肿瘤休眠研究进展

肿瘤休眠是一个临床概念，已有近50年的研究历史，经历了对肿瘤休眠的现象描述、肿瘤休眠动物模型的建立、肿瘤休眠机制研究、实验性肿瘤休眠诱导与肿瘤休眠疗法等阶段。休眠肿瘤细胞的长期存在是恶性肿瘤难以彻底根治的主要原因，也是导致肿瘤复发和远处转移的根源。彻底阐明肿瘤休眠机制，将有助于实现对肿瘤复发与转移的有效控制。     

肿瘤休眠研究进展

肿瘤休眠是一个临床概念,已有近50年的研究历史,经历了对肿瘤休眠的现象描述、肿瘤休眠动物模型的建立、肿瘤休眠机制研究、实验性肿瘤休眠诱导与肿瘤休眠疗法等阶段.休眠肿瘤细胞的长期存在是恶性肿瘤难以彻底根治的主要原因,也是导致肿瘤复发和远处转移的根源.彻底阐明肿瘤休眠机制,将有助于实现对肿瘤复发与转移的有效控制.     

肿瘤休眠细胞：复发根源和治疗靶标

随着肿瘤早期诊断及治疗水平的提高,肿瘤患者的无病生存率得以提高,但仍面临着较高的肿瘤复发风险。越来越多的证据显示,这些长期无病生存的肿瘤患者(甚至某些所谓健康人)的机体内存在着一种肿瘤休眠细胞,这些细胞被认为是导致肿瘤复发的主要根源。肿瘤休眠细胞是一群存在于患者或健康人群体内的数量极少且难以检测的静止细胞,目前对其形成的机制及休眠活动的时相规律均不十分清楚。对于患者而言,骨髓和外周血取材比较容易,所以人们通常会针对骨髓及外周血中的肿瘤休眠细胞建立相对敏感的检测方法。有证据显示,免疫抑制、新生血管生成及外科手术等因素可使肿瘤休眠细胞激活,从而引发肿瘤的复发和转移。肿瘤休眠细胞已成为我们根治肿瘤及预防肿瘤发生或复发的重要靶标。然而,由于处于休眠期的肿瘤细胞不发生活跃增殖,因此传统放、化疗不能将其有效清除,从而对肿瘤的彻底治愈造成了极大的困难。研究表明,免疫监控与肿瘤休眠现象高度相关,因此,针对肿瘤休眠细胞的肿瘤免疫过继细胞治疗将给肿瘤防治带来根本性的变革。我们相信,随着对肿瘤休眠细胞研究的不断深入,将会出现高效清除肿瘤休眠细胞或使肿瘤细胞永远休眠的崭新治疗方案。     

肿瘤休眠的周期和意义

休眠细胞是可逆的静止期细胞，肿瘤休眠细胞的生命周期包括休眠、复苏、出芽和种植，这个周期构成了肿瘤复发的根源。继续维持细胞休眠状态、杀灭肿瘤休眠细胞和诱导休眠细胞衰老的靶向肿瘤休眠策略将可能预防肿瘤复发。     

肿瘤细胞休眠与转移的生物学特性

细胞休眠是生物界普遍存在的一种现象,也是恶性肿瘤细胞生物学特征之一.肿瘤休眠细胞的存在,是导致其复发和远处转移的主要原因,其发生机制可能与休眠相关基因激活、肿瘤血管生成、肿瘤免疫逃逸、癌基因与抑癌基因、信号转导等因素相关.     

肿瘤休眠机制与治疗靶点的发现

肿瘤休眠（tumor dormancy）是指肿瘤细胞在人体内长期存在而没有明显生长的一种状态。肿瘤休眠的现象非常普遍,休眠的肿瘤细胞在部分肿瘤患者甚至正常人体内均可检测到。休眠细胞的长期存在是肿瘤复发和远处转移的根源之一,对肿瘤休眠机制和标志物的深入研究将有助于设计靶向治疗。本文中我们主要就肿瘤休眠发生的机制、肿瘤休眠与肿瘤干细胞的关系进行综述。     

肿瘤休眠与复苏的分子调节及临床对策

肿瘤转移实际上是一个低效率的过程。肿瘤休眠的病例在临床也很多见,比如乳腺癌在长期休眠之后才出现转移复发。阐明诱导、维持和终止肿瘤休眠的机制具有重要的临床意义。目前认为,一旦到达新的器官,癌细胞和靶器官之间的分子相互作用可能决定了癌细胞是进入休眠状态还是生长状态。转移生长提供了一个时空广阔的肿瘤治疗靶标。任何能够防止转移生长的治疗都具有临床应用潜能。     

肿瘤休眠与复苏的分子调节及临床对策

肿瘤转移实际上是一个低效率的过程.肿瘤休眠的病例在临床也很多见,比如乳腺癌在长期休眠之后才出现转移复发.阐明诱导、维持和终止肿瘤休眠的机制具有重要的临床意义.目前认为,一旦到达新的器官,癌细胞和靶器官之间的分子相互作用可能决定了癌细胞是进入休眠状态还是生长状态.转移生长提供了一个时空广阔的肿瘤治疗靶标.任何能够防止转移生长的治疗都具有临床应用潜能.     

