专题:类器官

结直肠癌类器官的应用进展与挑战

  • 李精伟 ,
  • 陈浩 ,
  • 沙卫红 ,
  • 熊霞 ,
  • 周健
展开
  • 1. 广东省人民医院消化内科, 广东省医学科学院, 广州 510080;
    2. 畜禽养殖污染控制与资源化技术国家工程实验室, 中国科学院亚热带农业生态研究所亚热带农业生态过程重点实验室, 长沙 410125;
    3. 中国科学院大学, 北京 100049
李精伟,博士研究生,研究方向为肠道类器官临床应用,电子信箱:352757782@qq.com

收稿日期: 2022-05-07

  修回日期: 2022-06-10

  网络出版日期: 2022-08-05

基金资助

国家自然科学基金项目(82171698,82170561,81741067,81300279);广东省自然科学基金杰出青年项目(2021B1515020003);广东省人民医院登峰计划项目(DFJH201803)

Modeling colorectal cancer with organoids: Clinical applications and challenges

  • LI Jingwei ,
  • CHEN Hao ,
  • SHA Weihong ,
  • XIONG Xia ,
  • ZHOU Jian
Expand
  • 1. Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China;
    2. National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production; Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China;
    3. University of Chinese Academy of Sciences, Beijing 100049, China

Received date: 2022-05-07

  Revised date: 2022-06-10

  Online published: 2022-08-05

摘要

结直肠癌(CRC)是全球发病率最高的消化道肿瘤之一,严重威胁人类的健康。近年来,类器官技术取得了令人欣喜的进展,已成为结直肠癌发生机制和临床转化研究的重要新工具。回顾了结直肠癌生态位信号通路的变化,总结了类器官技术在结直肠癌建模、肿瘤微环境研究、药物筛选、个体化治疗等方面的应用进展,讨论了当前类器官面临的挑战,并从类器官培养技术标准化和工程技术应用等角度展望了类器官的未来发展方向。

本文引用格式

李精伟 , 陈浩 , 沙卫红 , 熊霞 , 周健 . 结直肠癌类器官的应用进展与挑战[J]. 科技导报, 2022 , 40(12) : 28 -41 . DOI: 10.3981/j.issn.1000-7857.2022.12.003

Abstract

The colorectal cancer is one of the most common digestive tract tumors globally, which seriously threatens the human health. In recent years, a gratifying progress has been made in the organoid culture technology, making the organoid technology an essential new tool for studying the colorectal cancer mechanisms and the clinical translation. This paper reviews the niche signaling pathways in the colorectal cancer, the application progress of the organoid technology in the colorectal cancer modeling, the tumor microenvironment research, the drug screening and the individualized therapy, as well as the current challenges of the organoid technology and the future development directions of the organoids from the perspectives of the organoid culture technology standardization and the engineering technology applications.

