Article(id=1208795422408183865, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208795418612339683, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.10.12, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1610467200000, receivedDateStr=2021-01-13, revisedDate=1614700800000, revisedDateStr=2021-03-03, acceptedDate=null, acceptedDateStr=null, onlineDate=1766128887034, onlineDateStr=2025-12-19, pubDate=1635350400000, pubDateStr=2021-10-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766128887034, onlineIssueDateStr=2025-12-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766128887034, creator=13701087609, updateTime=1766128887034, updator=13701087609, issue=Issue{id=1208795418612339683, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='10', pageStart='955', pageEnd='1060', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766128886129, creator=13701087609, updateTime=1766128956061, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208795711982924071, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208795418612339683, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208795711982924072, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208795418612339683, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1029, endPage=1033, ext={EN=ArticleExt(id=1208795422714368079, articleId=1208795422408183865, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Current status and perspectives of patient-derived xenograft models in liver cancer research, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Patient-derived xenograft (PDX) model of liver cancer is created by transplanting the primary tumor tissue of patients with liver cancer into immunodeficient mice to simulate the biological characteristics of primary tumors, similar genetic characteristics and tumor heterogeneity with patients, which has been widely used in liver cancer research and plays an important role in drug research and clinical tumor treatment. This review firstly summarize the methodology to establish PDX models of liver cancer, four new PDX models of live cancer, and then go over recent application and function of liver cancer PDX models in basic cancer research and in preclinical explorations and finally give our perspectives on the future prospects of liver cancer PDX models.

, correspAuthors=Ya-Ling Li, authorNote=null, correspAuthorsNote=
*E-mail:
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肝癌人源肿瘤异种移植(PDX)模型是将肝癌患者的原发肿瘤组织移植到免疫缺陷小鼠体内,能较好地模拟原代肿瘤的生物学特性及与患者相似的遗传特性和肿瘤异质性,已广泛用于肝癌研究,在药物研究、临床肿瘤治疗中具有重要地位。该文总结了国内外建立肝癌PDX模型的方法,概述了4种新型肝癌PDX模型,回顾了肝癌PDX模型在基础研究与临床前研究中的应用现状,以期为肝癌研究提供新的视角并为后续研究提供参考。

, correspAuthors=李亚玲, authorNote=null, correspAuthorsNote=
李亚玲,E-mail:
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蒋林含,硕士研究生,主要从事肿瘤临床药学方面的研究。E-mail:

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蒋林含,硕士研究生,主要从事肿瘤临床药学方面的研究。E-mail:

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蒋林含,硕士研究生,主要从事肿瘤临床药学方面的研究。E-mail:

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Front Immunol, 2016, 7: 690., articleTitle=Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma, refAbstract=null), Reference(id=1208795439185400292, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, doi=null, pmid=null, pmcid=null, year=2008, volume=49, issue=1, pageStart=52, pageEnd=60, url=null, language=null, rfNumber=[37], rfOrder=38, authorNames=Huynh H, Chow PK, Palanisamy N, journalName=J Hepatol, refType=null, unstructuredReference=Huynh H, Chow PK, Palanisamy N, et al. Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma[J]. J Hepatol, 2008, 49(1): 52-60., articleTitle=Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma, refAbstract=null), Reference(id=1208795439260897765, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, doi=null, pmid=null, pmcid=null, year=2017, volume=27, issue=8, pageStart=60, pageEnd=65, url=null, language=null, rfNumber=[38], rfOrder=39, authorNames=Huang H, Li BL, Yang XJ, journalName=Chin J Comp Med, refType=null, unstructuredReference=Huang H, Li BL, Yang XJ, et al. Establishment and application of a patient derived xenograft mouse model of liver cancer[J]. Chin J Comp Med, 2017, 27(8): 60-65., articleTitle=Establishment and application of a patient derived xenograft mouse model of liver cancer, refAbstract=null), Reference(id=1208795439336395238, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, doi=null, pmid=null, pmcid=null, year=2017, volume=27, issue=8, pageStart=60, pageEnd=65, url=null, language=null, rfNumber=[38], rfOrder=40, authorNames=黄昊, 李宝亮, 杨星九, journalName=中国比较医学杂志, refType=null, unstructuredReference=[黄昊, 李宝亮, 杨星九, 等. 肝癌人源肿瘤异种移植模型构建及初步应用[J]. 中国比较医学杂志, 2017, 27(8): 60-65.], articleTitle=肝癌人源肿瘤异种移植模型构建及初步应用, refAbstract=null)], funds=[Fund(id=1208795434412282216, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, awardId=81803019, language=EN, fundingSource=National Natural Science Foundation of China(81803019), fundOrder=null, country=null), Fund(id=1208795434521334124, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, awardId=81803019, language=CN, fundingSource=国家自然科学基金(81803019), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1208795423322542201, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, xref=1, ext=[AuthorCompanyExt(id=1208795423339319419, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795423322542201, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Pharmacy, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China), AuthorCompanyExt(id=1208795423364485245, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795423322542201, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1西南医科大学附属医院药学部,四川泸州 646000)]), AuthorCompany(id=1208795423486120070, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, xref=3, ext=[AuthorCompanyExt(id=1208795423494508680, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795423486120070, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3Department of Chinese Traditional Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China), AuthorCompanyExt(id=1208795423502897289, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795423486120070, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2西南医科大学药学院,四川泸州 646000)]), AuthorCompany(id=1208795426602487956, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, xref=4, ext=[AuthorCompanyExt(id=1208795426610876566, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795426602487956, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=4Department of Hepatobiliary Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China), AuthorCompanyExt(id=1208795426619265174, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795426602487956, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3西南医科大学附属医院中医科,四川泸州 646000)]), AuthorCompany(id=1208795426787037340, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, xref=2, ext=[AuthorCompanyExt(id=1208795426795425949, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795426787037340, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China), AuthorCompanyExt(id=1208795426803814559, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, companyId=1208795426787037340, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=4西南医科大学附属医院肝胆外科,四川泸州 646000)])], figs=[ArticleFig(id=1208795432566788425, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, language=EN, label=Tab. 1, caption=

Mouse strains commonly used for PDX models of liver cancer

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品系特点寿命(年)价格(元)
C57BL/6-nu无毛无胸腺,易于种植及观察;缺乏T细胞,移植率低1.5~2120~140
CB17-scid缺乏成熟T、B细胞;存在固有免疫和NK细胞;渗漏现象>1180~200
NOD-scid缺乏成熟T、B细胞;固有免疫和NK细胞活性低下;移植率高;寿命短,淋巴瘤发生率高<1250~280
NSG、NOG缺乏成熟T、B、NK细胞;固有免疫低下;移植率高;寿命长<1.5>300
), ArticleFig(id=1208795432684228942, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, language=CN, label=表1, caption=

肝癌PDX模型常用小鼠品系

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品系特点寿命(年)价格(元)
C57BL/6-nu无毛无胸腺,易于种植及观察;缺乏T细胞,移植率低1.5~2120~140
CB17-scid缺乏成熟T、B细胞;存在固有免疫和NK细胞;渗漏现象>1180~200
NOD-scid缺乏成熟T、B细胞;固有免疫和NK细胞活性低下;移植率高;寿命短,淋巴瘤发生率高<1250~280
NSG、NOG缺乏成熟T、B、NK细胞;固有免疫低下;移植率高;寿命长<1.5>300
), ArticleFig(id=1208795432759726419, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, language=EN, label=Tab. 2, caption=

Methodology to establish PDX models of liver cancer

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移植方式部位特点不足
原位移植肝脏,多位于肝左叶能更准确地模拟肿瘤微环境,模拟包括浸润、转移、腹水在内的各种肝癌特征性生物学行为,较好地保留了患者肝癌的生物学特性;最理想的移植模型[10]操作相对复杂;不能直接观察肿瘤的生长情况,需要借助超声或腔镜等方法确认肿瘤
异位移植
 皮下双侧腹股沟、背部、腋下或前腹侧壁操作简单,局部成瘤快,易于监测;广泛采用的移植模型成瘤率较低;皮下缺乏肝癌相关基质成分;肝癌组织难以突破基膜而表现为成团生长,以致较少出现扩散和转移[11]
 肾包膜下肾包膜下血供丰富,基质含量高,为肝癌细胞的存活及生长提供充足的条件,有利于肝癌转移;生长、浸润能力明显增强[12]操作难度大,不易观察测量;损伤较大,易引起小鼠感染
皮下-原位移植皮下生长后移植至肝脏操作相对原位方式简单,效率增高,为原位移植提供了大量瘤源[13]不能直接观察肿瘤的生长情况,需要借助超声或腔镜等方法确认肿瘤
), ArticleFig(id=1208795432889749850, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, language=CN, label=表2, caption=

