循环肿瘤DNA应用于乳腺癌的潜在价值探索

循环肿瘤DNA（ctDNA）是肿瘤细胞通过坏死、凋亡或直接分泌的方式向血液中释放的游离DNA。ctDNA常携带肿瘤相关的单核苷酸变异、拷贝数改变及结构变异等遗传学改变,这一特点促使循环肿瘤DNA成为潜在的生物标记物。以聚合酶链式反应（PCR）或二代测序（NGS）为基础的检测技术的进步提高了ctDNA检测的敏感性和信息量。ctDNA作为一种“液体活检”方法因其简便易行、侵害性小、实时动态佳等优势在乳腺癌领域得到了广泛研究,可以协助早期诊断、监测疗效、探索耐药机制、预测疾病复发和判断预后,为确定肿瘤患者治疗策略提供依据,从而真正实现乳腺癌的个体化治疗。     

循环肿瘤细胞的检测及其临床应用

循环肿瘤细胞(CTC)可反映肿瘤的侵袭性.尽管许多检测及计数CTC的方法如磁性激活的细胞筛选、免疫细胞化学法、反转录聚合酶链式反应、流式细胞术开展了很久,直到最近这些方法才具有可行性.临床检测结果强烈提示,在某些肿瘤中,CTC的检测和计数可以用来预测预后、选择个体化治疗并可能作为评估治疗反应性的早期指标.     

循环肿瘤DNA检测在乳腺癌诊断中的临床应用

随着二代测序技术的发展,循环肿瘤DNA(circulating tumor DNA,ctDNA)检测在乳腺癌中的应用得到越来越多的关注。目前国内外大量研究显示ctDNA检测技术在监测肿瘤负荷、疗效预测、早期诊断、预后分析等方面具有广阔的应用价值。在乳腺癌诊疗走向个体化精准的时代,ctDNA检测能够为患者提供更为精准的诊断,指导临床治疗。     

乳腺癌患者循环肿瘤细胞在预后和疾病进展中的作用

检测外周血循环肿瘤细胞(circulating tumor cell,CTC)已经成为在癌症诊断中热门领域之一。目前已有证据表明CTC和无病生存期,无进展生存期和总生存期相关。在乳腺癌患者骨髓或循环血检测出CTC是微转移的早期提示。检测CTC预测癌转移的方法证明优于一些传统的方法,如患者的临床表现、影像学检查及血清肿瘤标志的检查等。且具有早期、高效、可靠及检测过程低侵袭性的特点。本文总结国内外乳腺癌循环肿瘤细胞(CTC)在检测手段及相关临床意义方面的研究进展,以及CTC检测项目在研究肿瘤转移过程中的地位、必要性及未来的发展方向。     

循环肿瘤细胞检测及其临床应用

循环肿瘤细胞(CTC)与恶性肿瘤的发生发展密切相关.目前检测CTC的方法有逆转录聚合酶链反应、免疫磁珠富集检测法等.检测CTC有助于发现早期肿瘤患者的微转移、重新确定临床分期,监测术后或者放化疗后患者肿瘤复发与转移,评估预后,选择个体化的治疗策略.     

循环肿瘤DNA的研究进展

循环肿瘤DNA(circulating tumor DNA,ctDNA)是由肿瘤细胞释放到循环系统中的基因组小片段,其来源于机体所有荷瘤部位,具有含量极低、个体间差异大、半衰期短、匀质性、携带有肿瘤特异性遗传学/表观遗传学变异等特点,与肿瘤的发展进化、休眠耐药、转移复发等密切相关,正逐渐成为肿瘤学分子研究领域的热点.目前针对ctDNA的检测方法和平台种类繁多,主要分为基于PCR和二代测序(next-generation sequence,NGS)的方法,二者各有利弊,需要根据研究目的灵活选择并建立统一标准.随着相关技术的发展和法规的不断完善,ctDNA可作为癌症筛查、早期诊断、个体化治疗及预后评估理想的血源性生物标志物,在肿瘤的精准医疗中必将大放异彩.     