参考文献

[1] Xi Y, Xu P F. Global colorectal cancer burden in 2020 and projections to 2040[J]. Translational Oncology, 2021, 14(10):101174.
[2] Schmitt M, Greten F R. The inflammatory pathogenesis of colorectal cancer[J]. Nature Reviews Immunology, 2021, 21(10):653-667.
[3] Sung H, Ferlay J, Siegel R L, et al. Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA:A Cancer Journal for Clinicians, 2021, 71(3):209-249.
[4] Auman J T, Mcleod H L. Colorectal cancer cell lines lack the molecular heterogeneity of clinical colorectal tumors[J]. Clinical Colorectal Cancer, 2010, 9(1):40-47.
[5] Hay M, Thomas D W, Craighead J L, et al. Clinical development success rates for investigational drugs[J]. Nature Biotechnology, 2014, 32(1):40-51.
[6] Sato T, Vries R G, Snippert H J, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche[J]. Nature, 2009, 459(7244):262-265.
[7] Sprangers J, Zaalberg I C, Maurice M M. Organoid-based modeling of intestinal development, regeneration, and repair[J]. Cell Death&Differentiation, 2021, 28(1):95-107.
[8] Kozlowski M T, Crook C J, Ku H T. Towards organoid culture without matrigel[J]. Communications Biology, 2021, 4:1387.
[9] Toshimitsu K, Takano A, Fujii M, et al. Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer[J]. Nature Chemical Biology, 2022, 18(6):605-614.
[10] Wallach T E, Bayrer J R. Intestinal organoids:New frontiers in the study of intestinal disease and physiology[J]. Journal of Pediatric Gastroenterology and Nutrition, 2017, 64(2):180-185.
[11] Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patientderived organoids model treatment response of metastatic gastrointestinal cancers[J]. Science, 2018, 359(6378):920-926.
[12] Sampaziotis F, Justin A W, Tysoe O C, et al. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids[J]. Nature Medicine, 2017, 23(8):954-963.
[13] Durinikova E, Buzo K, Arena S. Preclinical models as patients' avatars for precision medicine in colorectal cancer:Past and future challenges[J]. Journal of Experimental&Clinical Cancer Research:CR, 2021, 40(1):185.
[14] Weeber F, van de Wetering M, Hoogstraat M, et al. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases[J]. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(43):13308-13311.
[15] Barker N, van Es J H, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5[J]. Nature, 2007, 449(7165):1003-1007.
[16] Clevers H. The intestinal crypt, a prototype stem cell compartment[J]. Cell, 2013, 154(2):274-284.
[17] Sailaja B S, He X C, Li L H. The regulatory niche of intestinal stem cells[J]. The Journal of Physiology, 2016, 594(17):4827-4836.
[18] Sato T, van Es J H, Snippert H J, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts[J]. Nature, 2011, 469(7330):415-418.
[19] Vries R G J, Huch M, Clevers H. Stem cells and cancer of the stomach and intestine[J]. Molecular Oncology, 2010, 4(5):373-384.
[20] Basak O, Beumer J, Wiebrands K, et al. Induced quiescence of Lgr5+stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells[J]. Cell Stem Cell, 2017, 20(2):177-190.e4.
[21] Hilkens J, Timmer N C, Boer M, et al. RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis[J]. Gut, 2017, 66(6):1095-1105.
[22] Barker N, Ridgway R A, van Es J H, et al. Crypt stem cells as the cells-of-origin of intestinal cancer[J]. Nature, 2009, 457(7229):608-611.
[23] Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities[J]. Cell, 2017, 169(6):985-999.
[24] Eto T, Miyake K, Nosho K, et al. Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression[J]. The Journal of Pathology, 2018, 245(4):445-455.
[25] Wend P, Holland J D, Ziebold U, et al. Wnt signaling in stem and cancer stem cells[J]. Seminars in Cell&Developmental Biology, 2010, 21(8):855-863.
[26] Lombardo Y, Scopelliti A, Cammareri P, et al. Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice[J]. Gastroenterology, 2011, 140(1):297-309.e6.
[27] Gopalakrishnan N, Sivasithamparam N D, Devaraj H. Synergistic association of Notch and NFκB signaling and role of Notch signaling in modulating epithelial to mesenchymal transition in colorectal adenocarcinoma[J]. Biochimie, 2014, 107:310-318.
[28] Kopan R, Ilagan M X G. The canonical Notch signaling pathway:Unfolding the activation mechanism[J]. Cell, 2009, 137(2):216-233.