不同肝癌移植方式的特征

, figureFileSmall=null, figureFileBig=null, tableContent=
移植方式部位特点不足
原位移植肝脏,多位于肝左叶能更准确地模拟肿瘤微环境,模拟包括浸润、转移、腹水在内的各种肝癌特征性生物学行为,较好地保留了患者肝癌的生物学特性;最理想的移植模型[10]操作相对复杂;不能直接观察肿瘤的生长情况,需要借助超声或腔镜等方法确认肿瘤
异位移植
 皮下双侧腹股沟、背部、腋下或前腹侧壁操作简单,局部成瘤快,易于监测;广泛采用的移植模型成瘤率较低;皮下缺乏肝癌相关基质成分;肝癌组织难以突破基膜而表现为成团生长,以致较少出现扩散和转移[11]
 肾包膜下肾包膜下血供丰富,基质含量高,为肝癌细胞的存活及生长提供充足的条件,有利于肝癌转移;生长、浸润能力明显增强[12]操作难度大,不易观察测量;损伤较大,易引起小鼠感染
皮下-原位移植皮下生长后移植至肝脏操作相对原位方式简单,效率增高,为原位移植提供了大量瘤源[13]不能直接观察肿瘤的生长情况,需要借助超声或腔镜等方法确认肿瘤
), ArticleFig(id=1208795434106098013, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, language=EN, label=Tab. 3, caption=

Characteristics of the novel PDX models of liver cancer

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新型肝癌PDX模型特点局限性适用范围优势
诱导多能干细胞来源的PDX模型可在移植前进行细胞遗传操作肝癌细胞重编程的效率以及将肝癌诱导多能干细胞分化为目标细胞类型的能力不能直接植入小鼠体内的肿瘤研究基因对肝癌体内生长的影响
组合模型对患者进行治疗的同时可以进行药物敏感性分析及基因组分析需要更先进的技术支持探索潜在的治疗方法多途径进行有效的肝癌个性化治疗
肝脏疾病介导的PDX模型将肝脏疾病与PDX模型结合人和动物病理背景的差异肝损伤背景下的肝癌更好地模拟了肿瘤生长的微环境
人源化小鼠PDX模型采用人源化免疫系统小鼠或靶点基因人源化小鼠构建肝癌PDX模型操作复杂,昂贵采用免疫疗法治疗的肝癌研究免疫系统与肝癌的相互作用,对肝癌免疫疗法进行临床前评估
), ArticleFig(id=1208795434248704352, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795422408183865, language=CN, label=表3, caption=

新型肝癌PDX模型的特征

, figureFileSmall=null, figureFileBig=null, tableContent=
新型肝癌PDX模型特点局限性适用范围优势
诱导多能干细胞来源的PDX模型可在移植前进行细胞遗传操作肝癌细胞重编程的效率以及将肝癌诱导多能干细胞分化为目标细胞类型的能力不能直接植入小鼠体内的肿瘤研究基因对肝癌体内生长的影响
组合模型对患者进行治疗的同时可以进行药物敏感性分析及基因组分析需要更先进的技术支持探索潜在的治疗方法多途径进行有效的肝癌个性化治疗
肝脏疾病介导的PDX模型将肝脏疾病与PDX模型结合人和动物病理背景的差异肝损伤背景下的肝癌更好地模拟了肿瘤生长的微环境
人源化小鼠PDX模型采用人源化免疫系统小鼠或靶点基因人源化小鼠构建肝癌PDX模型操作复杂,昂贵采用免疫疗法治疗的肝癌研究免疫系统与肝癌的相互作用,对肝癌免疫疗法进行临床前评估
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肝癌人源肿瘤异种移植模型的应用研究进展
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蒋林含 1, 2 , 谭晓霞 1, 2 , 李俊 3 , 苏松 4 , 李亚玲 1, *
解放军医学杂志 | 综述 2021,46(10): 1029-1033
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解放军医学杂志 | 综述 2021, 46(10): 1029-1033
肝癌人源肿瘤异种移植模型的应用研究进展
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蒋林含1, 2 , 谭晓霞1, 2, 李俊3, 苏松4, 李亚玲1, *
作者信息
  • 1西南医科大学附属医院药学部,四川泸州 646000
  • 2西南医科大学药学院,四川泸州 646000
  • 3西南医科大学附属医院中医科,四川泸州 646000
  • 4西南医科大学附属医院肝胆外科,四川泸州 646000
  • 蒋林含,硕士研究生,主要从事肿瘤临床药学方面的研究。E-mail:

通讯作者:

李亚玲,E-mail:
Current status and perspectives of patient-derived xenograft models in liver cancer research
Lin-Han Jiang1, 2 , Xiao-Xia Tan1, 2, Jun Li3, Song Su4, Ya-Ling Li1, *
Affiliations
  • 1Department of Pharmacy, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
  • 3Department of Chinese Traditional Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
  • 4Department of Hepatobiliary Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
  • 2School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
出版时间: 2021-10-28 doi: 10.11855/j.issn.0577-7402.2021.10.12
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肝癌人源肿瘤异种移植(PDX)模型是将肝癌患者的原发肿瘤组织移植到免疫缺陷小鼠体内,能较好地模拟原代肿瘤的生物学特性及与患者相似的遗传特性和肿瘤异质性,已广泛用于肝癌研究,在药物研究、临床肿瘤治疗中具有重要地位。该文总结了国内外建立肝癌PDX模型的方法,概述了4种新型肝癌PDX模型,回顾了肝癌PDX模型在基础研究与临床前研究中的应用现状,以期为肝癌研究提供新的视角并为后续研究提供参考。

肝癌  /  人源肿瘤异种移植模型  /  基础研究  /  临床前研究  /  药物评估

Patient-derived xenograft (PDX) model of liver cancer is created by transplanting the primary tumor tissue of patients with liver cancer into immunodeficient mice to simulate the biological characteristics of primary tumors, similar genetic characteristics and tumor heterogeneity with patients, which has been widely used in liver cancer research and plays an important role in drug research and clinical tumor treatment. This review firstly summarize the methodology to establish PDX models of liver cancer, four new PDX models of live cancer, and then go over recent application and function of liver cancer PDX models in basic cancer research and in preclinical explorations and finally give our perspectives on the future prospects of liver cancer PDX models.