肿瘤休眠及其机制研究进展

肿瘤休眠(tumordormancy)是临床上普遍存在的一种现象,也是恶性肿瘤细胞的生物学特征之一,休眠细胞的长期存在是恶性肿瘤难以彻底根治的主要原因,也是导致肿瘤复发和远处转移的根源之一。本文从临床上发现肿瘤休眠存在、肿瘤休眠概念的演进、肿瘤休眠动物模型的建立、肿瘤休眠的分子及调控机制,以及肿瘤休眠的诱导、维持、再激活等方面进行了综述。旨在为开发诱导肿瘤休眠的药物和应用肿瘤休眠疗法根治肿瘤提供有益的线索。     

节律化疗诱导肿瘤休眠的研究进展

肿瘤休眠是恶性肿瘤复发转移的基础,各种微转移病灶及循环中的肿瘤细胞和肿瘤干细胞被认为是休眠状态的肿瘤细胞可能的存在形式。目前认为靶向治疗及内分泌治疗等手段可以诱导肿瘤细胞长期处于休眠状态,抑制肿瘤复发。节律化疗是以小剂量持续给药为特点的化疗方式,可以抑制肿瘤血管生成、恢复宿主抗肿瘤免疫,是一种作用于肿瘤微环境,诱导肿瘤休眠的治疗手段。但因其用药方式、剂量及疗效判定方式尚无统一认识,对肿瘤细胞生物学行为的影响尚未清楚,需要进一步体内、体外实验证实。     

β1-integrin: a potential therapeutic target in the battle against cancer recurrence

Primary cancer treatment, involving both local and often systemic adjuvant therapy, is often successful, especially if the cancer is detected at an early stage of progression. However, for some patients, the cancer may recur either locally or as distant metastases, in some cases many years after apparently successful primary treatment. Significant tumor dormancy has been documented in several cancers, such as breast, melanoma, and renal cancer. Tumor dormancy has long been recognized as an important problem in management of cancer patients. Recent work has clarified biologic aspects of tumor dormancy and has shown that dormant tumor cells may be resistant to cytotoxic chemotherapy and radiation. This work has led to recognition of a key role for β1-integrin in regulating the switch from a dormant state to active proliferation and metastasis. Here we discuss the role of β1-integrin and its signaling partners in regulating the dormant phenotype. We also consider possible therapeutic approaches, such as small molecules or antibodies (ATN-161, volociximab, and JSM6427), directed against β1-integrin signaling to target dormant cancer cells and to prevent metastatic recurrence.     

Development of the Relationship between Angiogenesis and Tumor Dormancy

Tumor dormancy, a complex and still poorly understood phenomenon, has been defined by the long-term persistence of occult can- cer cells during tumor progression. Recurrence and metastasis may occur just because of an activation of a small portion of the tumor cells. In our view, sustained angiogenesis is considered essential in triggering invasive tumor growth. Here we analyze the correlation between angiogenesis and tumor dormancy, the establishment of tumor dormancy models, the imaging strategies and the new biomarkers for dececting microscopic tumors before or during the angiogenic switch. It imperative to understand the role of an- giogenesis in tumor dormancy, as this will accelerate the development of anti-angiogenesis techniques to induce dormancy and/or eradicate dormant disease.     

New insights into tumor dormancy: Targeting DNA repair pathways

Over the past few decades, major strides have advanced the techniques for early detection and treatment of cancer. However, metastatic tumor growth still accounts for the majority of cancer-related deaths worldwide. In fact, breast cancers are notorious for relapsing years or decades after the initial clinical treatment, and this relapse can vary according to the type of breast cancer. In estrogen receptor-positive breast cancers, late tumor relapses frequently occur whereas relapses in estrogen receptor-negative cancers or triple negative tumors arise early resulting in a higher mortality risk. One of the main causes of metastasis is tumor dormancy in which cancer cells remain concealed, asymptomatic, and untraceable over a prolonged period of time. Under certain conditions, dormant cells can re-enter into the cell cycle and resume proliferation leading to recurrence. However, the molecular and cellular regulators underlying this transition remain poorly understood. To date, three mechanisms have been identified to trigger tumor dormancy including cellular, angiogenic, and immunologic dormancies. In addition, recent studies have suggested that DNA repair mechanisms may contribute to the survival of dormant cancer cells. In this article, we summarize the recent experimental and clinical evidence governing cancer dormancy. In addition, we will discuss the role of DNA repair mechanisms in promoting the survival of dormant cells. This information provides mechanistic insight to explain why recurrence occurs, and strategies that may enhance therapeutic approaches to prevent disease recurrence.     

