乳腺癌干细胞分子特性及其治疗新策略

乳腺癌是一种严重影响女性健康甚至危及生命的疾病。环境、饮食习惯、疾病等均有可能诱发人类乳腺细胞癌基因活化或抑癌基因失活,其诱发过程可通过细胞、动物模型所证实。最新研究指出,乳腺癌肿瘤干细胞的分子特性研究为乳腺癌发生、发展的认识提供了重要的佐证。另外,MicroRNAs在乳腺癌中表现促进或抑制瘤细胞生长与分化。这些研究的深入开展将为乳腺癌的防治提供新思路。     

乳腺癌干细胞和乳腺癌

肿瘤干细胞既包含干细胞的特性也包含肿瘤细胞的特性。乳腺癌起源于乳腺癌干细胞的说法能够合理地解释乳腺癌的不均一性及其治疗后的复发,这些变异的干细胞可能作为肿瘤预防策略的靶标。而且,由于乳腺癌干细胞能够抵抗辐射治疗和化学治疗,所以要想更好地治疗乳腺癌就需要寻找针对这些干细胞的靶标。我们综述了乳腺癌干细胞的发现、富集和分离、相关的信号途径,以及在乳腺癌治疗中的应用。     

乳腺癌实验动物模型的制备与应用

乳腺癌实验动物模型在研究人类乳腺癌的生物学行为及治疗等方面起着非常重要的作用。根据制备方法及研究目的的不同,乳腺癌实验动物模型可分为自发性、诱发性、移植性、转基因性及乳腺癌骨转移等动物模型,每种动物模型都有各自的特点和应用条件。     

乳腺癌干细胞调控及靶向治疗研究进展

乳腺癌干细胞是乳腺肿瘤内具有自我更新能力以及多向分化潜能的细胞,乳腺癌的发生﹑发展、转移﹑复发与干细胞的高致瘤性、高侵袭转移性、治疗抵抗能力密切相关。深入研究乳腺癌干细胞相关细胞因子及微环境因素的调控对乳腺癌的临床靶向治疗具有重要指导意义。该文就近年来乳腺癌干细胞调控相关信号转导通路、转录因子、表观遗传调控因子以及微环境因素进行综述,探讨乳腺癌干细胞及其相关信号因子作为乳腺癌治疗靶点的潜在价值,为临床靶向治疗乳腺癌提供新方向。     

乳腺癌干细胞的研究进展

乳腺癌是女性最常见恶性肿瘤.随着乳腺癌发生、发展研究的不断深入,乳腺癌干细胞日益受到研究者们的重视.乳腺癌干细胞是首次分离出来的实体干细胞,研究表明,它是一群未分化、具有多种分化和自我更新能力的细胞.正常情况下,乳腺干细胞的分化、更新能力受激素及信号转导通路的严格控制,一旦这种机制被破坏或发生异常,干细胞就会异常分化,变成乳腺癌干细胞,并无限生长形成肿瘤.乳腺癌干细胞具有放、化疗抵抗性,高致瘤性及高侵袭转移性,其在乳腺癌的发生、发展及复发、转移过程起到非常重要的作用.因而,要想更好地治疗乳腺癌就需要寻找针对这些干细胞的靶标,从而为临床靶向治疗乳腺癌提供依据.本文对乳腺癌干细胞在乳腺癌研究及治疗中的最新进展进行综述.     

乳腺癌干细胞研究进展

乳腺癌在女性肿瘤相关性疾病的死亡中占有主要地位,乳腺癌干细胞在乳腺癌的发生、发展、治疗抵抗性、转移及复发中起到了关键作用。鉴于乳腺癌干细胞对治疗乳腺癌的重要意义,我们就乳腺癌干细胞的发现、研究意义、研究现状及研究中存在的问题做简要综述,以期为乳腺癌的研究开拓新的思路。     

乳腺癌干细胞分选及相关信号通路研究进展

肿瘤干细胞是指存在于肿瘤组织中的具有干细胞特性,即能够多向分化和自我更新的一类细胞群。随着肿瘤干细胞概念的提出,乳腺癌干细胞成为当今科研领域的一个研究热点。因此,了解如何分选乳腺癌干细胞及如何维持其"干性"对治疗及预防乳腺癌具有至关重要的意义。主要从乳腺癌干细胞分选、相关信号通路、上皮-间充质转换(EMT)等方面进行综述。     

乳腺癌干细胞BCRP的表达及意义

目的 探讨乳腺癌干细胞耐药蛋白BCRP（breast cancer resistance protein）的表达情况及意义。方法 应用流式细胞分选技术从人乳腺癌组织中分离出乳腺癌干细胞和非干细胞,实时定量PCR（realtime-PCR）技术测定不同细胞亚群的BCRP表达情况。结果 与乳腺癌非干细胞相比,乳腺癌干细胞的BCRP表达水平明显增强（P〈0．01）,并且化疗后干细胞比例增加（P〈0．01）。结论 乳腺癌干细胞可以通过高表达BCRP具有更强的化疗耐药性,是乳腺癌化疗失败和复发的关键因素之一。     