liver cancer  /  patient-derived xenograft model  /  basic research  /  preclinical research  /  drug assessment
蒋林含, 谭晓霞, 李俊, 苏松, 李亚玲. 肝癌人源肿瘤异种移植模型的应用研究进展. 解放军医学杂志, 2021 , 46 (10) : 1029 -1033 . DOI: 10.11855/j.issn.0577-7402.2021.10.12
Lin-Han Jiang, Xiao-Xia Tan, Jun Li, Song Su, Ya-Ling Li. Current status and perspectives of patient-derived xenograft models in liver cancer research[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (10) : 1029 -1033 . DOI: 10.11855/j.issn.0577-7402.2021.10.12
肝癌发病率日益增长,在全球其死亡率居恶性肿瘤第3位[1-2]。在我国,肝癌是最常见的恶性肿瘤之一,其发病率在肿瘤谱中居第4位,死亡率居第3位[3]。2016年,美国启动“Cancer Moonshot”计划,旨在促进对肝癌等肿瘤的预防、早期诊断、治疗及治愈的理解,并基于大量肿瘤分析与数据共享发展,促进精准医学的应用[4]。过去50年,大量的肝癌模型采用细胞系或基于细胞系的异种移植,这些模型极大促进了对肝癌发生机制的理解及药物治疗的发展,但细胞系模型肿瘤与临床患者肿瘤组织的肿瘤异质性及微环境有所不同,因此,亟待开发新的肿瘤研究技术与工具来解决该困境。人源肿瘤异种移植(patient-derived xenograft,PDX)模型是将手术中获得的患者肿瘤组织移植到免疫缺陷小鼠上,依靠小鼠提供环境生长的异种移植模型。PDX模型保留了原发肿瘤结构及细胞与基质的相对比例,增加了动物模型与患者的一致性,并保留了不同患者的肿瘤特性,有效反映了患者肿瘤间与肿瘤内的异质性[5]。因此,PDX模型可高度再现人肝癌的生物学特性,为治疗提供策略,并可对药物进行临床前筛选与评估,是解决上述困境及实现精准医学的重要途径[6]。本文总结了构建肝癌PDX模型的常用小鼠品系、标本制备及移植方式,介绍了4种新型肝癌PDX模型:诱导多能干细胞来源的PDX模型、组合模型、肝脏疾病介导的PDX模型及人源化小鼠PDX模型,回顾了肝癌PDX模型在基础研究与临床前研究方面的最新进展,并对PDX模型的前景进行了展望,以期为肝癌PDX模型的进一步优化及应用提供参考。
为避免小鼠对人体肿瘤的排斥反应,肝癌PDX模型的构建一般选用免疫缺陷小鼠,包括多种品系。目前主要有C57BL/6-nu(裸鼠)、CB17-scid[严重联合免疫缺陷(SCID)]小鼠、NOD-scid[非肥胖糖尿病/重症联合免疫缺陷(NOD-SCID)]小鼠、NOD/LtSz-scid Il2rg-/-(NSG)及NOD/Shi-scid Il2rg-/-(NOG)小鼠等,详见表1
肝癌组织标本可从手术或穿刺活检中获取[7]。剔除肝癌组织内的纤维组织及坏死部分,用剪刀剪碎肿瘤组织至1~3 mm3,以套管针接种移植或以18号针头吸取0.2 ml肿瘤组织碎片接种移植[8]。肿瘤移植成功与否主要取决于肝癌的侵袭性及全程操作的无菌性。可将肿块浸润基质胶或将组织碎片与基质胶以1:1混合后再种植,可提高肿瘤的种植及生长效率[9]
通过原位或异位移植将肝癌组织种植到免疫缺陷小鼠体内以建立PDX模型(表2)。
传统肝癌PDX模型无法研究肿瘤微环境与免疫系统的相互作用,耗时长且成本高,阻碍了肝癌的基础研究及个性化治疗,开发更准确、完善的PDX模型有利于更好地了解肝癌的生物学特性并推进治疗的发展,主要的新型肝癌PDX模型见表3
将原发肿瘤细胞重新编程为诱导多能干细胞,移植到小鼠体内,建立诱导多能干细胞来源的PDX模型。诱导多能干细胞可以在移植前进行肿瘤细胞基因操作,如表达荧光素酶或荧光蛋白用以追踪或引入特定的遗传修饰,从而研究其对肿瘤体内生长的影响[14]。肿瘤的诱导多能干细胞也具有肿瘤早期阶段的特点,为研究肝癌早期生长特点及生物标志物提供了线索[15]
原代细胞系、类器官(patient-derived organoids,PDO)模型与PDX模型的组合可从多个途径探索肝癌的个性化治疗。在对新鲜肿瘤组织进行基因测序的同时,建立患者的PDO与PDX模型,并对肿瘤进行多点采样,可更好地进行个性化治疗,还原肿瘤的分子表型、异质性并进行耐药性评估[16]。肝癌原代细胞系、PDO与PDX组合模型有望在时间、经济成本及药物筛选能力等方面取得平衡。
