OBJECTIVE: To describe the development of organoid technology briefly and review the applications in cancer research. METHODS: Using the keywords of "organoid, three-dimensional culture, cancer research, stem cell" in English and Chinese, respectively, the first author retrieved relevant articles published from May 2013 to May 2018 in PubMed and CNKI databases. The literature types included clinical research, basic research and review articles. After removal of the articles that were not related to the purpose of the study or repetitive, 47 articles were finally analyzed.RESULTS AND CONCLUSION: Patient-derived organoids provide a reliable model for cancer research and treatment, and in particular, open up a new perspective for personalized cancer treatment. Patient-derived organoids are three-dimensional tissue cell clusters derived from tissues or tumor specific stem cells, which can recapitulate characteristics of tumors and heterogeneity of tumor cells in vivo. In cancer research, optimizing various culture conditions has resulted in the development of numerous patient-derived tumor organoids, including colon, prostate, gastric, breast, and pancreatic cancers, in addition to endometrial/ovary carcinomas, uterine carcinosarcoma, urothelial carcinoma, and renal carcinoma. However, there are obvious limitations in organoids culture, one of which is the lack of nerve, blood vessels and immune cells in this model. This cannot show all features of organs, and partially simulate the process of disease.
BACKGROUND: As a new kind of model in vitro, the organoid allows the in vitro long-term culture of patient-derived cancer cells that faithfully recapitulate the in vivo phenotype. This technology facilitates antineoplastic drug screening and personalized therapies. OBJECTIVE: To describe the development of organoid technology briefly and review the applications in cancer research. METHODS: Using the keywords of "organoid, three-dimensional culture, cancer research, stem cell" in English and Chinese, respectively, the first author retrieved relevant articles published from May 2013 to May 2018 in PubMed and CNKI databases. The literature types included clinical research, basic research and review articles. After removal of the articles that were not related to the purpose of the study or repetitive, 47 articles were finally analyzed.RESULTS AND CONCLUSION: Patient-derived organoids provide a reliable model for cancer research and treatment, and in particular, open up a new perspective for personalized cancer treatment. Patient-derived organoids are three-dimensional tissue cell clusters derived from tissues or tumor specific stem cells, which can recapitulate characteristics of tumors and heterogeneity of tumor cells in vivo. In cancer research, optimizing various culture conditions has resulted in the development of numerous patient-derived tumor organoids, including colon, prostate, gastric, breast, and pancreatic cancers, in addition to endometrial/ovary carcinomas, uterine carcinosarcoma, urothelial carcinoma, and renal carcinoma. However, there are obvious limitations in organoids culture, one of which is the lack of nerve, blood vessels and immune cells in this model. This cannot show all features of organs, and partially simulate the process of disease.
引文
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[31]Fujii M,Shimokawa M,Date S,et al.A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis.Cell Stem Cell.2016;18(6):827-838.
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[35]Huang L,Holtzinger A,Jagan I,et al.Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids.Nat Med.2015;21:1364-1371.
[36]Seino T,Kawasaki S,Shimokawa M,et al.Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.Cell Stem Cell.2018;22(3):454-467.
[37]Huch M,Gehart H,van Boxtel R,et al.Long-term culture of genome-stable bipotent stem cells from adult human liver.Cell.2015;160:299-312.
[38]Karthaus WR,Iaquinta PJ,Drost J,et al.Identification of multipotent luminal progenitor cells in human prostate organoid cultures.Cell.2014;159(1):163-175.
[39]Gao D,Vela I,Sboner A,et al.Organoid cultures derived from patients with advanced prostate cancer.Cell.2014;159(1):176-187.
[40]李飞,高栋.类器官及其在肿瘤研究中的应用[J].中国细胞生物学学报,2017,39(4):394-400.
[41]Chen Y,Chi P,Rockowitz S,et al.ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTENloss.Nat Med.2013;19(8):1023-1029.