乳腺癌肿瘤干细胞的研究进展

干细胞(stem cell,SC)是一类具有自我更新、多向分化潜能的特殊细胞群体.而肿瘤干细胞(cancer stem cell,CSC)不仅具备了干细胞方面的特征,同时还有其自身特殊性.乳腺癌中肿瘤干细胞的发现为乳腺癌的治疗提供了创新性策略.近年来,有关乳腺癌肿瘤干细胞的筛选标记和方法以及信号转导通路方面的研究颇多,但其中也不乏争议.就乳腺癌干细胞研究的最新进展作一端述.     

干细胞用于乳腺癌治疗的研究进展

乳腺癌是女性最常见的恶性肿瘤之一,是一种严重影响女性身心健康甚至危及生命的恶性肿瘤,男性乳腺癌罕见.目前,乳腺癌的治疗仍以外科治疗为主.随着干细胞生物学的发展,人们发现造血干细胞移植在恶性肿瘤大剂量放、化疗后的造血重建和免疫重建中有着重要作用,而间充质干细胞可以作为基因栽体而抑制肿瘤细胞的生长.这些研究为乳腺癌的治疗提供了全新的思路.分析目前人们应用干细胞治疗乳腺癌的研究现状,同时统计分析了中国临床试验注册中心数据库和美国clinicaltrials 数据库中用干细胞治疗乳腺癌的临床试验的最新数据,并且指出了干细胞用于乳腺癌治疗的研究趋势,目的是为后续开展的用干细胞治疗乳腺癌的研究提供一定的参考.     

Progress in the application of organoids to breast cancer research

Breast cancer is the most common cancer diagnosed in women. Breast cancer research is currently based mainly on animal models and traditional cell culture. However, the inherent species gap between humans and animals, as well as differences in organization between organs and cells, limits research advances. The breast cancer organoid can reproduce many of the key features of human breast cancer, thereby providing a new platform for investigating the mechanisms underlying the development, progression, metastasis and drug resistance of breast cancer. The application of organoid technology can also promote drug discovery and the design of individualized treatment strategies. Here, we discuss the latest advances in the use of organoid technology for breast cancer research.     

Mouse models for breast cancer metastasis

Metastasis of cancer cells is the main cause of death in most breast cancer patients. Although markers for early diagnosis and drugs that limit the spread of cancer to other organs have been developed, it is difficult to prevent the relapse of breast cancer. Recent research has highlighted the importance of tumor environment in which communication between tumor cells and the body system occurs. Emerging data have suggested that animal models are a good system to investigate this communication. Therefore, studies with mouse models have been developed as a reasonable method for a systemic approach to understand breast cancer metastasis. In this review, we summarize mouse models of breast cancer and their applications to the study of human breast cancers, and discuss limitation of model system and advanced techniques to overcome it.     

The biology of human breast epithelial progenitors

Current evidence suggests that similar to other tissues in the human body mammary epithelia cells are being maintained by the unique properties of stem cells, undifferentiated as well as lineage-restricted progenitors. Because of their longevity, proliferation and differentiation potentials these primitive breast epithelial cells are likely targets of transforming mutations that can cause them to act as cancer initiating cells. In this context, understanding the molecular mechanisms that regulate the normal functions of the human breast epithelial stem cells and progenitors and how alterations to these same mechanisms can confer a cancer stem cell phenotype on these rare cell populations is crucial to the development of new and more effective therapies again breast cancer. This review article will examine the current state of knowledge about the isolation and characterization of human breast epithelial progenitors and their relevance to breast cancer research.     

Fatty acids and breast cancer: The role of stem cells

Studies with animal models in vivo as well as with animal and human tumor cells in vitro suggest that specific fatty acids could reduce breast tumorigenesis. The most striking dietary fatty acid studies in animal models that show promise for reduction of breast cancer risk in humans are with conjugated linoleic acids (CLA) and n-3 fatty acids. Although a number of mechanisms have been proposed, the specific target of those fatty acids is not yet known. We sought to determine whether the effects of those fatty acids on terminally differentiated tumor cell seen could be due to alteration of breast cancer stem cells. The isomers, cis9, trans11-CLA and trans10, cis12-CLA, and the n-3 fatty acids, docosahexaenoic and eicosapentaenoic, reduced the proliferation of, and had increased toxicity towards, mammary tumor initiating cells. One mechanism involved in the effect of n-3 fatty acids may be due to alteration of the profile of prostaglandins. These results indicate that select fatty acids may be useful for preventing or reducing the risk of breast cancer as they may target the tumor initiating cell.     

