mtDNA与肿瘤关系的研究进展

随着现代社会的高速发展,人类肿瘤的发病率逐年升高,严重威胁人类健康,关于肿瘤的研究也越来越多,其 中不乏线粒体DNA（mtDNA）与肿瘤的相关研究,尤其近几年来,mtDNA 与肿瘤的研究已经逐渐成为肿瘤研究的热点。 mtDNA 的研究涉及点突变、片段缺失、含量的变化等方面。本文综合整理mtDNA 含量在肿瘤中的相关研究,查阅近10 年的国内外mtDNA 含量在不同肿瘤中相关研究文献资料,找出其研究的方式、方法及得到的相关资料、数据进行归纳、 分析、总结,发现肿瘤中mtDNA 含量相关研究较多,研究的肿瘤类型多样,并涉及不同肿瘤的发生、发展、治疗及预后 等多方面,不同研究的结果不尽相同,甚至有相反的结果。但大量研究显示：肿瘤的发生、发展中均有 mtDNA 含量的变 化,mtDNA 含量变化对肿瘤发生、发展及治疗、预后等方面均有影响,mtDNA 含量的变化在不同肿瘤中及肿瘤的不同阶 段发挥作用的方式等各不相同,其发挥作用的机理多样,这些研究资料为后期肿瘤中mtDNA含量相关研究提供理论参考, 有望为肿瘤的诊治做出一定贡献。     

肿瘤血管生成的分子机制与临床治疗研究进展

在肿瘤中,肿瘤血管生成的分子成分包括细胞因子、生长因子、趋化因子及蛋白酶、信号转导通路等.大量研究表明,肿瘤血管生成的过程中会释放促血管生成的因子及酶类,通过肿瘤微环境促进肿瘤血管的进一步稳定与成熟,参与肿瘤的侵袭及转移,与多种肿瘤的发生发展密切相关.近年研究表明,在临床肿瘤治疗中,控制肿瘤血管生成的分子靶点是很有前景的治疗策略.     

髓系抑制性细胞与肿瘤

髓系抑制性细胞(MDSC)是一群髓系来源具有抑制功能的天然免疫细胞,在肿瘤进展中发挥负向免疫调控作用.MDSC具有强大的抑制功能及显著的异质性,通过多种机制调控固有免疫及适应性免疫系统,发挥促肿瘤作用,同时可通过非免疫机制促进肿瘤血管生成及肿瘤转移等.近年来对其分化、增殖、抑制功能等的研究日趋成熟,由此衍生的靶向针对MDSC的肿瘤免疫治疗研究将为肿瘤疫苗的增效及肿瘤的治疗等带来新的希望.     

髓系抑制性细胞与肿瘤

髓系抑制性细胞(MDSC)是一群髓系来源具有抑制功能的天然免疫细胞,在肿瘤进展中发挥负向免疫调控作用。MDSC具有强大的抑制功能及显著的异质性,通过多种机制调控固有免疫及适应性免疫系统,发挥促肿瘤作用,同时可通过非免疫机制促进肿瘤血管生成及肿瘤转移等。近年来对其分化、增殖、抑制功能等的研究日趋成熟,由此衍生的靶向针对MDSC的肿瘤免疫治疗研究将为肿瘤疫苗的增效及肿瘤的治疗等带来新的希望。     

肿瘤中CCR5的表达及其临床意义

近年来在对肿瘤免疫的研究中发现,乳腺癌、胰腺癌、前列腺癌等多种肿瘤组织中存在趋化因子受体CCR5的高表达。进一步研究发现,CCR5不仅表达于肿瘤组织中,在Treg细胞（调节性T细胞）、淋巴细胞等免疫细胞上也有表达,参与肿瘤免疫、免疫逃避等行为,影响肿瘤的预后及进展。CCR5在肿瘤免疫中的作用机制正成为国内外研究的热点。作者就国内外有关CCR5在肿瘤的发生、发展中的最新研究进展进行综述。     

第二届全国肿瘤标志学术会议将于1992年9月在上海召开

为了更好地促进我国肿瘤标志基础研究和临床应用的发展,交流成果及推广应用,拟于1992年9月在上海召开第二届全国肿瘤标志学术会议。凡未在公开发行刊物上发表的有关肿瘤标志的基础理论及方法学的研究,和应用性成果均属征文范围。重点是肿瘤抗原、酶学、激素受体、癌基因及其产物等肿瘤标志物的临床与基础的应用性研究,更欢迎高技术应用性研究如免疫显像、导向治疗、肿瘤标志检测的新技术等内     

