乳腺癌循环肿瘤细胞

循环肿瘤细胞的播散是乳腺癌转移与复发的重要事件.检测循环肿瘤细胞,对判断患者预后、评价治疗效果、监测转移复发、指导治疗等有着重要的临床意义.完善循环肿瘤细胞的检测技术,研究循环肿瘤细胞的生物学特性及其机制,是乳腺癌循环肿瘤细胞研究需要解决的主要难题.目前,乳腺癌循环肿瘤细胞研究在检测技术及其指标的联合应用、低增殖活性循环肿瘤细胞研究等方面均取得了一定进展.     

食管癌放化疗中循环肿瘤细胞的变化及其临床意义

目的:探讨局部晚期食管癌放化疗中循环肿瘤细胞（circulating tumor cells ,CTCs）的动态变化,以及CTCs与食管癌临床特征和预后的相关性分析。方法:利用免疫磁珠富集联合免疫荧光检测2011年5 月至2013年5 月江苏大学附属人民医院48例局部晚期食管癌患者放化疗前后的循环血肿瘤细胞,对比分析放化疗前后的动态变化,并分析循环肿瘤细胞与患者临床特征及2 年生存率的关系。结果:循环血肿瘤细胞与肿瘤侵犯程度、淋巴结转移状态及临床分期均显著相关（P < 0.05）,治疗前循环血肿瘤细胞阳性率为52.1%（25/ 48）,治疗结束后为20.8%（10/ 48）,差异具有统计学意义（P < 0.01）。 放化疗前后的循环肿瘤细胞均与患者的2年生存率密切相关（P < 0.05）,Cox 回归分析提示临床分期及放化疗后循环血肿瘤细胞水平是食管癌患者的独立预后因子。结论:循环肿瘤细胞可以反映局部晚期食管癌患者的疾病进展程度,并且可以作为判断预后的指标。      

乳腺癌血清肿瘤标志物和循环肿瘤细胞检测的研究进展

 随着分子生物学的发展,乳腺癌的治疗正逐步进入分子分型治疗的时代,为了给患者提供更加有效的个体化治疗,研究者们不断努力寻找乳腺癌新的治疗靶点、疾病监控指标以及疗效预测和预后评估的指标,日益深入的研究显示血清肿瘤标志物和循环肿瘤细胞的检测在乳腺癌治疗中有重要价值。现就近年乳腺癌血清肿瘤标志物和循环肿瘤细胞检测的相关临床研究作一综述。     

循环肿瘤细胞自我种植对裸鼠骨肉瘤生长的促进作用

目的：通过建立骨肉瘤裸鼠荷瘤模型,观察骨肉瘤中是否存在循环肿瘤细胞自我种植现象,并探讨其在骨肉瘤进展中的作用。方法：建立骨肉瘤裸鼠原位荷瘤模型后,处理组尾静脉注射红色荧光蛋白（RFP）标记循环肿瘤细胞,对照组注射PBS,2周后将处理组原位瘤体冰冻切片荧光显微镜下观察有无自我种植,并根据肿瘤生长指标（大小、重量、生长曲线）将处理组与对照组进行比较分析。结果：处理组瘤体冰冻切片后荧光显微镜下观察发现,原位瘤组织中有红色荧光散在分布,即存在循环肿瘤细胞自我种植现象。肿瘤生长各指标比较发现,处理组瘤体在大小、重量、生长速率上均显著高于对照组（P〈0.05）,具有统计学意义。结论：骨肉瘤中存在循环肿瘤细胞自我种植现象,并且能够促进原位灶的生长。     

循环肿瘤细胞检测的临床有效性和实用性分析

循环肿瘤细胞(Circulating tumor cells,CTC)是一种特殊的可以作为诊断、预测多种肿瘤预后的生物标记物。目前,循环肿瘤细胞并未开始全面的临床应用,但关于循环肿瘤细胞的研究已经展示出较高的临床有效性,尤其是在乳腺癌、肺癌、前列腺癌及结直肠癌领域。本文综述了循环肿瘤细胞在转移癌和非转移癌的研究进展,并分析了循环肿瘤细胞的临床有效性和实用性。     

原发性肝癌血行转移相关基因的研究

肝细胞癌是常见的恶性肿瘤 ,早期易发生血行播散 ,而血循环中的肿瘤细胞被认为是血行或远处器官转移的指标。目前已提出AFPmRNA和白蛋白mRNA作为循环中存在肝肿瘤细胞的标志物。综述国内、外有关研究 ,探讨其在预测肝细胞癌发生血行转移中的价值以及与其他转移、预后指标的相关性     