多数肝癌是在肝损伤背景下发展而来的。肝细胞癌(hepatocellular carcinoma,HCC)是最常见的肝癌类型,约占肝癌患者总数的90%,其中超过90%的HCC发生在慢性肝病的背景下。乙型肝炎病毒(hepatitis B virus,HBV)感染是HCC发生的最主要危险因素,约占50%,其他疾病包括丙型肝炎病毒(hepatitis C virus,HCV)、丁型肝炎病毒(hepatitis D virus,HDV)、酒精性肝病(alcoholic liver disease,ALD)及非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)[1]。为了更好地模拟人类肿瘤模型,可以将诱导的病毒性肝炎(HBV、HCV)、肝硬化、脂肪性肝病、ALD、NASH、胆汁淤积等模型与肝癌PDX模型结合。目前已有研究者将HCV相关性肝癌患者的肝癌组织植入NSG小鼠,建立HCV相关的HCC-PDX模型,虽然移植瘤传代后无法检测HCV的RNA,但能显示出与原发肿瘤非常相似的表型与分子构成,分析其肿瘤特异性基因表达的改变有助于进一步改善治疗策略[17]。慢性肝脏疾病介导的PDX模型更好地模拟了肿瘤生长的微环境,是未来PDX模型发展的潜在方向。
动物模型在临床前抗肿瘤药物评价中发挥着重要作用,但经典的PDX模型采用免疫缺陷小鼠,无法模拟完整的免疫反应,在免疫疗法的转化研究中存在着严重的局限性;且由于种属差异,人与小鼠之间的抗肿瘤药物作用靶点分子可能不同,小鼠细胞上不存在相应靶点或不能被药物识别,故需应用人源化小鼠PDX模型以促进肿瘤研究及免疫疗法的临床前评估。人源化小鼠包括人源化免疫系统小鼠及靶点基因人源化小鼠。前者通过将人类造血干细胞(hematopoietic stem cell,HSC)及从胎儿脐带血或其他组织分离出的前体细胞转移到受亚致死剂量照射的新生小鼠的骨髓中,使其发育为功能性免疫系统;后者采用基因工程手段对小鼠的免疫检查点基因进行人源化改造,从而表达人类的靶点分子基因[5]。已有研究者使用人源化小鼠建立了HCC的PDX模型,以研究该环境下肿瘤变化、免疫反应及免疫治疗的作用,为肝癌免疫疗法的临床前研究提供了平台[18]。人源化小鼠在动物模型、免疫肿瘤学及个性化治疗等方面均是一个重要的突破,将在未来的肿瘤研究中被广泛应用[19]
PDX模型是研究肝癌的重要动物模型,但其是否能用于人类肝癌研究一直是关注的重点。肝癌PDX模型在连续传代后,组织学分析显示移植肿瘤仍保留原发肿瘤组分,且在连续移植模型中也能检测到肿瘤罕见间充质成分,说明肝癌PDX模型保留了原发肿瘤的正常结构及功能,可用于原发肿瘤的组织学、遗传学、生物学特征及转移行为方面的研究[20]。有研究对乳腺癌、结直肠癌、胃癌、胰腺癌、慢性淋巴细胞白血病等移植肿瘤进行各项生物学检测,也同样证实移植肿瘤保持了原代的生物学特性[21-22]。PDX模型为肿瘤研究提供了稳定而准确的动物模型。
PDX模型可用于研究参与肿瘤发生发展的细胞成分。肿瘤干细胞(cancer stem cell,CSC)假说表明,肿瘤细胞具有内在可变性,早期的肿瘤克隆产生了具有遗传异质性的亚克隆后代,由于应对环境选择的能力不同,其中一部分快速生长而其他部分萎缩,肿瘤克隆仅由部分具有干细胞特性的细胞维持[23]。同样,当肿瘤移植到小鼠体内,肿瘤中一部分特定的亚群比其他亚群更易形成肿瘤[24]。这种肿瘤内及肿瘤间的可变性会影响治疗效果,而肝癌PDX模型保留了肝癌患者肿瘤最原始的基因克隆结构,在转录组学、表观基因组学、组织学水平及共享信号通路方面与患者相似[25],可作为研究肿瘤异质性及其发生发展的临床前模型。
晚期肿瘤患者大多会出现多发转移,且可能具有不同程度的抗药性。有研究者用黑色素瘤[26]及肺癌[27]建立了转移性肿瘤的PDX模型进行耐药性研究并进一步证明了其临床预测作用。PDX模型也可用于转移相关的细胞亚群及分子,如乳腺癌PDX模型可分离出足量的转移起始细胞(metastasis-initiating cells,MICs)及循环肿瘤细胞(circulating tumor cell,CTC),用于研究其对肿瘤转移的影响[28]。肝癌术后复发转移率高,远期疗效并不理想,肝癌转移PDX模型对研究其机制及改善预后具有重要意义。
PDX模型在临床前研究中的作用主要是确定治疗靶点并指导临床治疗。此外,EurOPDX、美国国家癌症研究所(National Cancer Institute,NCI)患者模型存储库、异种移植公共存储库(the public repository of Xenogra ft s,PRoXe)等大规模PDX模型平台的创立,将进一步促进PDX在药物研发及生物标志物筛选中的应用[5];美国杰克逊实验室(the Jackson Laboratory)已在其网站上公布了450多种PDX的遗传信息及组织病理学信息,并将PDX小鼠用于商业化使用。我国亦有计划建立自己的PDX模型中心并已建立了肝癌PDX模型数据库[29-30]
