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.     

肿瘤休眠与血管新生

肿瘤休眠是指肿瘤细胞在宿主体内持续存在而没有明显生长的一种状态，存在复发和转移的可能性，是恶性肿瘤难以彻底根治的根源之一．现在研究表明血管新生与肿瘤演进密切相关本文从血管新生与肿瘤休眠的关系，肿瘤休眠模型的建立，肿瘤休眠的研究方法，休眠标志物的检测等方面进行了论述。旨在为阐明血管生成与肿瘤休眠的关系，以及临床应用抗血管生成疗法治疗肿瘤提供有益的线索.     

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。     

肿瘤休眠与血管新生

肿瘤休眠是恶性肿瘤的生物学特性之一,其机制未被完全阐明.研究表明,肿瘤休眠与血管新生受损有关,当环境中促血管生成因子超过抗血管生成因子时,休眠肿瘤可获得血管新生表型而逃脱休眠.虽然休眠肿瘤获得血管新生表型转换的机制还有待进一步研究,但抗血管生成治疗仍是一种很有应用前景的诱导肿瘤休眠的策略.     

恶性肿瘤休眠的研究进展

1肿瘤休眠的证据 恶性肿瘤休眠是一个临床概念,指病人体内有肿瘤存在但长期无变化,是许多医务工作者发现的一个现象.肿瘤休眠时患者既无特殊症状,也无特殊体征,临床上各种检查均在正常范围内[1].1954年,Hadfield观察发现乳腺癌、黑色素瘤、直肠癌多年以后出现了继发瘤,于是首先报道了肿瘤休眠(tumordormancy)这一暂时分裂停止的状态.Hadfield使用了休眠(dormancy)一词来描述这些长期生存而无明显增殖的恶性肿瘤,表明肿瘤休眠是肿瘤细胞在宿主内持续存在而又没有明显生长,是机体与肿瘤细胞保持平衡的一种状态.     

肿瘤休眠研究现状

肿瘤休眠(tumor dormancy)临床上常见于原发肿瘤行根治性切除后,患者体内存在微小瘤灶或微量肿瘤细胞,在一定时间范围内既没有被机体清除,也没有增殖生长,但这些肿瘤细胞仍具有增殖潜能,可在数年乃至数十年后再次增殖,导致肿瘤的复发或远处转移.旨在诱导肿瘤休眠,阻止肿瘤生长,延长患者生存期的肿瘤休眠疗法,逐渐成为肿瘤治疗的新策略.但目前对肿瘤休眠及其机制的研究尚不深入.     

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。     

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。     

Tumor dormancy therapy--what do you think of this therapy?]

The phrase tumor dormancy means that all tumor cells are in cell-cycle arrest. What then is tumor dormancy therapy? It is theoretically predicted that a poor environment for tumor tissue may induce tumor dormancy; an example is interruption of the tumor blood circulation. Some non-cytotoxic drugs in cancer treatment, for example angiogenesis inhibitors, may be able to induce and maintain tumor dormancy. Recently, some clinician groups in Japan have posited that tumor dormancy can be induced by low-dose chemotherapy. They assert that the aim of low-dose chemotherapy is to prolong time to progression (TTP), not to kill the cancer cells, so it may reasonably be called "tumor dormancy therapy". However, there is no evidence that survival is prolonged and tumor dormancy induced by low-dose chemotherapy. Tumor dormancy and prolonging TTP are very different matters. The term "tumor dormancy therapy" is better not used in cancer chemotherapy using cytotoxic drugs.     

肿瘤休眠机制研究进展

肿瘤休眠是肿瘤细胞在宿主体内持续存在而又没有明显生长的一种状态,是肿瘤细胞增殖与凋亡趋于平衡的结果。其发生机制可能与肿瘤血管生成受阻、癌基因与抑癌基因、宿主免疫状态、肿瘤细胞增殖周期及信号传导有关。本文就近年来有关肿瘤休眠的发生机制及诱导肿瘤休眠的最新研究成果进行综述。     

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.     

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.     

