Differentiation and transdifferentiation potentials of cancer stem cells

Tumor cells actively contribute to constructing their own microenvironment during tumorigenesis and tumor progression. The tumor microenvironment contains multiple types of stromal cells that work together with the extracellular matrix and local and systemic factors to coordinately contribute to tumor initiation and progression. Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis. The cancer stem cell (CSC) concept has been widely applied to interpreting tumor initiation, growth, metastasis, dormancy and relapse. CSCs have differentiation abilities to generate the original lineage cells that are similar to their normal stem cell counterparts. Interestingly, recent evidence demonstrates that CSCs also have the potential to transdifferentiate into vascular endothelial cells and pericytes, indicating that CSCs can transdifferentiate into other lineage cells for promoting tumor growth and metastasis in some tissue contexts instead of only recruiting stromal cells from local or distant tissues. Although the transdifferentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity, many aspects of CSC transdifferentiation remain elusive. In this review, we summarize the multi-lineage differentiation and transdifferentiation potentials of CSCs as well as discuss their potential contributions to tumor heterogeneity and tumor microenvironment in tumor progression.     

HIFs维持肿瘤干细胞生物学特性及研究进展*

缺氧微环境是实体肿瘤的典型特征，被认为是导致肿瘤进展及预后差的独立因素；作为肿瘤干细胞（cancerstem cells ，CSCs）壁龛的关键组成部分，缺氧微环境对肿瘤干细胞在肿瘤中的演进以及抗凋亡能力起着重要的作用。缺氧诱导因子（hypoxia-induciblefactors，HIFs ）是肿瘤适应缺氧微环境的中心调节因子，能够诱导肿瘤干细胞生物学行为的改变如抗凋亡、增强耐药基因表达、促进肿瘤侵袭转移等，从而加速肿瘤恶性转变；同时HIFs 也是维持肿瘤干细胞其干细胞特性的主要影响因素。本文对HIFs 在维持肿瘤干细胞生物学特性的研究进展进行综述。      

Hit 'em where they live: targeting the cancer stem cell niche

Cancer stem cells (CSCs) are thought to be critical for initiation and propagation of many types of cancer. Because these cells are resistant to conventional therapies, they have been very difficult to eliminate. A study in this issue of Cancer Cell suggests that brain tumor CSCs live in a "vascular niche" that promotes their long-term growth and self-renewal. Disrupting this niche impairs CSC self-renewal and thereby significantly inhibits the growth of tumors. Targeting the unique microenvironment of CSCs may be the key to effective cancer therapy.     

The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment

Despite recent progresses in tumor therapy and increased knowledge in tumor biology, tumor remains a common and lethal disease worldwide. Cancer stem cells (CSCs) are a subset of cancer cells with a stem cell-like ability, which may drive tumor growth and recurrence and are resistant to many current anticancer treatments. Solid tumors are regarded as “organs” which are comprised of cancer cells and the tumor stroma. The tumor microenvironment makes up the stroma of the tumor, which occupies the majority of the tumor mass, including the extracellular matrix (ECM), mesenchymal stem cells (MSCs), endothelial cells, immune cells, and, what is more, networks of cytokines and growth factors. The microenvironment or niche surrounding CSCs largely governs their cellular fate. Recent work has revealed that the microenvironment supports CSC self-renewal and simultaneously serves as a physical barrier to drug delivery. The tumor microenvironment plays pivotal roles in each stage of tumor development. Knowledge about the interactions of CSCs with their microenvironment would seem to be of most importance for developing new treatment strategies.     

Nanomedicine strategies for sustained,controlled, and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.     

Cancer stem cell dynamics in tumor progression and metastasis: Is the microenvironment to blame?

Stem cells are defined by their self-renewal capacity and the ability to give rise to all differentiated progeny necessary for one specific organ. These two characteristics are also inherent in cancer stem cells (CSCs), which are thought to be the only subpopulation within a tumor endowed with tumorigenic potential. CSCs combine many features that render cancer one of the leading causes of death in the Western world: metastasis, tumor recurrence, and therapy refractoriness. Strikingly, CSCs are not a fixed entity, but differentiated tumor cells are able to revert to a stem-like state. Thus, CSCs are not only intrinsically programmed to fulfill their detrimental roles, but are orchestrated by stromal cells residing in their vicinity and forming the CSC niche. Yet, this relationship is not a one-way road: CSCs are able to manipulate stromal cells to their needs, not only in the primary tumor, but also in distant organs and thus prime the foreign soil for their arrival by inducing a premetastatic niche. The suggested plasticity between the differentiation states of cancer cells and the regulation by microenvironmental cues provides new starting-points for novel cancer therapies.     

