Cancer and stem cells

Being the second leading cause of death globally, cancer has been a long-standing and rapidly evolving focus of biomedical research and practice in the world. A tremendous effort has been made to understand the origin of cancer cells, the formation of cancerous tissues, and the mechanism by which they spread and relapse, but the disease still remains mysterious. Here, we made an attempt to scrutinize evidences that indicate the role of stem cells in tumorigenesis and metastasis, and cancer relapse. We also looked into the influence of cancers on stem cells, which in turn represent a major constituent of tumor microenvironment. Based on current understandings of the properties of (cancer) stem cells and their relation to cancers, we can foresee that novel therapeutic approaches would become the next wave of cancer treatment.     

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。     

Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.     

E-cadherin 在肿瘤治疗中的研究进展

E-cadherin 参与形成细胞间黏附性连接,是胚胎发育过程中的一个关键因子。越来越多的研究表明,E-cadherin 在肿瘤的发生发 展过程中也发挥了至关重要的作用。在生物体内,E-cadherin 的表达和功能受到多个水平、多重因素的调控,而 E-cadherin 又可以影响 多条重要信号通路的活性,参与到多种生理病理过程中。E-cadherin 下调造成细胞间黏附性连接减少、极性减弱,细胞由上皮样转变为间 质样,这一变化是上皮间质转化（EMT）的重要标志之一。E-cadherin 与多种肿瘤的发生有一定的相关性。同时 E-cadherin 下调所引起 的 EMT 促进肿瘤细胞的迁移运动,肿瘤细胞侵袭力增强,促进转移的发生。近年来,大量研究关注到 E-cadherin 对肿瘤细胞的耐药及干 细胞特性的获得都有影响。综述 E-cadherin 在肿瘤发生发展中的作用,探讨以 E-cadherin 为靶点的肿瘤治疗的现状及展望。     

Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

1. Download : Download high-res image (181KB)
2. Download : Download full-size image

     

肿瘤干细胞与肿瘤相关巨噬细胞的相互作用

肿瘤微环境(tumor microenvironment,TME)不仅促进了肿瘤的早期形成和远处转移,而且随着肿瘤的进展,其自身也不断地发生变化。作为TME的重要组成部分,肿瘤相关巨噬细胞(tumor associated macrophages,TAMs)可通过分泌多种细胞因子激活IL-6/STAT3、TGF-β、Wnt/β-catenin等信号通路促进肿瘤干细胞(cancer stem cells,CSCs)的存活、自我更新和化疗耐药等。同时,CSCs也可通过分泌多种细胞因子和趋化因子等募集巨噬细胞,并将其诱导为TAMs重塑CSCs特定的生态位,维持CSCs表型并促进肿瘤进展。TAMs与CSCs的相互作用在促进肿瘤生长、转移及化疗耐药等方面发挥了重要作用。本文对TME中CSCs与TAMs相互作用的研究进行综述,并总结了以CSCs与TAMs相互作用为靶点在新型癌症治疗以及增强化疗效果等方面的重要潜力。     

肿瘤干细胞生物学特性及其干性维持机制的研究进展

肿瘤是威胁人类健康和社会发展最为严重的疾病之一,也是全球第二大常见疾病死因。最新统计数据显示,恶性肿瘤在发达国家已取代心血管疾病成为第一大疾病死因。肿瘤的耐药、转移和复发,仍然是临床治疗中亟需解决的难题。肿瘤干细胞(tumor stem cells, TSCs)是一类具有自我更新、分化潜能、高致瘤性和高耐药性等特征的细胞亚群,能够抵抗放化疗等非特异性治疗手段,在肿瘤发生、转移、耐药和复发中发挥关键作用。肿瘤干细胞标志物、干性维持机制、微环境和代谢重编程等领域已成为了研究热点,最新研究成果为肿瘤干细胞的鉴定和靶向治疗提供了新的靶标和策略。本文对肿瘤干细胞的表面标志物(CD133和CD44等)、自我更新和上皮细胞间充质转化(epithelial mesenchymal transition, EMT)信号通路(Wnt/β-catenin和Hedgehog等)、微环境特征、代谢重编程(糖酵解和氧化磷酸化等),及其在肿瘤的起始、发展、转移和耐药中的作用进行了综述。     