循环肿瘤细胞在乳腺癌诊疗中的应用

近年来外周血循环肿瘤细胞（CTC）检测的临床应用无疑是精准医学领域的研究热点之一。CTC检测因其具有非侵入性、易获取、可反复采集、具有高度可重复性等优势,可对肿瘤治疗进行实时全面监测,在乳腺癌的复发预警、疗效及时评价、预后判断以及个体化治疗用药指导等方面均有大量的应用。     

循环肿瘤细胞与个体化药物治疗

循环肿瘤细胞（circulating tumor cells,CTC）已经被证实存在于肿瘤患者尤其是晚期患者的外周血中。近年来CTC的研究技术迅速发展并且在肿瘤个体化药物治疗方面显示出良好的发展前景。CTC的重要性在于它可以使基因表达／突变的检测变得切实可行,从而实现“实时”个体化药物治疗。本文主要介绍现有的CTC检测／收集技术及其在个体化药物治疗方面的作用。     

循环肿瘤细胞与肺癌

循环肿瘤细胞(CTC)与肿瘤转移有明显的相关性,CTC检测有助于指导肿瘤治疗,为判断预后、预测疗效提供可靠依据.CTC与非小细胞肺癌的分期及远处转移相关.CTC数量变化与非小细胞肺癌患者化放疗疗效及预后有关.小细胞肺癌中CTC检出率和数量均明显高于其他肿瘤,与其分期及化疗疗效有关.CTC有望用于指导肺癌个体化治疗.初步研究结果提示可用CTC来动态了解肺癌患者分子靶向药物治疗过程中耐药肿瘤细胞的出现.     

循环肿瘤标志物在乳腺癌复发和预后评估中的研究进展

乳腺癌是女性癌症死亡最主要的原因，居女性恶性肿瘤发病率首位。对乳腺癌患者进行早期诊断以及更精准的疗效评估和复发监测，可为患者制定及时有效的个体化治疗方案提供更多的循证依据。本文就循环肿瘤细胞（circulating tumor cells，CTCs）、循环肿瘤DNA（ciculating tumor，ctDNA）、外泌体（Exosomes）、ctDNA甲基化以及循环肿瘤血小板（tumor-educated platelets，TEPs）等循环肿瘤标志物在乳腺癌复发监测和病情评估中的研究进展进行综述。     

Monitor tumor burden with circulating tumor DNA

There is a need to identify better biomarkers to monitor diseases and/or assess therapeutic responses. For those with cancer, one can identify DNA fragments that contain somatic mutations originating in the tumor DNA in plasma or serum. There have been several early studies suggesting that advances in sequencing technologies will allow identification of somatic genomic alterations that can be used to monitor tumor dynamics. Dawson et al. investigated circulating cell-free DNA carrying tumor specific alterations in patients with breast cancer. The authors compared CT imaging from 30 women with metastatic breast cancer receiving treatment, using two assays for circulating tumor DNA, CA 15-3, and CTCs. Taken the two methods together circulating tumor DNA was detected in 29 or 30 women (97%) and 115 of 141 plasma samples (82%). Circulating tumor DNA levels showed a greater dynamic range and greater correlation with changes in tumor burden than did CA 15-3 or CTC. The relatively small study showed that circulating tumor DNA has a superior sensitivity to other circulating biomarkers and a dynamic range that correlates with tumor burden.     

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。     

Breast cancer circulating tumor cells

Metastasization of breast cancer involves various mechanisms responsible for progression from invasive lesion to dissemination in distant organs. Regional lymph node metastasization was considered an initial step in this process, but it is now recognized that hematogenous dissemination is a deviation from lymphatic circulation. The detection of circulating tumor cells (CTC) is an aim in several oncology areas. For this purpose, several techniques have been used to detect CTC, including the use of antibodies and techniques with nucleic acids. This study reviews the published studies considering the detection of breast cancer CTC. There are focused the difficulties in identifying a CTC in a heterogeneous population, the handling of the sample, criteria of positivity, analytical techniques, and specific markers. There are systematized various specific markers of breast cancer cells also the problems with false positive results. Finally, we hypothesize clinical applications either as a prognostic marker or as a therapeutic response monitor.     

趋化因子与循环肿瘤细胞

趋化因子(chemokine,CK)和循环肿瘤细胞(circulating tumor cells,CTC)在肿瘤定向转移中发挥重要作用.CK通过诱导肿瘤细胞上调基质金属蛋白酶(matrix metalloproteinase,MMP),降解细胞外周基质(extracellular matrix,ECM),发生上皮间质转化(epithelial-mesenchymal transition,EMT),抵抗失巢凋亡(anoikis)和免疫逃避等机制,最终形成CTC,发生“信号”归巢和器官定植,其中每一个步骤都有不同CK的正向或反向参与,其中有共性,也有差异.本文综合阐述CK在CTC的形成及其完成转移过程中的作用及可能机制;分析CK在CTC中的作用差异;探讨靶向CK信号轴个体化治疗肿瘤的研究现状及主要方向;为建立基于靶向CK信号轴治疗肿瘤的个体化治疗模式提供理论基础.     