[42]Schwank G,Koo BK,Sasselli V,et al.Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.Cell Stem Cell.2013;13(6):653-658.
[43]Barretina J,Caponigro G,Stransky N,et al.The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity.Nature.2012;483:603-607.
[44]Kamb A.What’s wrong with our cancer models?Nat Rev Drug Discov.2005;4:161-165.
[45]Caponigro GS,Sellers WR.Advances in the preclinical testing of cancer therapeutic hypotheses.Nat Rev Drug Discov.2011;10(3):179-187.
[46]Sachs N,de Ligt J,Kopper O,et al.A living biobank of breast cancer organoids captures disease heterogeneity.Cell.2017;172:373-386.
[47]Vlachogiannis G,Hedayat S,Vatsiou A,et al.Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.Science.2018;359:920-926.
[2]Wilson HV.A new method by which sponges may be artificially reared.Science.1907;25:912-915.
[3]Sato TV,Robert GS,Hugo J,et al.Single Lgr5 stem cells build cryptvillus structures in vitro without a mesenchymal niche.Nature.2009;459(7244):262-265.
[4]Unbekandt M,Davies JA.Dissociation of embryonic kidneys followed by reaggregation allows the formation of renal tissues.Kidney Int.2010;77(5):407-416.
[5]Lancaster MA,Renner M,Martin CA,et al.Cerebral organoids model human brain development and microcephaly.Nature.2013;501:373-379.
[6]Shkumatov A,Baek K,Kong H.Matrix Rigidity-Modulated Cardiovascular Organoid Formation from Embryoid Bodies.PLoS One.2014;9(4):e94764.
[7]Takebe T,Enomura M,Yoshizawa E.Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation.Cell Stem Cell.2015;16(5):556-565.
[8]Sato T,Stange DE,Ferrante M,et al.Long-term expansion of epithelial organoids from human colon,adenoma,adenocarcinoma,and Barrett’s epithelium.Gastroenterology.2011;141:1762-1772.
[9]Li ML,Aggeler J,Farson DA,et al.Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells.Proc Natl Acad Sci USA.1987;84:136-140.
[10]Rios AC,Clevers H.Imaging organoids:a bright future ahead.Nat Methods.2018;15:24-26.
[11]Pereira JF,Awatade NT,Loureiro CA,et al.The third dimension:new developments in cell culture models for colorectal research.Cell Mol Life Sci.2016;73(21):3971-3989.
[12]Ahmed D,Eide PW,Eilertsen IA,et al.Epigenetic and genetic features of24 colon cancer cell lines.Oncogenesis.2013;2:e71.
[13]Ben DU,Ha G,Tseng YY,et al.Patient-derived xenografts undergo mousespecific tumor evolution.Nat Genet.2017;49:1567-1575.
[14]Byrne AT,Alférez DG,Amant F,et al.Interrogating open issues in cancer medicine with patient-derived xenografts.Nat Rev Cancer.2017;17:254-268.
[15]Weeber F,Van de Wetering M,Hoogstraat M,et al.Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases.Proc Natl Acad Sci USA.2015;112:13308-13311.
[16]Van de Wetering M,Francies HE,Francis JM,et al.Prospective derivation of a living organoid biobank of colorectal cancer patients.Cell.2015;161:933-945.
[17]Gao D,Vela I,Sboner A,et al.Organoid cultures derived from patients with advanced prostate cancer.Cell.2014;159:176-187.
[18]Boj SF,Hwang CI,Baker LA,et al.Organoid models of human and mouse ductal pancreatic cancer.Cell.2015;160:324-338.
[19]Bartfeld S,Bayram T,Van de Wetering M,et al.In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection.Gastroenterology.2015;148:126-136.
[20]Pauli C,Hopkins BD,Prandi D,et al.Personalized in vitro and in vivo cancer models to guide precision medicine.Cancer Discov.2017;7:462-477.
[21]Drost J,Van Jaarsveld RH,Ponsioen B,et al.Sequential cancer mutations in cultured human intestinal stem cells.Nature.2015;521:43-47.