乳腺癌循环肿瘤细胞生物学特性的研究进展

目的：总结乳腺癌循环肿瘤细胞生物学特性相关的研究进展。方法：以“乳腺肿瘤、循环肿瘤细胞和微转移”为关键词,系统检索PubMed、Ovid、EMBASE、WebofScience的中国生物医学文献数据库等医学数据库（2000-01—2011—12）。纳入标准：乳腺癌循环肿瘤细胞生物学特性。根据纳入标准,符合分析的文献34篇。结果：乳腺癌循环肿瘤细胞具有高度异形性,细胞增殖活性低,表达激素受体、血管生成相关分子等多种标志,且与上皮细胞间质化、肿瘤干细胞及肿瘤自身种植等密切相关。循环肿瘤细胞具有与原发灶、转移灶内肿瘤细胞明显不同的生物学特征。结论：乳腺癌循环肿瘤细胞具有自身独特的生物学特性,进一步深入研究其生物学特性有助于加深对肿瘤播散和转移机制的认识。     

肺癌中循环肿瘤细胞的检测

 循环肿瘤细胞为肿瘤复发转移的重要原因,检测循环肿瘤细胞能早期发现肿瘤的转移及复发,同时也将有助于判断疾病预后、指导治疗。循环肿瘤细胞检测通常包含有筛选和分离技术如免疫磁性分选技术和逆转录聚合酶链反应等。随着检测技术的发展出现了将筛选和分析技术合为一体的循环肿瘤细胞检测芯片。     

循环肿瘤细胞数量变化在预测局限性肾癌术后复发转移中的作用CSCD

目的探讨局限性肾癌患者行部分切除术后循环肿瘤细胞数量的变化在预测肿瘤复发转移中的作用。方法收集41例局限性肾癌患者,依据术前及术后3月循环肿瘤细胞数量变化分为阳性组(n=23)和阴性组(n=18)。对两组患者进行随访,终点事件为肿瘤复发转移。对所得数据进行统计学分析。结果阳性组复发转移率为43.5%,明显高于阴性组11.1%,差异有统计学意义(P=0.024);阳性组5年生存率为58.0%,阴性组为88.9%,差异有统计学意义(P=0.048)。结论术后3月循环肿瘤细胞计数较术前增加的局限性肾癌患者易出现复发转移。循环肿瘤细胞数量变化可作为较好的术后监测指标。     

循环肿瘤细胞检测及临床应用的研究进展

研究发现，实体瘤患者外周血中存在循环肿瘤细胞。循环肿瘤细胞的检测有助于发现早期肿瘤患者的微转移，重新确定临床分期，监测患者术后肿瘤是否复发与转移，评估预后，选择个体化的治疗策略。由于存在循环肿瘤细胞检测方法、原发肿瘤细胞的不连续脱落、基因组的不稳定性及无效转移等诸多问题，循环肿瘤细胞检测的生物学意义和临床意义仍存在很大争议。本文综述了对实体瘤患者循环肿瘤细胞检测的方法和结果，并探讨当前肿瘤研究领域面临的问题和潜在的进展。     

Significant down-regulation of alpha-albumin in human hepatoma and its implication

The potential association of alpha-albumin (ALF) with hepatocellular carcinoma (HCC) was investigated. Expression of ALF was significantly reduced in HCC tumor tissue as compared with the paired peritumor tissue from 16 patients and in four HCC cell lines as compared with normal hepatocytes. ALF mRNA was also down-expressed in circulating HCC cells compared to circulating normal hepatocytes. The proliferation of Hep3B cells was inhibited by over-expression of ALF. Taken together, ALF is significantly down-regulated in HCC, and this might facilitate the proliferation of HCC. Thus, detection of ALF mRNA, in addition to that of alpha-fetoprotein (AFP) mRNA, might help to distinguish normal or malignant hepatocytes in peripheral blood.     

甲胎蛋白mRNA检测方法

本文设计了两对特异性引物，用聚合酶链反应法（PCR）检测肝细胞癌病人静脉血中微量癌细胞的甲胎蛋白mRNA，PCR反应后出现与已知序列相符的101bp条带，并用Pstl限制性内切酶消化确认其特异性。该方法灵敏度达0．01fg重组DNA，在5ml静脉血中有1～10个癌细胞即可检出，且重复性好，可用于判断肝癌的早期转移。     

Vascular endothelial growth factor in the management of hepatocellular carcinoma

The importance of tumor angiogenesis in tumor biology is now widely accepted. Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression. The authors reviewed the role of circulating vascular endothelial growth factor (VEGF) in screening for HCC and in risk stratification and treatment monitoring. They searched the world medical literature by accessing MEDLINE and PubMed for articles on: 1) the utility of circulating VEGF for HCC screening in patients with cirrhosis; 2) the role of circulating VEGF as a predictor of the invasive potential of HCC; and 3) monitoring anti‐HCC treatment effects by serial measurements of circulating VEGF. They found evidence to support a potential role for VEGF in screening and surveillance of HCC. They also found support for developing the use of VEGF in the monitoring of treatment outcomes. Several studies suggested that the circulating VEGF level may be an independent prognostic marker in HCC. Further studies are needed to determine the utility of circulating VEGF in screening of patients with cirrhosis and to determine its potential role as a prognostic and predictive biomarker in patients with HCC. Cancer 2009. © 2009 American Cancer Society.     