脂肪因子Omentin-1与肿瘤相关性的研究

Omentin-1是脂肪因子Omentin在血液循环中的主要形式。研究发现,Omentin-1与消化系统肿瘤、泌尿系统肿瘤、女性肿瘤及神经系统肿瘤等多种肿瘤相关,但其在不同类型的肿瘤中表现出高度异质性。Omentin-1参与多个肿瘤相关的信号通路及抑癌因子的调解,其在肿瘤发生发展中所起的作用和相关机制的研究越来越多。     

肿瘤进化异质性研究现状及进展

肿瘤进化是肿瘤异质性、肿瘤转移及药物靶向治疗的研究基础。近年来,肿瘤原发灶与转移灶进化关系的研究取得快速进展。肿瘤进化研究涉及基因组学、转录组学、表观遗传学等多种组学研究方法,通过不同的研究方法构建了多种肿瘤进化模型。本文通过文献回顾,对肿瘤进化的基因组学基础、肿瘤进化的基因组学研究方法及肿瘤进化的不同模式的研究现状及进展进行综述,并对肿瘤进化研究的新方法进行展望。     

hPTTG1与肿瘤发生发展的研究进展

人垂体瘤转化基因（hPTTG）是一种潜在的癌基因,自发现以来一直是研究的热点,在人体肿瘤中主要表达hPTTG1,且在多种肿瘤中高表达。研究证实,hPTTG1具有促进细胞转化、血管生成及肿瘤转移等生物学功能,在肿瘤的发生、发展、侵袭、转移及复发中起重要作用。hPTTG1对肿瘤的诊断具有重要的参考价值,有望成为肿瘤基因治疗的新靶点。     

第二届中国肿瘤标志学术会议征文通知

为了促进我国肿瘤标志基础研究和临床应用的发展、交流成果及推广应用,拟于1992年9月在上海召开第二届全国肿瘤标志学术会议。一、征文内容凡未在公开发行刊物上发表的有关肿瘤标志的基础理论及方法学的研究,应用性成果均属征文范围。重点是肿瘤抗原、酶学、激素受体、癌基因及其产物等肿瘤标志物的临床与基础的应用性研究,更欢迎高技术应用性研究,如免疫显像,导向治疗、肿瘤标志检测的     

卵巢癌临床前模型:从细胞系到类器官体

卵巢癌作为妇科三大恶性肿瘤之一，严重威胁着女性的生命健康。因其早期临床症状隐匿，往往在晚期甚至已经转移才被诊断出来。所以卵巢癌的总生存率一直不是很理想，寻找和开发新的治疗方案一直是卵巢癌的研究重点。在此过程中，准确模拟体内肿瘤生物学特征的临床前模型是必不可少的。细胞系因其培养简单，可大规模生产等优点，曾经是卵巢癌临床前研究的金标准。之后由于精准医学强调患者衍生材料的重要性，患者来源的异体移植模型(PDX)逐渐受到大家的重视。随后又出现了三维结构的球状体和更加能体现肿瘤异质性的类器官体。类器官体是利用干细胞直接诱导生成的三维组织模型，为人类生物学研究提供了新的方法，此项研究正在不断发展进步中。类器官体可以被应用到卵巢肿瘤的基因分析和药物筛选等各方面研究，为卵巢癌临床前研究提供了一个新的平台。     

Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer

A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient''s tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor''s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer     

PDX1在胃癌中的表达及与临床病理之间的关系

目的:探讨胰十二指肠同源基因1（pancreatic duodenal homeobox gene 1,PDX1）表达水平与胃癌临床病理之间的关系。方法:应用RT-PCR法分别测定AGS、BCG823、SGC7901等三株胃癌细胞中PDX1mRNA的表达,免疫印迹法测定胃癌组织芯片中PDX1蛋白表达水平。构建PDX1表达载体,转染胃癌细胞,转染后应用免疫印迹法测定胃癌细胞中PDX1、胃癌增殖相关蛋白（PCNA、Ki-67）和凋亡蛋白（Caspase3）的表达情况,并对胃癌细胞增殖及凋亡情况进行分析。结果:胃癌组织芯片中包括腺癌110例,黏液腺癌 18例,印戒细胞癌15例,正常胃黏膜组织10例。正常胃黏膜组织中PDX1蛋白表达呈高水平,而在胃癌组织中PDX1蛋白表达水平下降或缺失（P<0.05）。PDX1表达水平与淋巴结转移及肿瘤分化程度有关（P<0.05）。PDX1表达载体经转染后,PDX1表达水平升高（P<0.05）,而PCNA、Ki-67表达水平下降（P<0.05）,Caspase3表达水平上调（P<0.05）。结论:PDX1在胃癌组织中表达下调与胃癌分化程度及淋巴结转移密切相关,其表达水平下调可能在胃癌病情进展中起到重要的作用。     

The fidelity of cancer cells in PDX models: Characteristics,mechanism and clinical significance

Patient-derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next-generation preclinical models.     

