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。     

Cancer stem cell niche: the place to be

Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a "stem cell niche" that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the "CSC niche," which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies.     

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.     

Pluripotency transcription factors and cancer stem cells:small genes make a big difference

Cancer stem cells (CSCs) are thought to drive uncontrol ed tumor growth, and the existence of CSCs has recently been proven by direct experimental evidence, including tracing cel lineages within a grow...     

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.     

Cancer stem cells and cancer therapy

Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the stem cell properties of self-renewal and differentiation. Stem cells might be the target cells responsible for malignant transformation, and tumour formation may be a disorder of stem cell self-renewal pathway. Epigenetic alterations and mutations of genes involved in signal transmissions may promote the formation of CSCs. These cells have been identified in many solid tumours including breast, brain, lung, prostate, testis, ovary, colon, skin, liver, and also in acute myeloid leukaemia. The CSC theory clarifies not only the issue of tumour initiation, development, metastasis and relapse, but also the ineffectiveness of conventional cancer therapies. Treatments directed against the bulk of the cancer cells may produce striking responses but they are unlikely to result in long-term remissions if the rare CSCs are not targeted. In this review, we consider the properties of CSCs and possible strategies for controlling the viability and tumourigenecity of these cells, including therapeutic models for selective elimination of CSCs and induction of their proper differentiation.     

First among equals: the cancer cell hierarchy

Primary cancer cells exhibit heterogeneity in their proliferative ability. The cancer stem cell (CSC) model accounts for this heterogeneity by proposing that each cancer consists of a small population of CSCs that are capable of unlimited growth and self-renewal and a much larger population of cells, descendants of the CSCs, that have lost self-renewal capacity. The CSC model has important implications for cancer therapy. Eradication of CSCs, the cells responsible for maintenance of the neoplasm, would be necessary and sufficient to achieve cure. By extension, both the frequency of stem cells in a tumor and their propensity to undergo self-renewal (P_sr) would have a direct impact on the curability of that tumor. The P_sr is a critical biological characteristic of CSCs—small differences in P_sr have enormous impact on the probability of success in cancer therapy. Differentiation therapy, defined as treatment that reduces the P_sr of CSCs, is one approach to targeting CSCs.     

肿瘤干细胞的研究进展

肿瘤干细胞是存在于肿瘤中的一小部分具有干细胞性质的细胞群,具有高度的致瘤性和耐药性。同正常干细胞一样,肿瘤干细胞具有无限的自我更新和多向分化的潜能,使肿瘤在体内不断扩大或形成新的肿瘤,导致肿瘤复发和转移。肿瘤干细胞的研究有助于认识和理解肿瘤发生发展的机制,指导肿瘤的临床治疗。     

肿瘤干细胞的研究进展

肿瘤干细胞是存在于肿瘤中的一小部分具有干细胞性质的细胞群,具有高度的致瘤性和耐药性。同正常干细胞一样,肿瘤干细胞具有无限的自我更新和多向分化的潜能,使肿瘤在体内不断扩大或形成新的肿瘤,导致肿瘤复发和转移。肿瘤干细胞的研究有助于认识和理解肿瘤发生发展的机制,指导肿瘤的临床治疗。     

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.     

Cancer stem cells,metabolism, and therapeutic significance

Cancer stem cells (CSCs) have attracted much attention of the research community in the recent years. Due to their highly tumorigenic and drug-resistant properties, CSCs represent important targets for developing novel anticancer agents and therapeutic strategies. CSCs were first described in hematopoietic malignancies and subsequently identified in various types of solid tumors including brain, breast, lung, colon, melanoma, and ovarian cancer. CSCs possess special biological properties including long-term self-renewal capacity, multi-lineage differentiation, and resistance to conventional chemotherapy and radiotherapy. As such, CSCs are considered as a major source of residual disease after therapy leading to disease occurrence. Thus, it is very important to understand the cellular survival mechanisms specific to CSCs and accordingly develop effective therapeutic approaches to eliminate this subpopulation of cancer cells in order to improve the treatment outcome of cancer patients. Possible therapeutic strategies against CSCs include targeting the self-renewal pathways of CSCs, interrupting the interaction between CSCs and their microenvironment, and exploiting the unique metabolic properties of CSCs. In this review article, we will provide an overview of the biological characteristics of CSCs, with a particular focus on their metabolic properties and potential therapeutic strategies to eliminate CSCs.     

Immunology of cancer stem cells in solid tumours. A review

Cancer stem cells (CSCs) represent a minor subpopulation of tumour cells that share some features with the normal stem cells of the tissue from which tumour derives and have the properties of self-renewal, multiple differentiation and tumour initiation (tumour-initiating cells, TICs). Thus CSCs/TICs need to survive cancer therapies in order to provide new, more differentiated, metastatic-prone tumour cells. This occurs through different signals delivered within the tumour microenvironment. The immune system of cancer patients may recognise CSCs/TICs and kill them though it is unclear whether this may occur in vivo during spontaneous tumour growth. This review summarises findings on the immunological profile of CSCs/TICs as compared with neoplastic non-stem cells and discusses the possible antigens recognised by the patients’ immune system, the in vitro and the potential in vivo immunogenicity of such antigens and the ability of human CSCs/TICs to down-regulate the immune response by the release of a variety of suppressive factors. We conclude that available data on immunological characterisation of CSCs/TICs may be useful in the perspective of designing new translational immunotherapy protocols targeting CSCs/TICs.     

