结直肠癌患者外周血循环肿瘤细胞的检测及临床研究进展

结直肠癌是最常见的恶性肿瘤之一,虽然综合治疗的开展使其疗效有较大改善,但仍有较多患者死于术后的复发和转移。循环肿瘤细胞(circulating tumor cell,CTC)来源于肿瘤组织,与肿瘤转移及预后密切相关。对CTC检测方法及其在结直肠癌中的临床研究进行综述。     

结直肠癌中循环肿瘤细胞的表达及与Ki-67的关系研究

目的 探讨结直肠癌中循环肿瘤细胞(CTC)及其分型的表达,并分析其与Ki-67表达的关系.方法 选取230例结直肠癌患者,收集临床资料,利用CanPatrolTM二代检测技术检测CTC及其分型[上皮型CTC(eCTC)、混合型CTC(bCTC)和间质型CTC(mCTC)]的表达情况;采用免疫组化法检测结直肠癌患者结直肠癌组织中Ki-67的表达情况,分析结直肠癌患者CTC及其分型的表达与Ki-67表达的关系.结果 230例结直肠癌患者中,CTC阳性率为69.13％(159/230),Ⅰ、Ⅱ、Ⅲ期结直肠癌患者CTC阳性率分别为55.56％、64.58％、76.64％,mCTC阳性表达率分别为51.85％、66.71％、79.44％,CTC、mCTC阳性表达率随临床分期的升高而逐渐升高.不同分化程度、淋巴结转移情况、TNM分期结直肠癌患者CTC阳性表达率、mCTC阳性表达率及Ki-67表达情况比较,差异均有统计学意义(P<0.05).Ki-67≥60％结直肠癌患者mCTC阳性表达率为73.85％,高于Ki-67<60％患者的57.14％(P<0.05).结论 随着结直肠癌的进展,CTC、mCTC阳性表达率逐渐升高,且mCTC可能参与结直肠癌血行转移过程;Ki-67表达水平与mCTC的阳性表达可能有关,二者对结直肠癌的发展、转移及预后评估有重要意义.     

乳腺癌循环肿瘤细胞检测及其研究进展

循环肿瘤细胞(CTC)为肿瘤发生转移的重要原因.检测CTC能早期发现肿瘤的转移及复发.在乳腺癌中,CTC检测与其他检测方式相比有较高的可重复性和敏感性,并能更早地提供预后信息.     

循环肿瘤细胞检测在结直肠癌临床中的应用

结直肠癌是常见的恶性肿瘤之一,其复发和转移是导致患者死亡的主要原因。外周血循环肿瘤细胞（circulating tumor cells,CTCs）是导致结直肠癌患者复发转移的关键性因素之一,在结直肠癌患者复发转移的监测、预后、病情评估以及治疗等临床问题中有重要的应用价值,已成为近年来研究的热点。本文从CTCs的分离富集、检测技术及在结直肠癌患者中的临床应用价值等几个方面,全面阐述了CTCs检测在结直肠癌临床应用中的研究进展。     

非小细胞肺癌患者中循环肿瘤细胞的预测作用

恶性肿瘤患者的血液中可检测到循环肿瘤细胞（circulating tumor cells,CTC）。转移性乳腺癌、结直肠癌和前列腺癌中外周血CTC与疾病的复发及治疗反应的临床相关性已经被确立。研究晚期肺癌患者中CTC与临床的相关性对指导临床治疗的非常重要。CTC可能成为临床上提示肺癌预后;预测疾病进展;指导治疗的重要因素,将CTC检测转化到临床实践中并进一步改善标准化的CTC检测技术有重要意义。     

循环肿瘤细胞及磷酸酶张力蛋白同源物基因检测在Ⅲ期结直肠癌中的临床意义

目的 探讨术后Ⅲ期结直肠癌患者外周血循环肿瘤细胞(CTC)、磷酸酶张力蛋白同源物(PTEN)基因水平与临床特征的关系及对预后的影响.方法 应用CanPatrolTM CTC二代技术联合RNA多重原位杂交分析技术,检测77例结直肠癌患者外周血中CTC及PTEN表达情况,并对CTC进行分型.结果 低分化结直肠癌患者CTC阳性率明显高于中分化患者,且随着T分期升高CTC阳性率升高,差异均有统计学意义(P﹤0.01).不同T分期、分化程度的结直肠癌患者上皮型CTC比例比较及不同T分期、N分期的结直肠癌患者混合型CTC比例比较,差异均有统计学意义(P﹤0.05).CTC与PTEN基因表达水平呈负相关(P﹤0.01).CTC阴性患者无进展生存时间(PFS)及生存时间(OS)均长于阳性组,亚型中,间质型CTC阴性患者PFS及OS均长于阳性组,PTEN基因中表达患者PFS及OS均长于低表达患者,差异均有统计学意义(P﹤0.05).结论 CTC及PTEN基因的检测对于结直肠癌患者病情判断、预后评估、预测术后进展等有一定的临床意义.     

