人源性肿瘤组织异种移植模型的建立及应用CSCD

人源性肿瘤组织异种移植(PDTX)模型是指将患者新鲜的肿瘤组织移植到免疫缺陷小鼠,依靠小鼠提供的微环境生长的一种异种肿瘤移植模型。此模型高度保留了原代肿瘤的生物学特征,维持了肿瘤细胞生长的微环境,可代替患者进行临床前试验研究,为临床前药效的评估、个体化治疗方案的筛选提供了有效的研发基础。本文就PDTX模型在肿瘤研究中的建立、临床应用及其局限性进行综述。     

PDTX模型在消化系统肿瘤研究中的应用进展#br# #br#

人源性肿瘤组织异种移植（PDTX）模型是通过将患者新鲜的肿瘤组织植入免疫缺陷小鼠,依靠小鼠提供的微环境生长。此模型保留了原代肿瘤的病理生理特性、组织学和表型特征,维持了肿瘤细胞的基质和干细胞组成,可代替患者进行临床前试验研究,以便找到更加真实可靠的抗癌策略。消化系统肿瘤是发病率和死亡率极高的疾病,目前已有多项国内外实验开发了消化系统PDTX模型并用于相应肿瘤的研究。本文就PDTX模型在消化系统肿瘤研究中的最新应用成果进行综述,并讨论和展望未来肿瘤治疗的发展方向。     

肺癌PDTX模型的研究进展

当前随着肿瘤分子生物学及基因组学的发展,人们已经认识到同一瘤种在不同个体间其生物学特征、分子分型以及对药物干预的反应性都存在巨大的异质性,这种个体化差异是导致肿瘤治疗过程中同病同治而不同效的重要原因,因此为了实现真正的肿瘤个体化精准治疗,肿瘤研究领域提出了一个新的概念即人源肿瘤组织异种移植模型(patient derived tumor xenograft, PDTX);该模型可以真实地反映患者肿瘤组织的生物学特性以及药物疗效,是研究个体化治疗、药物耐药以及新药研发的重要手段,已被运用包括肺癌在内多个瘤种的临床诊治过程中.本文就当前肺癌PDTX模型的研究进展进行综述.     

患者来源肿瘤异种移植模型研究的新进展

患者来源的肿瘤异种移植（patient-derived tumor xenografts,PDTX）模型,因其较好地保留了原代肿瘤的遗传、分子、形态结构等方面的特征,维持了肿瘤干细胞的特性,能反映患者肿瘤的遗传多样性,并且在对治疗的反应性上也与患者保持较高的一致性,现已越来越多地被应用于临床前期研究。近年来,NSG(NOD/LtSz-Prkdcscid Il2rgtm1Wjl/J)、NOG(NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl)和NCG(NOD-Prkdcem26Cd52Il2rgem26Cd22/Nju）等免疫缺陷小鼠的研发成功,推动了新一代PDTX模型研究的快速发展。由于新一代PDTX模型建立所需样本量小,经过冷冻的组织与新鲜组织成瘤率无明显差异,为一些难以获取大量样本的肿瘤组织提供了研究材料。笔者对近年来PDTX模型用于个性化治疗方案的筛选制定、药物的临床前研究、肿瘤耐药机制的研究、肿瘤标志物及敏感指标的筛选、肿瘤微环境的研究以及患者预后的评估等的发展现状作一综述。     

裸小鼠人癌异种移植及影响移植成功的因素(综述)

一个世纪以来,人们为探索人癌异种移植进行了不懈的努力,但均未获得满意结果。1966年裸小鼠(nude mice)的发现以及证实这种裸小鼠先天性无胸腺,为人癌异种移植提供了较理想的实验动物。1969年Ryg-aard 首先报告人结肠癌在裸小鼠移植成功,此后裸小鼠人癌模型便广泛应用于肿瘤的基础理论及实验性治疗等研究。裸小鼠虽无胸腺,但并非全无免疫力,因此,寻求可靠、稳定的提高移植成功率的方法仍为各国学者所重视。本文综述与此有关的问题。     

肺癌防治动物模型研究进展

精准模拟肺癌发病病理过程的动物模型是促进肺癌基础和转化研究的关键,而目前常用的皮下移植瘤模型难以体现肺脏的基质环境特征。小动物活体成像技术可客观、动态地评价肺癌的肿瘤负荷变化及转移发生情况,在此基础上建立的肺癌原位移植瘤动物模型可解决以上难题,充分体现肺癌的发病学特征。而人源性肿瘤组织异种移植(patient derived tumor xenograft,PDTX)原位模型和类器官模型也可部分体现肿瘤微环境和肿瘤细胞的异质性,均已成为该领域的重要发展方向。     

肿瘤转移动物模型

研究肿瘤转移需要建立与临床病理过程相近的肿瘤转移动物模型.目前动物模型主要有基因工程模型和异种移植模型,这对探讨肿瘤转移机制、探索实验治疗手段提供了可能的研究工具.其中,细胞株的筛选、实时检测成像技术等都是非常重要的因素.     