手术与肿瘤转移

在形成新的转移灶之前,原发肿瘤释放的大量癌细胞会进入一个休眠阶段,休眠状态一旦被打破,肿瘤细胞将恢复增殖能力.近年来关于肿瘤转移的各种假说和机制研究层出不穷,原发瘤切除术被看作是打破肿瘤休眠稳态的一个重要因素,因而被认为是促进肿瘤转移的重要原因.手术技术的改良和对休眠机制的进一步研究,可以为转移瘤的治疗提供新的思路.     

Tumor cell dormancy: an NCI workshop report

The long latency period that occurs in some patients between initial treatment and evidence of metastases is attributed to tumor cell dormancy. Although the clinical occurrence of these late developing metastases has intrigued the medical community for years, there's a paucity of experimental data, especially among the solid tumors. Of clinical importance is that dormant tumor cells are highly refractory to chemotherapy. For these reasons, the NIH convened a small workshop in July 2006 of investigators with interests in this field to review the challenges and research opportunities. This report summarizes the key outcomes of this workshop. The mechanisms associated with tumor cell dormancy are poorly defined, in part because the dormant tumor cells have been extraordinarily difficult to isolate. New isolation and characterization techniques were presented. One of the critical limitations confronting the field is that molecular markers of dormancy are not now known. The workshop considered the role of the microenvironment in promoting and maintaining dormant tumor cells as well as events in the microenvironment that could activate the dormant cells. There was also discussion of new models of dormancy and new imaging modalities. Furthermore, the workshop reviewed studies of hematological tumor cell dormancy and how this insight could best be applied to the solid tumors. Finally, there was discussion related to the design of clinical trials for the study of tumor cell dormancy. The workshop concluded with an overall summary of the challenges and research opportunities associated with this field with recommendations for consideration by the NIH.     

Circulating tumor cells in patients with breast cancer dormancy.

PURPOSE: The purpose of this study was to test the hypothesis that circulating tumor cells (CTCs) are present in patients many years after mastectomy without evidence of disease and that these CTCs are shed from persisting tumor in patients with breast cancer dormancy. EXPERIMENTAL DESIGN: We searched for CTCs in 36 dormancy candidate patients and 26 age-matched controls using stringent criteria for cytomorphology, immunophenotype, and aneusomy. RESULTS: Thirteen of 36 dormancy candidates, 7 to 22 years after mastectomy and without evidence of clinical disease, had CTCs, usually on more than one occasion. Only 1 of 26 controls had a possible CTC (no aneusomy). The statistical difference of these two distributions was significant (exact P = 0.0043). The CTCs in patients whose primary breast cancer was just removed had a half-life measured in 1 to 2.4 hours. CONCLUSIONS: The CTCs that are dying must be replenished every few hours by replicating tumor cells somewhere in the tissues. Hence, there appears to be a balance between tumor replication and cell death for as long as 22 years in dormancy candidates. We conclude that this is one mechanism underlying tumor dormancy.     

Systems biology of tumor dormancy: linking biology and mathematics on multiple scales to improve cancer therapy

For many decades, it has been appreciated that tumor progression is not monotonic, and development of a cancer cell does not equate to inevitable cancer presentation in the clinic. Tumor progression is challenged by numerous intrinsic and extrinsic bottlenecks that can hold the tumor in dormant stages for prolonged periods. Given the complex, multiscale nature of these bottlenecks, the Center of Cancer Systems Biology organized a workshop on critical issues of systems biology of tumor dormancy. The program for the meeting this past July, chaired by N. Almog and H. Enderling, included discussions and interactive breakout sessions on regulation of tumor dormancy by angiogenesis, tumor-immune system interactions, cancer stem cell kinetics, and cell signaling pathways. Three important conclusions emerged from the meeting. The first was the urgent need to differentiate between tumor cell and tumor population dormancy of the primary tumor and metastatic deposits, the second was the continued need for interdisciplinary dialogs, and the third was the need to bring cross-scale mechanistic thinking to the field to achieve a more robust understanding of tumor dormancy and its clinical implications.