人源免疫重建PDX模型构建及其在肿瘤免疫治疗中的应用进展

免疫治疗已成为肿瘤治疗领域最具潜力的手段之一。由于肿瘤存在高度异质性等特点,导致免疫治疗响应率偏低,疗效有限。因此,迫切需要具有预测性的临床前模型,用于推动合理、安全的免疫治疗策略开发。传统体内、外肿瘤研究模型受限于人源免疫系统的缺失。因此,构建同时具有人源免疫系统和肿瘤的研究模型成为热点。将患者来源肿瘤移植入人源免疫系统重建小鼠体内肿瘤、免疫双人源化模型,具有可重现人体内免疫细胞与肿瘤间相互作用的优势,成为生理和病理条件下模拟人体肿瘤免疫治疗疗效的新模型。本文主要对多种类型人源化免疫重建PDX模型构建、优缺点及其在肿瘤免疫治疗研究中的最新应用进展进行综述。      

Vandetanib as a potential new treatment for estrogen receptor‐negative breast cancers

The receptor tyrosine kinase RET is implicated in the progression of luminal breast cancers (BC) but its role in estrogen receptor (ER) negative tumors is unknown. Here we investigated the expression of RET in breast cancer patients tumors and patient‐derived xenografts (PDX) and evaluated the therapeutic potential of Vandetanib, a tyrosin kinase inhibitor with strong activity against RET, EGFR and VEGFR2, in ER negative breast cancer PDX. The RT‐PCR analysis of RET expression in breast tumors of 446 patients and 57 PDX, showed elevated levels of RET in ER+ and HER2+ subtypes and in a small subgroup of triple‐negative breast cancers (TNBC). The activity of Vandetanib was tested in vivo in three PDX models of TNBC and one model of HER2+ BC with different expression levels of RET and EGFR. Vandetanib induced tumor regression in PDX models with high expression of RET or EGFR. The effect was associated with inhibition of RET/EGFR phosphorylation and MAP kinase pathway and increased necrosis. In a PDX model with no expression of RET nor EGFR, Vandetanib slowed tumor growth without inducing tumor regression. In addition, treatment by Vandetanib decreased expression of murine Vegf receptors and the endothelial marker Cd31 in the four PDX models tested, suggesting inhibition of tumor vascularization. In summary, these preclinical results suggest that Vandetanib treatment could be useful for patients with ER negative breast cancers overexpressing Vandetanib's main targets.     

Report of the use of patient‐derived xenograft models in the development of anticancer drugs in Japan

Cell line‐derived xenograft (CDX) models created by implanting cancer cell lines into immunodeficient mice have contributed largely to the development of cancer drug therapies. However, cell lines often lose their original biological characteristics through many passages and cancer tissues in CDX models have many cancer cells and few cancer stromal cells, therefore CDX models are currently considered not suitable for predicting the results of clinical studies. Conversely, patient‐derived xenograft (PDX) models are gaining importance, as human cancer biological characteristics and microenvironments are recreated by implanting tumor tissue into immunodeficient mice. These highly expected, evidently beneficial PDX models have been used in some basic research and are becoming more generalized. However, quality control and quality assurance criteria have not been established for them, and challenges and problems in the utilization of valuable PDX models in drug development have yet to be clarified. In this report, we conducted a questionnaire survey among researchers in Japanese academic institutions and pharmaceutical companies to understand the current status of PDX models in Japan. Based on the questionnaire results, we summarized the situations surrounding respondent's utilization and quality control in the development of anticancer drugs and proposed several measures to facilitate the utilization of PDX models in the development of anticancer drugs.     

Upregulation of S100A10 in metastasized breast cancer stem cells

Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient‐derived tumor xenograft (PDX) mouse model in which CSC marker CD44⁺ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44⁺ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell–related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.