循环肿瘤细胞检测在胃肠道肿瘤诊疗中的应用中国专家共识（2023版）

循环肿瘤细胞（circulating tumor cell,CTC）作为新型肿瘤标志物,具有无创、动态监测和准确度高等特点,可以提供精确的肿瘤分子特征,帮助了解肿瘤发展过程中的变化。因此,CTC在肿瘤进展的动态监测中具有重要临床价值。为了规范和指导CTC检测在胃肠道肿瘤诊疗中的应用,中华医学会肿瘤学分会胃癌学组、中国医师协会结直肠肿瘤专业委员会、中国抗癌协会大肠癌专业委员会、中国抗癌协会胃癌专业委员会和中国抗癌协会消化道息肉及癌前病变专业委员会联合并召集国内部分专家,讨论制定了《循环肿瘤细胞检测在胃肠道肿瘤诊疗中的应用中国专家共识（2023版）》。本共识围绕CTC检测在胃肠道肿瘤诊疗中的检测技术和临床应用（包括预后判断、复发转移监测、疗效监测和辅助诊断）提供共识意见,以期为临床应用提供指导。     

直肠癌循环肿瘤细胞与原发肿瘤组织基因表达谱的差异分析

目的:通过直肠癌循环肿瘤细胞(circulating tumor cell,CTC)与原发肿瘤组织基因表达谱的差异分析,筛选直肠癌CTC的特异性基因.方法:选取2015年9月至2015年12月福建省肿瘤医院收治的直肠癌患者4例,取肿瘤组织和相应的癌旁组织并采集外周血20 ml.应用流式细胞术检测血液CTC,抽提癌组织和CTC的总RNA,采用人全转录组表达谱芯片检测CTC及相应肿瘤组织mRNA表达谱,经聚类分析筛选CTC特异性基因,并采用生物分子注释系统MAS软件对其进行基因功能及其相关的信号通路分析.结果:4例直肠癌患者检测到CTC数目分别是67、78、53和120个.筛选出肿瘤与癌旁组织差异基因共7 755个、CTC与白细胞差异基因共567个,肿瘤组织及CTC差异基因交集后共同上调或下调的特异性基因共36个,其中上调16个、下调20个(P＜0.05或P＜0.01).CTC特异性基因与肿瘤转移和干细胞功能有关,涉及与细胞转移、干细胞功能和免疫功能相关的22条信号通路.结论:CTC与原发肿瘤基因相比,具有独特的表达谱,是肿瘤复发和转移的重要基础.     

乳腺癌循环肿瘤细胞研究及其检测进展

乳腺癌是女性发生率最高的恶性肿瘤之一,其引起死亡的主要原因是乳腺癌的复发转移.转移灶的形成是一个连续复杂的过程,从原发灶生长的早期即已开始.肿瘤细胞进入血液循环是乳腺癌发生转移的基础.经过多种复杂机制最终形成转移灶.因此,检测循环肿瘤细胞(CTC)对预测转移有重要作用.由于外周血中CTC数量稀少,增加了其检测的难度.目前对CTC的检测主要分为基于抗体的技术、核酸技术以及联合检测、系统检测等方式,随着试验方法的改进和新技术的不断出现,CTC检测的敏感度和特异性有较大提高.然而缺乏高特异性的标志物仍是CTC检测面临的最大问题.乳腺癌患者CTC水平与肿瘤的分期相关,其水平的升高提示有更高转移的可能.预示患者的预后较差.与传统的组织学及影像学检查相比,CTC检测有更高的可重复性和敏感度,并能更早地提供预后信息.与骨髓微转移肿瘤细胞检测相比,CTC检测具有创伤小、可连续多次检测等特点.CTC检测更重要的意义是能够帮助指导临床个体化治疗方案的制定.通过对CTC连续的检测可以及早地评估治疗效果,据此及时转变为更有效的治疗方案,提高患者的生存率.本文对乳腺癌循环肿瘤细胞的研究、检测技术和临床应用的新进展进行综述.     