人肝癌NOD-SCID小鼠原位移植模型的建立及其生物学特性的研究

目的：建立人肝癌NOD-SCID小鼠原位移植模型,并通过和裸小鼠原位移植模型生物学特性的比较,对两种不同类型免疫缺陷动物在人肝癌异种移植方面的应用价值进行初步探讨。方法：将组织学完整的SMMC-LTNM瘤块植入NOD- SCID小鼠和裸小鼠肝脏内,观察成瘤率、肿瘤体积和重量、脏器的转移情况以及血清甲胎蛋白(AFP)、γ-谷氨酰转肽酶同工酶Ⅱ(γ-GTⅡ)等。结果：NOD-SCID小鼠于移植后5周可扪及肿瘤的生长,成瘤率为100%,11周肿瘤体积为(4．48±0．93) cm~3,瘤重为(7．02±1．15)g,肺部转移率为53．85%；裸小鼠于移植后6～7周可扪及肿瘤的生长,成瘤率为100%,11周肿瘤体积为(1．02±0．70)cm~3,瘤重为(2．87±0．44)g,体内未见转移发生。NOD-SCID小鼠的瘤体积、瘤重、肺转移率均高于裸小鼠(P＜0．01)。两者均保持AFP高分泌和γ-GTⅡ同工酶阳性的特性。结论：建立了一个与临床相似的人肝癌动物模型,与裸小鼠相比,NOD-SCID小鼠在建立人肝癌异种移植模型方面有更大的应用价值。     

基于PDX模型的胃癌个体化治疗研究进展

胃癌是全球尤其是东亚地区高发恶性肿瘤之一,在中国60%的患者初诊时即为进展期且异质性强、传统治疗疗效低,故需要更精准的治疗方案。目前,缺乏快速有效的筛选与验证平台是肿瘤精准治疗的瓶颈。人源肿瘤异种移植瘤（patient derived tumor xenograft,PDX）模型已在多种类型的肿瘤中被证实是研究肿瘤生物学及评价抗肿瘤药物疗效的有效平台。本文将从三个层面对PDX模型在胃癌个体化治疗中研究进展进行综述,包括PDX在临床前药物疗效评估中的作用,PDX对生物标志物的鉴定及耐药机制研究,以及PDX在人-鼠联合临床试验中的作用。      

人源性肺癌组织移植瘤模型的研究进展

人源性肺癌组织移植瘤模型（patient-derived xenografts ,PDX ）是指将肺癌患者的肿瘤组织移植于免疫缺陷鼠进行增殖传代,传代的肺癌组织高度保存肿瘤生长所处的微环境,且保留原发肺癌组织的生物学、组织病理学特征以及肿瘤标志物等,是一种理想的模拟人体内环境的动物模型。该模型对肿瘤临床前期评估、抗肿瘤药物疗效评价、分析生物标志物等有重要意义,为肺癌的个体化治疗研究带来了新方向。      

Patient-derived tumour xenografts as models for oncology drug development

Progress in oncology drug development has been hampered by a lack of preclinical models that reliably predict clinical activity of novel compounds in cancer patients. In an effort to address these shortcomings, there has been a recent increase in the use of patient-derived tumour xenografts (PDTX) engrafted into immune-compromised rodents such as athymic nude or NOD/SCID mice for preclinical modelling. Numerous tumour-specific PDTX models have been established and, importantly, they are biologically stable when passaged in mice in terms of global gene-expression patterns, mutational status, metastatic potential, drug responsiveness and tumour architecture. These characteristics might provide significant improvements over standard cell-line xenograft models. This Review will discuss specific PDTX disease examples illustrating an overview of the opportunities and limitations of these models in cancer drug development, and describe concepts regarding predictive biomarker development and future applications.     