间充质干细胞与肿瘤转移

间充质干细胞是一类能够自我更新、具有多向分化潜能的成体干细胞。近年来,有证据认为间充质干细胞是肿瘤组织中基质细胞的祖先,因此间充质干细胞微环境与肿瘤转移的关系逐渐成为研究热点,但间充质干细胞对肿瘤转移是促进还是抑制,目前的研究并不一致。我们简要综述了间充质干细胞参与肿瘤转移的研究进展。     

微流控芯片在乳腺癌骨转移研究中的应用

乳腺癌骨转移患者死亡率高达70%～80%,目前缺乏有效的治疗药物.微流控芯片技术能够有效模拟骨组织的生化和生物物理微环境,便捷地实现模拟骨微环境中乳腺癌骨转移的研究,这将为探索乳腺癌骨转移的细胞和分子机制、进而进行抗乳腺癌骨转移药物高通量筛选提供有价值的技术方法和平台.本综述简要介绍了乳腺癌骨转移的分子机制和治疗药物研究现状,详细阐述了乳腺癌骨转移的微流控芯片模型,分析了基于微流控芯片技术进行抗乳腺癌骨转移药物高通量筛选的优势和挑战,旨在为乳腺癌骨转移机制研究和药物筛选提供参考.     

Three-dimensional culture models to study drug resistance in breast cancer

Despite recent advances in breast cancer treatment, drug resistance frequently presents as a challenge, contributing to a higher risk of relapse and decreased overall survival rate. It is now generally recognized that the extracellular matrix and cellular heterogeneity of the tumor microenvironment influences the cancer cells' ultimate fate. Therefore, strategies employed to examine mechanisms of drug resistance must take microenvironmental influences, as well as genetic mutations, into account. This review discusses three-dimensional (3D) in vitro model systems which incorporate microenvironmental influences to study mechanisms of drug resistance in breast cancer. These bioengineered models include spheroid-based models, biomaterial-based models such as polymeric scaffolds and hydrogels, and microfluidic chip-based models. The advantages of these model systems over traditionally studied two-dimensional tissue culture polystyrene are examined. Additionally, the applicability of such 3D models for studying the impact of tumor microenvironment signals on drug response and/or resistance is discussed. Finally, the potential of such models for use in the development of strategies to combat drug resistance and determine the most promising treatment regimen is explored.     

肿瘤微环境中上皮–间质转化与肿瘤干细胞的调控

肿瘤微环境是一个复杂的组织样结构,具有丰富的表型和功能异质性。不同浓度的趋化因子、细胞因子与组成肿瘤微环境的细胞间相互作用,可激活上皮–间质转化(epithelial-mesenchymal transition,EMT)相关的信号通路及控制肿瘤干细胞(cancer stem cells,CSCs)的生成。EMT的异常激活会促进肿瘤细胞的可塑性,赋予上皮细胞间充质特性,并与癌细胞获得侵袭性的特征密切相关。CSCs是一类具有高致瘤潜能的细胞群,其能很容易地适应周围环境的变化,与肿瘤内其他细胞相比具有较强的抗药性。该文对肿瘤微环境中EMT与CSC的作用机制及相关信号通路的研究进展进行综述。     

Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer

1. Download : Download high-res image (154KB)
2. Download : Download full-size image

     