结直肠癌循环肿瘤细胞及DNA的研究进展

结直肠癌是最常见的恶性肿瘤之一,尽管联合应用手术、化疗、放疗可提高患者的生存率,但仍有大量患者因术后转移和复发死亡。循环肿瘤细胞及循环肿瘤DNA对结直肠癌的早期诊断、疗效监测、预后评估以及个体化治疗方案制定均有重要意义,已成为近年来研究的热点。本文对近年来结直肠癌循环肿瘤细胞及循环肿瘤DNA的检测技术及其在早期诊断、疗效监测和预后判断中的应用进展作一综述。     

The clinical significance of circulating tumor cells in non-metastatic colorectal cancer - A review

Background

Finding a clinical tool to improve the risk stratification and identifying those colorectal cancer patients with an increased risk of recurrence is of great importance. The presence of circulating tumor cells (CTC) in peripheral blood can be a strong marker of poor prognosis in patients with metastatic disease, but the prognostic role of CTC in non-metastatic colorectal cancer is less clear. The aim of this review is to examine the possible clinical significance of circulating tumor cells in non-metastatic colorectal cancer (TNM-stage I-III) with the primary focus on detection methods and prognosis.

Methods

The PubMed and Cochrane database and reference lists of relevant articles were searched for scientific literature published in English from January 2000 to June 2010. We included studies with non-metastatic colorectal cancer (TNM-stage I-III) and CTC detected pre- and/or post-operatively in peripheral blood.

Results

Nine studies qualified for further analyses. Detection rates of CTC in peripheral blood of patients with non-metastatic colorectal cancer varied from 4% to 57%. Seven studies applied RT-PCR and two studies used immunocytochemical methods. Seven studies found the presence of CTC to be a prognostic marker of poor disease-free survival.

Conclusion

The presence of CTC in peripheral blood is a potential marker of poor disease-free survival in patients with non-metastastic colorectal cancer. The low abundance of CTC in non-metastatic colorectal cancer requires very sensitive and specific detection methods. An international consensus on choice of detection method and markers, is warranted before incorporating CTC into risk stratification in the clinical setting.     

循环肿瘤细胞检测技术及其在胃癌中的研究现状

胃癌是全球最常见的恶性肿瘤之一,其发病率高,死亡率高,且预后较差。循环肿瘤细胞是存在于肿瘤患者外周血中的少量恶性肿瘤细胞,它与患者转移复发关系密切,因此也是胃癌预后较差的关键因素之一。随着生物科技的发展,循环肿瘤细胞的检测方法层出不穷,依据不同的原理出现了不同的方法,且不同方法的特异性和灵敏性也各不相同。本研究就循环肿瘤细胞现有的各项检测技术及在胃癌中的临床应用做一综述。     

Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives

Hepatocellular carcinoma (HCC) is a primary liver cancer with a huge challenge in terms of its complex etiology and its management. The fact that the most common site of early tumor recurrence in liver transplantation for HCC is the transplanted allograft strongly suggests that circulating tumor cells (CTCs) are really an active source of HCC metastasis or recurrence. In the past decade, with the tremendous progress in the technology of CTC detection, there is convincing evidence that CTCs have great potential as a marker for metastatic disease and poor prognosis in patients with a malignancy. Currently some interesting and encouraging results have been achieved in HCC CTC detection, although the knowledge about its clinical relevance in HCC is lagging behind other major tumor types. Here we will review existing and developing methodologies for CTC detection, discuss future perspectives, and describe the potential clinical impact of the identification and molecular characterization of CTC subset or circulating cancer stem cells in HCC patients. Particular attention is given to the results based on the HCC CTC study.     

循环肿瘤细胞的异质性在转移性乳腺癌中的作用研究进展

循环肿瘤细胞（CTC）的计数可以预测转移性乳腺癌的预后,但其改善患者预后的能力在临床试验中尚未得到证实。目前研究专注于CTC的分子表征,作为肿瘤组织的“替代物”以非侵入性地方式评估癌症基因组表达及其在治疗过程中的演变。CTC中存在上皮-间质转化过程（EMT）,其特点为上皮标志物的缺失。EMT过程可以存在于侵袭性及耐药性较强的细胞,其计数和表征,能够引起肿瘤的复发和进展,具有较高的临床价值。本文深入探讨循环肿瘤细胞的异质性及在转移性乳腺癌上皮-间质转化过程中的作用。使其成为乳腺癌患者监测转移和预后的常规的检测指标,并有助于明确转移的机制,更有望发现乳腺癌转移治疗的新靶点。     

PD-1/PD-L1信号通路在结直肠癌免疫逃逸及其治疗中作用的研究进展

结直肠癌是常见的消化系统肿瘤。近年来,免疫治疗是继放化疗及靶向治疗之后,结直肠癌治疗领域的新方向。而作为T细胞免疫反应的协同刺激信号通路,程序性死亡分子1（programmed death-1,PD-1）/PD-1配体（PD-1 ligand,PD-L1)信号通路在肿瘤的免疫治疗中起着至关重要的作用。PD-1/PD-L1信号通路被激活后,可参与肿瘤的免疫逃逸,与肿瘤的发生、发展密切相关。体内外实验证实,阻断该通路可增强机体内源性抗肿瘤免疫效应。本文就PD-1/PD-L1信号通路及其阻滞剂在结直肠癌领域中的研究进展作一综述。     