肿瘤干细胞的临床意义

肿瘤干细胞(cancer stem cell, CSC)是近年来在许多肿瘤组织中发现的一类特殊干细胞。肿瘤干细胞具有自我更新和分化的能力,可以通过不断分化肿瘤细胞使新的肿瘤产生;肿瘤干细胞具有很强的耐药性和放射抗拒,这可以用来解释肿瘤的复发和转移。肿瘤干细胞可用于对肿瘤的诊断和治疗：通过对肿瘤干细胞标志物的鉴定可实现对一些肿瘤的早期诊断;一些新的治疗手段则通过作用于肿瘤干细胞的信号转导途径、表面标记和其生存的微环境,以及诱导其分化,从而达到靶向治疗肿瘤的目的。深入研究肿瘤干细胞的耐药性以及确定更多的肿瘤干细胞标志物,可为肿瘤治疗提供新途径。     

The clinical and therapeutic implications of cancer stem cell biology

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs - allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.     

胃癌干细胞与微环境的研究进展

胃癌目前是仅次于肺癌的第二大致死性肿瘤,目前胃癌的发病机制还不是很清楚。近年来随着对肿瘤干细胞（CSC）和肿瘤生物学的研究,目前已经在多种实体瘤中发现CSC,但是由于胃癌干细胞缺乏特异性的标志物,因此还有很多空白待探究。虽然已发现一些胃癌干细胞表面标志物如CD44、CD133等,但缺乏特异性,仍需进一步探究更具特异性的胃癌干细胞标志物。CSC生存的环境在肿瘤的进程中也起重要的作用。文章对胃癌干细胞和微环境进行研究将有助于胃癌的诊断和治疗。     

The clinical and therapeutic implications of cancer stem cell biology

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs – allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.     

Human renal cancer stem cells

Cancer stem cells (CSCs), isolated in renal carcinomas, exhibit tumor-initiating capabilities and pluripotency. No specific CSC markers have been identified so far; therefore, their characterization is mainly based on functional studies. As they are resistant to chemo and radio therapy, renal CSCs may have a relevant role in tumor establishment, progression, and recurrence. CSCs were also shown to contribute to intra-tumor vasculogenesis through an endothelial differentiation and to favor the generation of the pre-metastatic niche through the release of exosomes/microvesicles.     

Chemokines in neuroectodermal development and their potential implication in cancer stem cell-driven metastasis

Chemokines regulate proliferation and migration of various types of normal stem and progenitor cells, including precursor cells of neuroectodermal origin. Based on this it is conceivable that the established role of chemokines in cancer cell proliferation and organ-specific metastasis might also be associated with stem cell-like cells present in the tumor. Such cancer stem cells (CSCs) represent a small subpopulation of tumor cells that are thought to initiate and sustain tumor formation. More recently, characteristics of stem cells have also been observed in metastatic cancer cells, and it has been suggested that CSCs might play a crucial role in the metastatic process as such. Intriguingly, first evidence has been provided that the metastatic spread of specific CSCs is driven by chemokine signaling. Thus it is possible that chemokine-mediated CSC regulation might be a general feature of metastasis formation.     

Implications of cancer stem cells in the treatment of cancer

Identification of cancer stem cells (CSCs) in both hematological and solid malignancies suggests that CSCs may be a common phenomenon for most malignancies. Similarly to normal stem cells, CSCs can self-renew and differentiate into progeny cancer cells. Almost all current therapy against cancer targets differentiated cancer cells. CSCs are more resistant to therapy secondary to quiescence, increased expression of antiapoptotic proteins and drug efflux transporters. In this article, we review the current status of CSC research and propose the targeting of CSC cell-surface molecules, signal transduction pathways, the stem cell niche, stem cell differentiation and drug resistance.     

肿瘤转移干细胞与抗转移策略

肿瘤干细胞（cancer stem cell,CSC）能自我更新,分化形成异质性的肿瘤子代细胞群,是肿瘤复发与转移的主要原因。肿瘤转移干细胞（metastatic cancer stem cell,MCSC）具有CSC特性,同时伴有转移能力。肿瘤转移既发生于肿瘤晚期,也发生于早期。MCSC在起源、上皮-间质转变（epithelial-mesenchymal transition,EMT）、间质-上皮转变（mesenchymal-epithelial transition,MET）和靶器官小生境（niche）等方面与CSC不同,因而MCSC是肿瘤转移的基础。杀灭CSC、阻断EMT和MET、抑制MCSC微血管黏附和阻断MCSC依赖的小生境可构建抗肿瘤转移的治疗策略。本文主要介绍MCSC的可能来源,MCSC的生物学特性,MCSC近期研究中可能取得的突破,以及针对MCSC的抗转移策略,为肿瘤转移机制研究和抗转移研究提供参考。     

Cancer stem cells maintain a hierarchy of differentiation by creating their niche

The self‐renewal and differentiation properties of cancer stem cells (CSCs) are regulated and maintained by the CSC niche. However, the mechanism of this maintenance, especially the maintenance contributed by differentiated cancer cells, remains to be fully elucidated. Recently, we have established a model of CSCs, miPS‐LLCcm, from mouse induced pluripotent stem cells (miPSCs). In vitro cultured miPS‐LLCcm cells were autonomously balanced with stem‐like cells and differentiated cells including vascular endothelial cells. Under these conditions, the CSC properties appeared to be stable in the presence of the factor(s) secreted by the differentiated cells. The factor(s) activated Notch signaling and promoted self‐renewal of CSCs. In addition, the secreted factor(s) appeared to regulate the differentiation lineage of CSCs. Our results indicate that the differentiated progenies of CSCs containing vascular endothelium play important roles for regulating the CSC's properties. Therefore, miPS‐LLCcm cells create their own in vitro niche to maintain themselves in the hierarchy of differentiating CSCs.     