外周血GGTmRNA-H亚型表达与原发性肝癌转移的关系

目的:探索外周血GGTmRNA-H亚型表达与肝癌血源性播散的关系.方法:以逆转录聚合酶链反应(RT-PCR)技术,检测原发性肝癌(HCC)、肝转移癌、良性肝病患者及健康者外周血γ-谷氨酰转移酶mRNA-H亚型(GGTmRNA-H).结果:38例HCC患者中有16例检出GGTmRNA-H,阳性率为42.1%.肝转移癌、良性肝病及健康者均为阴性.外周血GGTmRNA-H阳性率与临床分期、肝内转移、门静脉癌栓和远处转移密切相关.结论:外周血GGTmRNA-H是反映HCC患者有无血源性播散的重要标志,并对AFP阴性或低值的HCC患者有补充诊断的作用.     

MiR-22 regulated T cell differentiation and hepatocellular carcinoma growth by directly targeting Jarid2

MiR-22 has been demonstrated to inhibits tumor growth in several cancers. However, its function in the tumor microenvironment is still unclear, especially for T cell differentiation. Here, miR-22 expression in the circulating T cells from hepatocellular carcinoma (HCC) patients and healthy controls was analyzed with quantitative polymerase chain reaction (qPCR). Diethylnitrosamine (DEN)/phenobarbital (PB)-mediated primary HCC and Hepa1-6 subcutaneous tumor mouse models were established and subjected to lenti-miR-22 injection. Mice immunoreconstituted with miR-22-overexpressing T cells were employed to investigate the antitumor effect of miR-22 in mice. Luciferase assay, immunofluorescent staining, in vitro Th17 cell differentiation assay, and rescue experiments were employed to investigate the mechanism underlying the miR-22-mediated regulation of Th17 cell differentiation and liver tumor growth. Results confirmed the dramatic downregulation of miR-22 expression in malignant tissues and circulating T cells from patients with HCC. MiR-22 expression correlated with good prognosis of patients. Overexpression of miR-22 impaired the DEN/PB-induced primary HCC formation and the growth of Hepa1-6 subcutaneous tumors by promoting Th17 differentiation. Injection of miR-22-overexpressing T cells in irradiated mice resulted in the inhibition of Hepa1-6 subcutaneous tumor growth via Th17 differentiation promotion. MiR-22 could directly bind to Jarid2, which played an important role during the miR-22-mediated regulation of Th17 differentiation. Taken together, our study expands the understanding of miR-22 function and provides a therapy target for HCC.     

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.     

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Circulating tumor DNA (ctDNA) provides a potential non‐invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real‐time track the therapeutic responses in the longitudinal monitoring.     

Detection of circulating intercellular adhesion molecule-1 in hepatocellular carcinoma

Serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) were measured in 23 patients with chronic hepatitis (CH), 22 with liver cirrhosis (LC) and 45 with hepatocellular carcinoma (HCC) using an ELISA. Serum samples from all patients showed significantly higher cICAM-1 levels than serum from 50 normal controls. The cICAM-l level was significantly increased in LC or HCC when compared with CH, but no differences were noted between LC and HCC. Levels of cICAM-1 correlated well with serum bilirubin, retention rate of indocyanine green, hyaluronic acid, type IV collagen 7-S and type III procollagen peptide levels but not with tumor size or circulating tumor markers (α-fetoprotein and des-γ-carboxyprothrombin). Our findings indicate that the measurement of cICAM-l is useful for the determination of the severity of liver disease and hepatic fibrosis. HCC tissues obtained from 10 patients were immunohistochemically stained for ICAM-I. Enhanced ICAM-I expression was found on the tumor cell membranes. Sequential measurements of cICAM-1 levels showed that they changed in a similar manner to those of a-fetoprotein during the course of treatment of HCC in a patient with very high pretreatment levels of both markers. These results suggest that HCC cells shed ICAM-1 into the circulation. We conclude that cICAM-1 is not a diagnostic marker for HCC, but may be useful for monitoring the response to treatment.