Cancer dormancy: a model of early dissemination and late cancer recurrence

Cancer dormancy is a stage in tumor progression in which residual disease remains occult and asymptomatic for a prolonged period of time. Dormant tumor cells can be present as one of the earliest stages in tumor development, as well as a stage in micrometastases, and/or minimal residual disease left after an apparently successful treatment of the primary tumor. The general mechanisms that regulate the transition of disseminated tumor cells that have lain dormant into a proliferative state remain largely unknown. However, regulation of the growth from dormant tumor cells may be explained in part through the interaction of the tumor cell with its microenvironment, limitations in the blood supply, or an active immune system. An understanding of the regulatory machinery of these processes is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cells. This review focuses on the different signaling models responsible for early cancer dissemination and tumor recurrence that are involved in dormancy pathways.     

Dormancy in cancer

The idea of tumor dormancy originated from clinical findings that recurrence of cancer occurs several years or even several decades after surgical resection of the primary tumor. Tumor mass dormancy was proposed as a model, where there is equal balance between increases in the number of cancer cells by proliferation and decreases as a result of cell death. Tumor mass dormancy includes angiogenic dormancy and immune‐mediated dormancy. Another emerging type of tumor dormancy is cellular dormancy in which cancer cells are in a quiescent state. Cellular dormancy is induced by cues such as the extracellular matrix environment, metastatic niches, a hypoxic microenvironment, and endoplasmic reticulum stress. Even the oncogenic pathways, on which active cancer cells depend for survival and growth, are suppressed in the dormant state. As tumor dormancy is one of the mechanisms of resistance against various cancer therapies, targeting dormant cancer cells should be considered for future treatment strategies.     

Angiogenesis,Metastasis, and Endogenous Inhibition

Angiogenesis and the development of metastases are intrinsically connected. Experimental data suggest that establishment and growth of metastases are influenced by soluble factors secreted from the originating solid tumor. Among these factors are so-called endogenous inhibitors of angiogenesis which keep metastasis in a non-proliferating quiescent state. For a number of tumors it has been shown that this dormant state is mediated through inhibition of angiogenesis. This dormant state is characterized by normal proliferation, increased apoptosis, and insufficient neovascularization. Removal of inhibiting anti-angiogenic factors led to growth of dormant metastases. A number of endogenous inhibitors have been identified and have shown success in experimental therapeutic trials. This might be of special interest for the treatment of cerebral metastases which are the most common type of malignant brain tumors. Similar to the spread of metastases, it is known that single glioma cells can be found in distant parts of the brain. While local recurrence is a common phenomenon in glioma, formation of clinical apparent distant metastasis occurs rarely. Several lines of evidence suggest that growth inhibition of remote glioma cells may be mediated by an endogenous inhibitory mechanism.     

循环肿瘤细胞检测与结直肠癌复发转移的研究进展

结直肠癌发病率在逐年上升,转移和复发是结直肠癌死亡的主要原因。血液循环中的肿瘤细胞可能具有增生能力或转移潜能,循环肿瘤细胞（circulating tumor cell,CTC）的检测为预测评估复发转移及疗效、肿瘤分期及个体化治疗提供了一个可靠手段,随着检测技术的不断优化发展,将为临床提供更好的支持。本文旨在对CTC检测与结直肠癌复发转移等方面的研究进展进行综述。      

肿瘤消融技术联合免疫检查点抑制剂治疗的进展

随着微创手术的广泛应用及微创技术的发展,肿瘤消融技术已成为肿瘤局部治疗的重要替代方法,肿瘤消融在其杀灭肿瘤细胞的同时将肿瘤的自身抗原释放到循环中使机体产生了免疫抗肿瘤反应,但这种作用可能不足以克服一些已经进化出免疫应答的检查点逃逸机制的肿瘤的复发及转移。临床前和临床证据表明肿瘤消融技术联合免疫检查点抑制剂可产生更强的免疫抗肿瘤反应。本文的目的是总结肿瘤消融技术联合免疫检查点抑制剂在原发及继发肿瘤治疗的现状及进展。     

Transcriptional profiling of circulating tumor cells: quantification and cancer progression (Review)

Circulating tumor cells in peripheral blood have been demonstrated to reflect the biological characteristics of tumors including the potential for metastasis development and tumor recurrence. A number of mRNA markers may feasibly enable the detection of circulating tumor cells from virtually all patients with different cancer types. Of clinical relevance, quantification of circulating tumor cell mRNAs in cancer patients may prove valuable for monitoring disease progression and patients' response to treatment, and assessing the risk for metastasis or recurrence. With prognostic implications, the quantities of mRNA markers in blood could indicate the stage of cancer progression and the need for more intensive therapeutic intervention to better the outcome of cancer patients.