[29] Zhang Y, Li B, Ji Z Z, et al. Notch1 regulates the growth of human colon cancers[J]. Cancer, 2010, 116(22):5207-5218.
[30] Fender A W, Nutter J M, Fitzgerald T L, et al. Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer[J]. Journal of Cellular Biochemistry, 2015, 116(11):2517-2527.
[31] Pal D, Tyagi A, Chandrasekaran B, et al. Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer[J]. Cell Death&Disease, 2018, 9:798.
[32] Fre S, Pallavi S K, Huyghe M, et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine[J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(15):6309-6314.
[33] van Es J H, van Gijn M E, Riccio O, et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells[J]. Nature, 2005, 435(7044):959-963.
[34] Sato T, Stange D E, Ferrante M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and barrett's epithelium[J]. Gastroenterology, 2011, 141(5):1762-1772.
[35] Jung P, Sato T, Merlos-Suárez A, et al. Isolation and in vitro expansion of human colonic stem cells[J]. Nature Medicine, 2011, 17(10):1225-1227.
[36] Fujii M, Matano M, Toshimitsu K, et al. Human intestinal organoids maintain self-renewal capacity and cellular diversity in niche-inspired culture condition[J]. Cell Stem Cell, 2018, 23(6):787-793.e6.
[37] Hughes C S, Postovit L M, Lajoie G A. Matrigel:Acomplex protein mixture required for optimal growth of cell culture[J]. Proteomics, 2010, 10(9):1886-1890.
[38] Giobbe G G, Crowley C, Luni C, et al. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture[J]. Nature Communications, 2019, 10:5658.
[39] Luo X B, Fong E L S, Zhu C J, et al. Hydrogel-based colorectal cancer organoid co-culture models[J]. Acta Biomaterialia, 2021, 132:461-472.
[40] Hunt D R, Klett K C, Mascharak S, et al. Engineered matrices enable the culture of human patient-derived intestinal organoids[J]. Advanced Science, 2021, 8(10):2004705.
[41] Fujii M, Shimokawa M, Date S, et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis[J]. Cell Stem Cell, 2016, 18(6):827-838.
[42] Bergin C J, Benoit Y D. Protocol for serial organoid formation assay using primary colorectal cancer tissues to evaluate cancer stem cell activity[J]. STAR Protocols, 2022, 3(1):101218.
[43] Drost J, van Jaarsveld R H, Ponsioen B, et al. Sequential cancer mutations in cultured human intestinal stem cells[J]. Nature, 2015, 521(7550):43-47.
[44] Fumagalli A, Oost K C, Kester L, et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer[J]. Cell Stem Cell, 2020, 26(4):569-578.e7.
[45] de Angelis M L, Francescangeli F, Nicolazzo C, et al. An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile[J]. Journal of Experimental&Clinical Cancer Research:CR, 2022, 41(1):86.
[46] Li X N, Nadauld L, Ootani A, et al. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture[J]. Nature Medicine, 2014, 20(7):769-777.
[47] Wang X, Yamamoto Y, Wilson L H, et al. Cloning and variation of ground state intestinal stem cells[J]. Nature, 2015, 522(7555):173-178.
[48] Lewis S K, Nachun D, Martin M G, et al. DNA methylation analysis validates organoids as a viable model for studying human intestinal aging[J]. Cellular and Molecular Gastroenterology and Hepatology, 2020, 9(3):527-541.
[49] Buzzelli J N, Ouaret D, Brown G, et al. Colorectal cancer liver metastases organoids retain characteristics of original tumor and acquire chemotherapy resistance[J]. Stem Cell Research, 2018, 27:109-120.
[50] Wan M L, Wang Y, Zeng Z, et al. Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways[J]. Bioscience Reports, 2020, 40(3):BSR20200265.
[51] Angius A, Scanu A M, Arru C, et al. Portrait of cancer stem cells on colorectal cancer:Molecular biomarkers, signaling pathways and miRNAome[J]. International Journal of Molecular Sciences, 2021, 22(4):1603.
[52] Vogelstein B, Papadopoulos N, Velculescu V E, et al. Cancer genome landscapes[J]. Science, 2013, 339(6127):1546-1558.
[53] Matano M, Date S, Shimokawa M, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids[J]. Nature Medicine, 2015, 21(3):256-262.
[54] Bolhaqueiro A C F, Ponsioen B, Bakker B, et al. Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids[J]. Nature Genetics, 2019, 51(5):824-834.