4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance,proliferation and metastasis

Cancer death is a leading cause of global mortality. An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred worldwide in 2012 alone. Cancer stem cells (CSCs) within tumors are essential for tumor metastasis and reoccurrence, the key factors of cancer lethality. Here we report that 4EGI-1, an inhibitor of the interaction between translation initiation factors eIF4E1 and eIF4G1 effectively inhibits breast CSCs through selectively reducing translation persistent in breast CSCs. Translation initiation factor eIF4E1 is significantly enhanced in breast CSCs in comparison to non-CSC breast cancer cells. 4EGI-1 presents increased cytotoxicity to breast CSCs compared to non-CSC breast cancer cells. 4EGI-1 promotes breast CSC differentiation and represses breast CSC induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs). 4EGI-1 isomers suppress breast CSC tumorangiogenesis and tumor growth in vivo. In addition, 4EGI-1 decreases proliferation in and induces apoptosis into breast CSC tumor cells. Furthermore, 4EGI-1 selectively inhibits translation of mRNAs encoding NANOG, OCT4, CXCR4, c-MYC and VEGF in breast CSC tumors. Our study demonstrated that 4EGI-1 targets breast CSCs through selective inhibition of translation critical for breast CSCs, suggesting that selective translation initiation interference might be an avenue targeting CSCs within tumors.     

胃癌干细胞研究进展

肿瘤干细胞(CSC)是一群具有自我更新能力和多向分化潜能的肿瘤细胞,许多研究已证实在多种实体瘤中存在CSC.虽然CSC在肿瘤细胞总数中只占很小比例,但在肿瘤的起源、发展、转移及复发等方面均有重要的作用.胃癌CSC的研究尚处于探索阶段,仍未发现胃癌CSC特异性标记物,但对其存在和来源均开展了一系列的研究.     

Breast Cancer Heterogeneity: Need to Review Current Treatment Strategies

Although the heterogeneity of breast cancer has long been recognized, the hierarchical organization and existence of tumor initiating subpopulation within breast tumors was not known until the last decade. These tumor initiating cells called cancer stem cells (CSCs) display features of stem cells such as unlimited ability to self-renew and lineage differentiation. Accumulating evidence now suggests that by virtue of their relative resistance to both radiation and chemotherapy, these cells contribute to resistance and relapse following therapy. Utilizing cell cultures and mouse xenograft models, we and others demonstrated that breast CSCs have far greater invasive and metastatic potential than differentiated tumor cells which comprise the tumor bulk. Altogether, these studies suggest that targeting and elimination of breast CSCs may be required to improve patient outcome. In this review, we will discuss recent developments in breast CSC research and advances in CSC specific targeted therapies that are in preclinical and clinical trials.     

Dynamic regulation of cancer stem cells and clinical challenges

A small population of cancer cells referred to as cancer stem cells (CSCs) have received particular attention, as they have been revealed to acquire stem cell-like properties and become the main cause of tumor propagation, metastasis and drug resistance. The CSC theory of tumor formation was believed to follow the hierarchical model initially, and therefore many CSC-targeted therapy methods were expected to cure cancer by eradicating CSCs. However, subsequent CSC research has revealed that rather than a distinct entity, the CSC is a dynamic status that can be continually dedifferentiated from progenitor or differentiated cancer cells. Elucidation of this bidirectional transition mechanism would help perfect the CSC theory and be of great value in the development of more effective anti-cancer drugs. Here, we reviewed the mechanisms of reciprocal conversion between non-CSCs and CSCs. Moreover, several approaches of target CSCs and non-CSCs together with unbiased eradication of all cancer cells are also discussed.     

小细胞肺癌干细胞信号通路的研究进展

小细胞肺癌是具有高度侵袭性的肺肿瘤,其主要临床特征是化疗有效率高但易在短时间内复发转移,这一特点可能与肿瘤干细胞的存在有关。肿瘤干细胞被认为是恶性肿瘤发生发展、耐药、复发及转移的根源。目前多认为肿瘤干细胞与正常干细胞有着相同的信号通路,如Hedgehog、Notch、Wnt等通路。本文就这几条信号通路在小细胞肺癌干细胞中所起的作用以及针对这几条信号通路治疗药物的研究进展和可能的信号通路交互作用等方面进行综述。