Selection of a Relevant In Vitro Blood-Brain Barrier Model to Investigate Pro-Metastatic Features of Human Breast Cancer Cell Lines

Around 7–17% of metastatic breast cancer patients will develop brain metastases, associated with a poor prognosis. To reach the brain parenchyma, cancer cells need to cross the highly restrictive endothelium of the Blood-Brain Barrier (BBB). As treatments for brain metastases are mostly inefficient, preventing cancer cells to reach the brain could provide a relevant and important strategy. For that purpose an in vitro approach is required to identify cellular and molecular interaction mechanisms between breast cancer cells and BBB endothelium, notably at the early steps of the interaction. However, while numerous studies are performed with in vitro models, the heterogeneity and the quality of BBB models used is a limitation to the extrapolation of the obtained results to in vivo context, showing that the choice of a model that fulfills the biological BBB characteristics is essential. Therefore, we compared pre-established and currently used in vitro models from different origins (bovine, mice, human) in order to define the most appropriate tool to study interactions between breast cancer cells and the BBB. On each model, the BBB properties and the adhesion capacities of breast cancer cell lines were evaluated. As endothelial cells represent the physical restriction site of the BBB, all the models consisted of endothelial cells from animal or human origins. Among these models, only the in vitro BBB model derived from human stem cells both displayed BBB properties and allowed measurement of meaningful different interaction capacities of the cancer cell lines. Importantly, the measured adhesion and transmigration were found to be in accordance with the cancer cell lines molecular subtypes. In addition, at a molecular level, the inhibition of ganglioside biosynthesis highlights the potential role of glycosylation in breast cancer cells adhesion capacities.     

Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization

The purpose of this study was to investigate how human umbilical cord mesenchymal stem cells (HUMSCs) affect breast cancer tumourigenesis. To observe the influence of HUMSCs on tumourigenesis in vitro, we performed a co-culture of MDA MB-231 breast cancer cells with HUMSCs, and a result of HUMSCs on tumourigenesis in vivo was achieved by injection of HUMSCs into nonobese diabetic/severe combined immunodeficient mice following tumour establishment with MDA-MB231. During the co-culture, apoptosis of MDA-MB231 was noted, which was driven either by binding with HUMSC through direct cell-cell contact or by formation of a novel cell-in-cell phenomenon after internalization of HUMSC. Also, treatment with HUMSC injection was efficacious in both in situ and metastatic breast cancers in the animal models. Since HUMSCs were proved to efficaciously suppress breast cancer tumourigenesis both in vitro and in vivo, it is our expectation that treatment with HUMSCs can be a viable therapy for breast cancer in the near future. In addition, we share a new point of view on the role of HUMSCs in foetal development during pregnancy.     

Doxorubicin in Combination with a Small TGFβ Inhibitor: A Potential Novel Therapy for Metastatic Breast Cancer in Mouse Models

Background

Recent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFβ is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models.

Principal Findings

We report that chemotherapeutic drug doxorubicin activates TGFβ signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGFβ type I receptor kinase inhibitor (TβRI-KI). We investigated the potential synergistic anti-tumor activity of TβR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TβRI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when TβR1-KI was administered in combination with doxorubicin.

Conclusions

These observations suggest that the adverse activation of TGFβ pathway by chemotherapeutics in the cancer cells together with elevated TGFβ levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGFβ inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis.     

人干细胞实验动物嵌合体模型的研究进展

动物模型是疾病研究、发病机制、药物治疗的必要工具,目前一些困扰人类健康的重大疾病如艾滋病、乙型肝炎等因为还没有能反映人类疾病发病机理的理想动物模型。人干细胞是能在体外长期培养的、高度未分化的全能细胞系,亚全能细胞系和分化的干细胞等。如果能将人的干细胞成功移植入实验动物体内形成人源化嵌合体动物,有希望为艾滋病、肝炎等的研究制备适当的模型。人类干细胞在动物中的移植研究中主要的实验动物是绵羊,小鼠等,本文介绍了人干细胞在动物体内移植的研究进展。     

自发性树鼩乳腺肿瘤的特性(英文)

乳腺癌是严重危害女性健康的常见恶性肿瘤,建立合适的乳腺癌动物模型对于研究人类乳腺癌的生物学机制及发展新的防治方法至关重要。相对于常用的啮齿类动物,树鼩(Tupaia belangeri chinensis,tree shrew)因在进化层次上更接近于人类而可用于建立更适合的乳腺癌模型。该文详细了介绍一例树鼩自发性乳头状良性乳腺肿瘤。免疫组化结果显示该例肿瘤孕激素受体阳性且Ki-67阳性细胞比例显著增加;而活化的Caspase3阳性细胞比例较低;且肿瘤的形态和病理与人导管内乳头状肿瘤非常接近。提示利用树鼩建立乳腺肿瘤模型的可行性。