[55] Bae J M, Kim J H, Kang G H. Molecular subtypes of colorectal cancer and their clinicopathologic features, with an emphasis on the serrated neoplasia pathway[J]. Archives of Pathology&Laboratory Medicine, 2016, 140(5):406-412.
[56] Fessler E, Drost J, van Hooff S R, et al. TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype[J]. EMBO Molecular Medicine, 2016, 8(7):745-760.
[57] Kawasaki K, Fujii M, Sugimoto S, et al. Chromosome engineering of human colon-derived organoids to develop a model of traditional serrated adenoma[J]. Gastroenterology, 2020, 158(3):638-651.e8.
[58] Lannagan T R M, Lee Y K, Wang T T, et al. Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis[J]. Gut, 2019, 68(4):684-692.
[59] Drost J, van Boxtel R, Blokzijl F, et al. Use of CRISPRmodified human stem cell organoids to study the origin of mutational signatures in cancer[J]. Science, 2017, 358(6360):234-238.
[60] Sakai E R, Nakayama M, Oshima H, et al. Combined mutation of Apc, kras, and Tgfbr2 effectively drives metastasis of intestinal cancer[J]. Cancer Research, 2018, 78(5):1334-1346.
[61] Fumagalli A, Drost J, Suijkerbuijk S J E, et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids[J]. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(12):E2357-E2364.
[62] O'rourke K P, Loizou E, Livshits G, et al. Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer[J]. Nature Biotechnology, 2017, 35(6):577-582.
[63] Roper J, Tammela T, Cetinbas N M, et al. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis[J]. Nature Biotechnology, 2017, 35(6):569-576.
[64] Chen Y P, Zheng X, Wu C P. The role of the tumor microenvironment and treatment strategies in colorectal cancer[J]. Frontiers in Immunology, 2021, 12:792691.
[65] Crotti S, Piccoli M, Rizzolio F, et al. Extracellular matrix and colorectal cancer:How surrounding microenvironment affects cancer cell behavior[J]. Journal of Cellular Physiology, 2017, 232(5):967-975.
[66] Markman J L, Shiao S L. Impact of the immune system and immunotherapy in colorectal cancer[J]. Journal of Gastrointestinal Oncology, 2015, 6(2):208-223.
[67] Neal J T, Li X N, Zhu J J, et al. Organoid modeling of the tumor immune microenvironment[J]. Cell, 2018, 175(7):1972-1988.e16.
[68] Zheng L L, Wang B, Sun Y F, et al. An oxygen-concentration-controllable multiorgan microfluidic platform for studying hypoxia-induced lung cancer-liver metastasis and screening drugs[J]. ACS Sensors, 2021, 6(3):823-832.
[69] Dijkstra K K, Cattaneo C M, Weeber F, et al. Generation of tumor-reactive T cells by Co-culture of peripheral blood lymphocytes and tumor organoids[J]. Cell, 2018, 174(6):1586-1598.e12.
[70] Schnalzger T E, de Groot M H, Zhang C C, et al. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids[J]. The EMBO Journal, 2019, 38(12):e100928.
[71] Wen Y G, Xing X P, Harris J W, et al. Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[J]. Cell Death&Disease, 2017, 8(2):e2593.
[72] Hawinkels L J A C, Paauwe M, Verspaget H W, et al. Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts[J]. Oncogene, 2014, 33(1):97-107.
[73] Oszvald Á, Szvicsek Z, Sándor G O, et al. Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche[J]. Stem Cells, 2019, 38(2):291-300.
[74] Szvicsek Z, Oszvald Á, Szabó L, et al. Extracellular vesicle release from intestinal organoids is modulated by Apc mutation and other colorectal cancer progression factors[J]. Cellular and Molecular Life Sciences, 2019, 76(12):2463-2476.
[75] Öhlund D, Handly-Santana A, Biffi G, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer[J]. The Journal of Experimental Medicine, 2017, 214(3):579-596.
[76] van de Wetering M, Francies H E, Francis J M, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients[J]. Cell, 2015, 161(4):933-945.
[77] Kondo J, Ekawa T, Endo H, et al. High-throughput screening in colorectal cancer tissue-originated spheroids[J]. Cancer Science, 2019, 110(1):345-355.
[78] Du Y H, Li X N, Niu Q K, et al. Development of a miniaturized 3D organoid culture platform for ultra-highthroughput screening[J]. Journal of Molecular Cell Biology, 2020, 12(8):630-643.
[79] Shen X H, Zhang Y C, Xu Z Q, et al. KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response[J]. Cell Death&Disease, 2022, 13:303.