应用基因表达谱芯片从不同转移能力的 乳腺癌细胞中筛选转移相关基因

人乳腺癌细胞系 MCF-7 及其转移亚克隆 LM-MCF-7 为肿瘤转移分子机制的研究提供了细胞模型 . 应用基因芯片技术比较两种具有不同转移能力细胞系基因表达谱的差异,寻找乳腺癌转移相关基因 . 提取两种细胞总 RNA ,分别用 Cy5-dCTP 、 Cy3-dCTP 标记 LM-MCF-7 和 MCF-7 的 cDNA ,并与含有 21 329 个基因的芯片进行杂交并扫描,利用 GenePix Pro 4.0 图像分析软件处理数据判断基因是否在两个细胞中存在表达差异 . 经互换荧光标记物重复两次实验,共筛选出差异表达基因 67 个,其中 41 个在 LM-MCF-7 细胞中表达上调, 26 个在 LM-MCF-7 细胞中表达下调 . 应用实时定量 RT-PCR 对 7 个表达差异明显的基因进行了验证 . 生物信息学分析结果提示,上述发现的差异基因编码产物与细胞内信号转导、转录调节、应激反应、新陈代谢、发育、细胞运动、细胞凋亡和细胞粘连等功能有关 . 据文献报道,这些差异表达的基因中有 35 个与肿瘤有关,其中 9 个与乳腺癌转移有关, 6 个可能参与肿瘤浸润和转移过程 . 根据基因芯片检测的结果,从功能上对 LM-MCF-7 细胞和 MCF-7 细胞与细胞凋亡的关系进行了研究,发现具有高转移倾向的 LM-MCF-7 细胞与 MCF-7 细胞相比,抗凋亡能力较强 . 上述与肿瘤转移相关基因在肿瘤转移中的作用及其分子机理有待深入研究 .     

胃癌干细胞研究进展

胃癌是仅次于肺癌的第二大致死率癌症,尽管近年来对胃癌研究有了很大进展,但由于缺乏良好的动物模型,对胃癌的发病机理仍然不是很清楚.近年的研究表明,肿瘤组织不是由均一细胞构成的,其中存在一些少量细胞可以自我更新并可以分化为肿瘤组织的其他细胞,这类细胞具有类似成体组织干细胞（tissue stem cells）的特性称之为肿瘤干细胞（cancer stem cells）.肿瘤干细胞被认为在肿瘤的生长、转移、复发中发挥着重要作用.有证据表明在胃癌组织中存在胃癌干细胞（gastric cancer stem cells）,但是对胃癌干细胞的来源仍然不是十分明确.对肿瘤干细胞的研究有助于癌症的治疗,改变目前药物针对所有癌细胞的治疗策略.     

肿瘤研究的金钥匙:肿瘤干细胞

“肿瘤干细胞学说”认为肿瘤组织不是均一的,其中只有一小部分肿瘤干细胞具有诱发并维持肿瘤恶性表达的能力。这一概念的提出为肿瘤真正意义上的靶向治疗找到了良方妙药,即选择性杀伤肿瘤干细胞从而治愈肿瘤。找到肿瘤干细胞并了解其生物学特性对我们真正理解肿瘤的发生、发展和转归机制,根治肿瘤并防止肿瘤的转移和复发具有积极意义。本文概述对人淋巴细胞白血病、乳腺肿瘤、脑部肿瘤及其他肿瘤的肿瘤干细胞及其相关机制的研究进展。     

微小RNA与肿瘤干细胞耐药的研究进展

肿瘤干细胞（Cancer stem cells,CSCs）是肿瘤组织中一小部分具有自我更新和致瘤性的细胞,具有特殊的耐药机制,与肿瘤的复发和治疗失败关系密切。微小RNA（microRNAs,miRNAs）是一类长度约为19～25个核苷酸的内源性非编码单链RNA,能够通过调控相关靶基因的表达,参与调控肿瘤干细胞增殖、凋亡、上皮-间质转化等重要的生命过程,引起CSCs对化疗药物产生原发性多药耐药性。本论文就miRNAs在调控CSCs多药耐药性方面的研究进展作一综述。     

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.     

Targeting Breast Cancer Stem Cells

The potential roles of breast cancer stem cells (BCSCs) in tumor initiation and recurrence have been recognized for many decades. Due to their strong capacity for self-renewal and differentiation, BCSCs are the major reasons for poor clinical outcomes and low therapeutic response. Several hypotheses on the origin of cancer stem cells have been proposed, including critical gene mutations in stem cells, dedifferentiation of somatic cells, and cell plasticity remodeling by epithelial-mesenchymal transition (EMT) and the tumor microenvironment. Moreover, the tumor microenvironment, including cellular components and cytokines, modulates the self-renewal and therapeutic resistance of BCSCs. Small molecules, antibodies, and chimeric antigen receptor (CAR)-T cells targeting BCSCs have been developed, and their applications in combination with conventional therapies are undergoing clinical trials. In this review, we focus on the features of BCSCs, emphasize the major factors and tumor environment that regulate the stemness of BCSCs, and discuss potential BCSC-targeting therapies.