A Multicentre Clinical Study of Sarcoma Personalised Treatment Using Patient-Derived Tumour Xenografts

AimsMedication for advanced sarcomas has not improved for three decades. Patient-derived tumour xenografts (PDTX) are a promising solution for developing new therapies and real-time personalised medicine because of their highly effective prediction of drug efficacy. However, there is a dearth of PDTX models for sarcomas due to the scarcity and heterogeneity of the disease.Materials and methodsA multicentre clinical collaborative study (ChiCTR–OOC–17013617) was carried out. Fresh patient tumour tissues via resection or biopsy were used for the PDTX set-up. The standard medical care chosen by the physician was given to the patient, in parallel with testing on multiple regimens. The outcomes of patients' responses and PDTX tests were compared. Comprehensive analyses were carried out to assess the clinical value of PDTX for the treatment of sarcomas. Living tissues from successfully engrafted cases were deposited into a repository.ResultsForty-two cases, including 36 bone sarcomas and six soft-tissue sarcomas, were enrolled; the overall engraftment rate was 73.8%. Histopathological examination showed a 100% consistency between primary tumours and tumour grafts. The engraftment rate was independent of age, gender and sampling methods, but was associated with subtypes of tumour. The outgrowth time of tumour grafts could be associated with prognosis. Major somatic mutations in tumour grafts occurred primarily in common tumour driver genes. Poor prognosis was associated with the KMT2C mutation. A drug efficacy test showed complete concordance between the PDTX model and patients' responses in 17 regimens.ConclusionPDTX is an ideal preclinical model for sarcomas because of its faithful preservation of the heterogeneity of the disease, a satisfactory engraftment rate and high accuracy in its prediction of drug efficacy.     

基于PDTX模型研究原发性肺癌顺铂耐药与ERCC1IGFBP5 表达水平的关系*

目的:构建PDTX（patient-derived tumor xenografts）肺癌模型,探索ERCC1、IGFBP 5 的表达水平与原发性肺癌顺铂耐药的关系。方法:取新鲜切除的84例肺癌组织移植于裸鼠（BALB/c）的皮下,构建PDTX 模型,分析一代成瘤率与临床病理参数关系。三代移植瘤接受顺铂化疗,采用免疫组织化学方法检测敏感组和耐药组ERCC1、IGFBP 5 的表达情况。结果:移植瘤一代成瘤率32.14%（27/ 84）,二代成瘤率88.89%（24/ 27）,三代成瘤率95.83%（23/ 24）,能否一代成瘤与肿瘤的大小、分化、分级、病理类型相关;此模型移植瘤在传代中能够保持亲代肿瘤的结构特征。ERCC1 在耐药组表达高于敏感组,而IGFBP 5 在耐药组表达低于敏感组。结论:构建了肺癌组织块移植瘤模型,其能够保持亲代癌种的结构特征,是研究肺癌发生和探索肿瘤耐药机制的理想模型。原发性肺癌顺铂耐药性与ERCC1、IGFBP 5 的表达水平相关。      

类器官在肿瘤转化医学中的应用和进展

随着精准医学概念的提出，肿瘤作为一类高度异质性的疾病，其个体化治疗已成为精准医学的一个关键领域也受到更多关注。近期提出的类器官模型为肿瘤的基础研究和个体化治疗带来了新突破。类器官指从干细胞或器官祖细胞来源，以类似体内细胞分化的方式组织成的器官特异性的细胞集合。肿瘤类器官指利用原代恶性细胞经过体外3D培养构建的恶性细胞团，在体外培养条件下可持续增殖，一定程度上保留了原代肿瘤的病理学形态特征、基因组与转录组特征、药物敏感性及恶性细胞间异质性，为体外肿瘤研究提供了新方法，尤其在预测患者药物敏感性、药物高通量筛选等方面有巨大潜力，为肿瘤个体化治疗作出了贡献。但该模型仍存在不足，如无法重现体内肿瘤微环境等，使其在临床等方面的应用受限。目前将肿瘤类器官与其他肿瘤成分共培养、与微流控设备和生物打印技术等联合应用将有望弥补其缺陷、突破肿瘤治疗领域的瓶颈。本文将常用肿瘤研究模型的特点进行对比，总结部分肿瘤类器官的培养方法，并描述了肿瘤类器官的临床相关应用，最后对其与其他技术联合应用进行了叙述，并对未来肿瘤类器官的发展方向予以展望。     

Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models

The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.