[80] Crespo M, Vilar E, Tsai S Y, et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing[J]. Nature Medicine, 2017, 23(7):878-884.
[81] Costales-Carrera A, Fernández-Barral A, BustamanteMadrid P, et al. Plocabulin displays strong cytotoxic activity in a personalized colon cancer patient-derived 3D organoid assay[J]. Marine Drugs, 2019, 17(11):648.
[82] Aberle M R, Burkhart R A, Tiriac H, et al. Patient-derived organoid models help define personalized management of gastrointestinal cancer[J]. British Journal of Surgery, 2018, 105(2):e48-e60.
[83] Ooft S N, Weeber F, Dijkstra K K, et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients[J]. Science Translational Medicine, 2019, 11(513):eaay2574.
[84] Yao Y, Xu X Y, Yang L F, et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer[J]. Cell Stem Cell, 2020, 26(1):17-26.e6.
[85] Schumacher D, Andrieux G, Boehnke K, et al. Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures[J]. PLoS Genetics, 2019, 15(3):e1008076.
[86] Cho Y H, Ro E J, Yoon J S, et al. 5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation[J]. Nature Communications, 2020, 11:5321.
[87] Pauli C, Hopkins B D, Prandi D, et al. Personalized in vitro and in vivo cancer models to guide precision medicine[J]. Cancer Discovery, 2017, 7(5):462-477.
[88] Narasimhan V, Wright J A, Churchill M, et al. Mediumthroughput drug screening of patient-derived organoids from colorectal peritoneal metastases to direct personalized therapy[J]. Clinical Cancer Research:An Official Journal of the American Association for Cancer Research, 2020, 26(14):3662-3670.
[89] Wang M, Yu H, Zhang T, et al. In-depth comparison of matrigel dissolving methods on proteomic profiling of organoids[J]. Molecular&Cellular Proteomics:MCP, 2022, 21(1):100181.
[90] Romero-López M, Trinh A L, Sobrino A, et al. Recapitulating the human tumor microenvironment:Colon tumorderived extracellular matrix promotes angiogenesis and tumor cell growth[J]. Biomaterials, 2017, 116:118-129.
[91] Hernandez-Gordillo V, Kassis T, Lampejo A, et al. Fully synthetic matrices for in vitro culture of primary human intestinal enteroids and endometrial organoids[J]. Biomaterials, 2020, 254:120125.
[92] Kim S, Min S, Choi Y S, et al. Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids[J]. Nature Communications, 2022, 13:1692.
[93] Gjorevski N, Sachs N, Manfrin A, et al. Designer matrices for intestinal stem cell and organoid culture[J]. Nature, 2016, 539(7630):560-564.
[94] Nikolaev M, Mitrofanova O, Broguiere N, et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis[J]. Nature, 2020, 585(7826):574-578.
[95] Gjorevski N, Nikolaev M, Brown T E, et al. Tissue geometry drives deterministic organoid patterning[J]. Science, 2022, 375(6576):eaaw9021.
[96] Clevers H. Modeling development and disease with organoids[J]. Cell, 2016, 165(7):1586-1597.
[97] Holloway E M, Wu J H, Czerwinski M, et al. Differentiation of human intestinal organoids with endogenous vascular endothelial cells[J]. Developmental Cell, 2020, 54(4):516-528.e7.
[98] Rajasekar S, Lin D S Y, Abdul L, et al. IFlowPlate-a customized 384-well plate for the culture of perfusable vascularized colon organoids[J]. Advanced Materials, 2020, 32(46):e2002974.
[99] Seiler K M, Bajinting A, Alvarado D M, et al. Patientderived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic gut-on-a-chip model[J]. Scientific Reports, 2020, 10:3842.
[100] Nashimoto Y, Okada R, Hanada S, et al. Vascularized cancer on a chip:The effect of perfusion on growth and drug delivery of tumor spheroid[J]. Biomaterials, 2020, 229:119547.
[101] Enrico A, Voulgaris D, Östmans R, et al. 3D microvascularized tissue models by laser-based cavitation molding of collagen[J]. Advanced Materials, 2022, 34(11):2109823.
[102] Akhtar A A, Sances S, Barrett R, et al. Organoid and organ-on-a-chip systems:New paradigms for modeling neurological and gastrointestinal disease[J]. Current Stem Cell Reports, 2017, 3(2):98-111.
[103] Shirure V S, Hughes C C W, George S C. Engineering vascularized organoid-on-a-chip models[J]. Annual Review of Biomedical Engineering, 2021, 23:141-167.
文章导航

/