CTC、ctDNA在结直肠癌诊断中的研究进展

结直肠癌（colorectal cancer,CRC）是世界上第三大最常见的癌症类型,也是导致癌症死亡的第四大原因。CRC的常规治疗策略包括手术、新辅助治疗和辅助治疗。不幸的是,大约50％的CRC患者仅在晚期被诊断,因此显著降低了不同治疗方案的可用性。学者们不断寻找更准确的诊断结直肠癌的方法,除了通过蛋白质组学技术研究新的血清肿瘤生物标记物外,还引入循环肿瘤细胞（CTC）和循环肿瘤DNA（ctDNA）等新概念。本文就血液中CTC、ctDNA在结直肠癌诊断中的研究进展作一综述。     

Cell-free circulating tumor DNA in cancer

Cancer is a common cause of death worldwide. Despite significant advances in cancer treatments, the morbidity and mortality are still enormous. Tumor heterogeneity, especially intratumoral heterogeneity, is a significant reason under-lying difculties in tumor treatment and failure of a number of current therapeutic modalities, even of molecularly targeted therapies. The development of a virtually noninvasive“liquid biopsy”from the blood has been attempted to characterize tumor heterogeneity. This review focuses on cell-free circulating tumor DNA (ctDNA) in the bloodstream as a versatile biomarker. ctDNA analysis is an evolving field with many new methods being developed and optimized to be able to successfully extract and analyze ctDNA, which has vast clinical applications. ctDNA has the potential to accurately genotype the tumor and identify personalized genetic and epigenetic alterations of the entire tumor. In addition, ctDNA has the potential to accurately monitor tumor burden and treatment response, while also being able to monitor minimal residual disease, reducing the need for harmful adjuvant chemotherapy and allowing more rapid detection of relapse. There are still many challenges that need to be overcome prior to this biomarker getting wide adoption in the clinical world, including optimization, standardization, and large multicenter trials.     

循环肿瘤细胞株的建立

循环肿瘤细胞(CTC)具有的特异性(上皮间质转化、与骨髓来源细胞的融合、抗失巢凋亡)决定了将其作为原代目标进行培养的必要性,所培养出的细胞株将为进一步研究恶性肿瘤的转移机制提供良好的物质基础,为患者的靶向治疗提供个体化的新方向.     

Clinical usefulness of circulating tumor markers

There are many molecular tumor markers for diagnosing and monitoring cancer patients. Especially, quantitative assay for serum levels of tumor markers; such as AFP, CEA, PSA, hCG, CA 19-9 and CA 125, are frequently used in daily practice because of their relative specificities and usefulness to the common cancers. Though not suitable for early diagnosis, but they are used in monitoring patients with advanced caner, especially after treatments. Two of them, AFP and PSA, are also used in the screening and monitoring of high-risk groups, namely patients with chronic viral hepatitis and old male, who are the high risk for hepatoma and proste cancer respectively. Problems in using serum markers are; relatively low specificity and low sensitivity to cancer, confusing naming for similar markers that recognize almost the same molecule of cancer. Users must understand that CA 19-9, CA 50, KM-O 1 and SPAN-1 are in the same sialylated Lewis A group, and CA 125, CA 130 and CA 602; in the mucin antigen group, and STN, CA 54/61 and CA 72-4; in the sialyl Tn antigen group. Combination of two or more markers may inform us the biological characteristics of the cancer. For example, a germ-cell tumors may produce hCG and placental marker. That is of the choriocarcinoma type. Those with hCG and fetal antigens are the ordinal type of germ cell tumors, and those with AFP, CEA and cytokeratin are teratoma, and those with LDH and ALP only but negative for hCG and AFP must be seminoma. For the bronchial and alveolar carcinomas, CEA, SCC, NSE and cytokeratin 19 fragments are useful. Combination may be difficult for beginners but once understood, it will be an art in clinical oncology.     

Single-cell analyses of circulating tumor cells

Circulating tumor cells (CTCs) are a population of tumor cells mediating metastasis, which results in most of the cancer related deaths. The number of CTCs in the peripheral blood of patients is rare, and many platforms have been launched for detection and enrichment of CTCs. Enumeration of CTCs has already been used as a prognosis marker predicting the survival rate of cancer patients. Yet CTCs should be more potential. Studies on CTCs at single cell level may help revealing the underlying mechanism of tumorigenesis and metastasis. Though far from developed, this area of study holds much promise in providing new clinical application and deep understanding towards metastasis and cancer development.KEYWORDS : Circulating tumor cells (CTCs), single cell sequencing, metastasis