肝癌PDX模型有助于识别特定的肿瘤标志物,用于诊断、评估预后及靶向治疗。PDX保留了HCC中优先表达的分子标志物,可用于监测治疗反应;亦保留了与原发肿瘤基因表达及单核苷酸多态性(single nucleotide polymorphism,SNP)图谱的一致性,可用于预测药物的疗效;通过转录组与基因组分析,可验证肿瘤临床前研究中的分子标志物,并能用于研究肝癌患者的耐药机制、药物筛选及个性化用药[25]。利用PDX模型也可评估肝癌干细胞标志物在HCC预后中的价值[31]
药物治疗是延长肝癌患者生存期及治愈肝癌的重要方式,但新药在成功完成临床试验后用于临床的比例只有5%,且在完成前期试验后无法进入后期开发的情况也十分普遍,即许多在临床前研究中作用显著的药物未能证实对患者具有足够的功效。PDX模型可保持患者的肿瘤异质性并预测治疗效果,用于评估治疗药物的效果,从而正确指导临床治疗[32]
在肝癌PDX模型中,靶向重组人成纤维细胞生长因子受体-1(FGFR1)多激酶抑制剂乐伐替尼(lenvatinib)在高表达FGFR1的小鼠中显示出比索拉非尼(sorafenib)更好的治疗效果[33],而乐伐替尼被批准为晚期肝癌患者的一线治疗方案,证实了PDX模型的临床价值[34]。将PDX模型用于体外高通量筛选抗肿瘤药物,证实了氧化磷酸化抑制剂可用于治疗具有高水平人类婆罗双树样基因4(SALL4)的肝肿瘤[35]。免疫疗法方面,glypican 3(GPC3)-CAR T细胞抑制了PDX模型中HCC的生长,在细胞系基础上进一步证实了CAR T细胞疗法的有效性[36]。通过建立肝癌PDX模型观察贝伐珠单抗(bevacizumab)、雷帕霉素(rapamycin)的疗效,发现贝伐珠单抗与雷帕霉素联合用药比单一用药的效果更佳[37]。我国学者利用肝癌患者术后肿瘤组织建立肝癌PDX模型,同时对行肝右叶部分切除术、胆囊切除术后接受索拉非尼单药治疗的患者进行临床观察,发现患者于术后6个月出现肝癌复发,且伴腹腔淋巴结转移,这与建立的肝癌PDX模型药效学评价结果相似,很好地反映了药物在个体化患者中的作用,有望为肝癌患者个体化治疗带来新的突破[38]
肝癌PDX模型保留了患者原发肿瘤的基本特征,以体内实验验证并支持体外实验的发现,架起了肝癌基础研究与临床研究之间的桥梁,在临床前评估、指导治疗及预后预测等方面均具有重要意义。但是,肝癌PDX模型也具有一定局限性,包括肿瘤患者来源的间质被小鼠间质细胞替代、成瘤时间长、成本投入大、缺乏免疫系统等。肝脏疾病介导的PDX模型进一步缩小了肿瘤微环境的差异,人源化PDX模型更准确地描述了人肝癌的生理学特性,但这些新型肝癌PDX模型不仅需要克服现有技术局限,而且成本高昂,制作耗时,并不利于肝癌个性化治疗的发展。为减少建立模型所需的时间及经济成本,有必要进一步改进并优化当前的建模技术,以更好地模拟体内肿瘤微环境与肿瘤的相互作用,建立更优化的药物筛选途径,实现个体化治疗与精准医学的目标。
  • 国家自然科学基金(81803019)
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2021年第46卷第10期
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doi: 10.11855/j.issn.0577-7402.2021.10.12
  • 接收时间:2021-01-13
  • 首发时间:2025-12-19
  • 出版时间:2021-10-28
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  • 收稿日期:2021-01-13
  • 修回日期:2021-03-03
基金
National Natural Science Foundation of China(81803019)
国家自然科学基金(81803019)
作者信息
    1西南医科大学附属医院药学部,四川泸州 646000
    2西南医科大学药学院,四川泸州 646000
    3西南医科大学附属医院中医科,四川泸州 646000
    4西南医科大学附属医院肝胆外科,四川泸州 646000

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2种不同金属材料的力学参数

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Percentage of
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种数
Number of
species
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Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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