Circulating tumor cells in high-risk nonmetastatic colorectal cancer

The identification of patients at higher risk of recurrence after primary colorectal cancer resection is currently one of the challenges facing medical oncologists. Circulating tumor cell (CTC) may represent a surrogate marker of an early spread of disease in patients without overt metastases. Thirty-seven high-risk stages II–III colorectal cancer patients were evaluated for the presence of CTC. Enumeration of CTCs in 7.5 ml of blood was carried out with the FDA-cleared CellSearch system. CTC count was performed after primary tumor resection and before the start of adjuvant therapy. CTC was detected in 22 % of patients with a significant correlation with regional lymph nodes involvement and stage of disease. No significant correlation was found among the presence of CTC and other clinicopathological parameters. These data suggest that CTCs detection might help in the selection of high-risk stage II colorectal cancer patient candidates for adjuvant chemotherapy.     

循环肿瘤细胞及其与肿瘤转移复发的相关性研究

肿瘤细胞血液播散至远处器官和后来形成的转移灶是上皮来源恶性肿瘤最主要的死亡原因。对恶性肿瘤发生远处转移和复发等研究认为是由外周血中存在的循环肿瘤细胞所致（circulating tumor cell,CTC）。CTCs存在于外周循环中,激发机体的免疫反应,大部分肿瘤细胞被机体免疫系统所识别难以生存,只有小部分细胞继续在循环中,穿透基底膜,侵出血管在远端形成肿瘤转移灶。CTCs是肿瘤发生远处转移的必要条件,深入研究循环肿瘤细胞有助于对肿瘤的转移机制有更多的了解。本文对CTCs的分离与鉴定技术方法和CTCs与肿瘤复发转移的机制进行综述。     

A novel platform for detection of CK+ and CK- CTCs

Metastasis is a complex, multistep process that begins with the epithelial-mesenchymal transition (EMT). Circulating tumor cells (CTC) are believed to have undergone EMT and thus lack or express low levels of epithelial markers commonly used for enrichment and/or detection of such cells. However, most current CTC detection methods target only EpCAM and/or cytokeratin (CK) to enrich epithelial CTCs, resulting in failure to recognize other, perhaps more important, CTC phenotypes that lack expression of these markers. Here, we describe a population of complex aneuploid CTCs that do not express CK or CD45 antigen in patients with breast, ovarian, or colorectal cancer. These cells were not observed in healthy subjects. We show that the primary epithelial tumors were characterized by similar complex aneuploidy, indicating conversion to an EMT phenotype in the captured cells. Collectively, our study provides a new method for highly efficient capture of previously unrecognized populations of CTCs. Significance: Current assays for CTC capture likely miss populations of cells that have undergone EMT. Capture and study of CTCs that have undergone EMT would allow a better understanding of the mechanisms driving metastasis.     

Circulating tumour cells as a predictive factor for response to systemic chemotherapy in patients with advanced colorectal cancer

Circulating tumour cells (CTC) can be traced in patients with different types of cancer. The aim of this study was to detect CTC in patients with advanced colorectal cancer and whether CTC are still detectable after systemic chemotherapy. Blood from 34 patients with advanced colorectal cancer was analysed for the presence of CTC before chemotherapy was given and after 3 months. Eleven patients demonstrated a tumour remission after chemotherapy. In 6 cases CTC were detectable before but not after initiation of chemotherapy. Ten patients demonstrated a progression. In 5 cases CTC were detected before and after chemotherapy. Our data suggest that the detection of CTC will help to identify patients responding to chemotherapy or with a risk of a therapy failure.     

Circulating Tumor Cells and Colorectal Cancer

The significance of circulating tumor cells (CTCs) has been discussed for more than a century. The advent of modern technology has allowed for more reliable detection of CTCs, and recent studies have provided compelling evidence that CTCs predict clinical response in metastatic colorectal cancer (mCRC). Combination of CTC analysis with independent prognostic factors has demonstrated powerful synergy in some studies. The ability of CTCs to predict metastasis and therapy-specific response has high potential clinical utility, with early studies showing promising results in colorectal cancer (CRC). Reliable CTC detection has also allowed for examination of tumor cell dissemination during surgery, and there appears to be a heavy dependence on the approach chosen. This review discusses the evidence for CTC significance, with particular focus on detection methods, novel markers, and clinical outcomes in CRC. Numerous opportunities exist for preclinical, clinical, and translational studies to explore molecular determinants within CTCs, as well as the value of CTCs in directing targeted therapeutics.