Targeting Cancer Stem Cells by Phytochemicals: a Multimodal Approach to Colorectal Cancer

Cancer stem cells (CSCs) exist within a tumor as a rare subpopulation, with the capacity of self-renewal and the ability to differentiate into heterogeneous population of cancer cells. CSCs are increasingly being implicated in tumor recurrence thereby further augmenting the menace of the malignant disease. Characterization of CSCs has unearthed their pivotal role in all the hallmarks of cancer including tumorigenesis, angiogenesis, metastasis and drug resistance, thereby designating cancer as a “stem cell disease.” Here, we discuss the limitations of current therapeutic strategies that spare CSCs thereby failing to achieve complete cure of colorectal cancer, and elucidate the role of multimodal CSC-targeted treatment strategies, using natural phytochemicals and their derivatives. With emerging evidences identifying the molecular targets of phytochemicals in colorectal CSCs, development of better therapeutic strategies uprooting CSCs, the root of all evils, can be envisaged.     

Targeting the K-Ras - JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation

Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras – JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre-established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras – JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer.     

MicroRNA在肿瘤干细胞中的调控作用研究进展

肿瘤干细胞(CSCs)是导致肿瘤复发、转移和耐药的根源之一。microRNA(miRNAs)是一类小分子非编码RNA,可与靶mRNA的3’UTR区域结合而导致该mRNA分子的翻译受到抑制,参与多种生物功能的调节。最近的研究发现,miRNAs参与CSCs的分化、自我更新等生物学特性的调控。miRNAs可以作为CSCs研究的一个新的切入点。本文就近年来该方面的研究进展做简要综述。     

MicroRNA在肿瘤干细胞中的调控作用研究进展

肿瘤干细胞（CSCs）是导致肿瘤复发、转移和耐药的根源之一。microRNA（miRNAs）是一类小分子非编码RNA,可与靶mRNA的3＇UTR区域结合而导致该mRNA分子的翻译受到抑制,参与多种生物功能的调节。最近的研究发现,miRNAs参与CSCs的分化、自我更新等生物学特性的调控。miRNAs可以作为CSCs研究的一个新的切入点。本文就近年来该方面的研究进展做简要综述。     

In vitro models of cancer stem cells and clinical applications

Cancer cells, stem cells and cancer stem cells have for a long time played a significant role in the biomedical sciences. Though cancer therapy is more effective than it was a few years ago, the truth is that still none of the current non-surgical treatments can cure cancer effectively. The reason could be due to the subpopulation called “cancer stem cells” (CSCs), being defined as those cells within a tumour that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumours.The phenomenon of CSCs is based on their resistance to many of the current cancer therapies, which results in tumour relapse. Although further investigation regarding CSCs is still needed, there is already evidence that these cells may play an important role in the prognosis of cancer, progression and therapeutic strategy. Therefore, long-term patient survival may depend on the elimination of CSCs. Consequently, isolation of pure CSC populations or reprogramming of cancer cells into CSCs, from cancer cell lines or primary tumours, would be a useful tool to gain an in-depth knowledge about heterogeneity and plasticity of CSC phenotypes and therefore carcinogenesis. Herein, we will discuss current CSC models, methods used to characterize CSCs, candidate markers, characteristic signalling pathways and clinical applications of CSCs. Some examples of CSC-specific treatments that are currently in early clinical phases will also be presented in this review.     

Cancer stem cells: in the line of fire

Most tumours appear to contain a sub-population(s) of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The CSC model proposes that CSCs are at the apex of a hierarchically organized cell population, somewhat akin to normal tissue organization. Selection pressures may also facilitate the stochastic clonal expansion of sub-sets of cancer cells that may co-exist with CSCs and their progeny, moreover the trait of stemness may be more fluid than hitherto expected, and cells may switch between the stem and non-stem cell state. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In this review we discuss the basis of such resistance that highlights the roles of ABC transporters, aldehyde dehydrogenase (ALDH) activity, intracellular signalling pathways, the DNA damage response, hypoxia and proliferative quiescence as being significant determinants. In the light of such observations, we outline strategies for the successful eradication of CSCs, including targeting the self-renewal controlling pathways (Wnt, Notch and Hedgehog), ALDH activity and ABC transporters, blocking epithelial mesenchymal transition (EMT), differentiation therapy and niche targeting.     

Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation

Introduction  

The irregular vasculature of solid tumors creates hypoxic regions, which are characterized by cyclic periods of hypoxia and reoxygenation. Accumulated evidence suggests that chronic and repetitive exposure to hypoxia and reoxygenation seem to provide an advantage to tumor growth. Although the development of hypoxia tolerance in tumors predicts poor prognosis, mechanisms contributing to hypoxia tolerance remain to be elucidated. Recent studies have described a subpopulation of cancer stem cells (CSC) within tumors, which have stem-like properties such as self-renewal and the ability to differentiate into multiple cell types. The cancer stem cell theory suggests CSCs persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Since hypoxia is considered to be one of the critical niche factors to promote invasive growth of tumors, we hypothesize that repetitive cycles of hypoxia/reoxygenation also play a role in the enrichment of breast CSCs.