[22]Cancer Genome Atlas N.Comprehensive molecular characterization of human colon and rectal cancer.Nature.2012;487:330-337.
[23]Drost J,Karthaus WR,Gao D,et al.Organoid culture systems for prostate epithelial and cancer tissue.Nat Protoc.2016;11:347-358.
[24]Wang K,Yuen ST,Xu J,et al.Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet.2014;46:573-582.
[25]Petersen OW,R?nnov JL,Howlett AR,et al.Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells.Proc Natl Acad Sci USA.1992;89:9064-9068.
[26]Huang L,Holtzinger A,Jagan I,et al.Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell-and patient-derived tumor organoids.Nat Med.2015;21:1364-1371.
[27]Batchelder CA,Martinez ML,Duru N,et al.Three-dimensional culture of human renal cell carcinoma organoids.PLoS One.2015;10:e0136758.
[28]Fujii M,Matano M,Nanki K,et al.Efficient genetic engineering of human intestinal organoids using electroporation.Nat Protoc.2015;10:1474-1485.
[29]Barker N,Ridgway RA,Van Es JH,et al.Crypt stem cells as the cells-of-origin of intestinal cancer.Nature.2009;457:608-611.
[30]Fumagalli A,Drost J,Suijkerbuijk SJ,et al.Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.Proc Natl Acad Sci USA.2017;114(12):2357-2364.
[31]Fujii M,Shimokawa M,Date S,et al.A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis.Cell Stem Cell.2016;18(6):827-838.
[32]Abbruzzese,JL,Hess KR.New option for the initial management of metastatic pancreatic cancer?J Clin Oncol.2014;32:2405-2407.
[33]Nicolle R,Blum Yuna,Marisa Laetitia,et al.Pancreatic adenocarcinoma therapeutic targets revealed by tumor-stroma cross-talk analyses in patient-derived xenografts.Cell Rep.2017;21:2458-2470.
[34]Herreros-Villanueva M,Hijona E,Cosme A.Mouse models of pancreatic cancer.World J Gastroenterol.2012;18:1286-1294.
[35]Huang L,Holtzinger A,Jagan I,et al.Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids.Nat Med.2015;21:1364-1371.
[36]Seino T,Kawasaki S,Shimokawa M,et al.Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.Cell Stem Cell.2018;22(3):454-467.
[37]Huch M,Gehart H,van Boxtel R,et al.Long-term culture of genome-stable bipotent stem cells from adult human liver.Cell.2015;160:299-312.
[38]Karthaus WR,Iaquinta PJ,Drost J,et al.Identification of multipotent luminal progenitor cells in human prostate organoid cultures.Cell.2014;159(1):163-175.
[39]Gao D,Vela I,Sboner A,et al.Organoid cultures derived from patients with advanced prostate cancer.Cell.2014;159(1):176-187.
[40]李飞,高栋.类器官及其在肿瘤研究中的应用[J].中国细胞生物学学报,2017,39(4):394-400.
[41]Chen Y,Chi P,Rockowitz S,et al.ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTENloss.Nat Med.2013;19(8):1023-1029.
[42]Schwank G,Koo BK,Sasselli V,et al.Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.Cell Stem Cell.2013;13(6):653-658.
[43]Barretina J,Caponigro G,Stransky N,et al.The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity.Nature.2012;483:603-607.
[44]Kamb A.What’s wrong with our cancer models?Nat Rev Drug Discov.2005;4:161-165.
[45]Caponigro GS,Sellers WR.Advances in the preclinical testing of cancer therapeutic hypotheses.Nat Rev Drug Discov.2011;10(3):179-187.
[46]Sachs N,de Ligt J,Kopper O,et al.A living biobank of breast cancer organoids captures disease heterogeneity.Cell.2017;172:373-386.
[47]Vlachogiannis G,Hedayat S,Vatsiou A,et al.Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.Science.2018;359:920-926.