To wake up cancer stem cells,or to let them sleep,that is the question

Cancer stem cells (CSCs) generate transient‐amplifying cells and thereby contribute to cancer propagation. A fuller understanding of the biological features of CSCs is expected to lead to the development of new anticancer therapies capable of eradicating this life‐threatening disease. Cancer stem cells are known to maintain a non‐proliferative state and to enter the cell cycle only infrequently. Given that conventional anticancer therapies preferentially target dividing cells, CSCs are resistant to such treatments, with those remaining after elimination of bulk cancer cells potentially giving rise to disease relapse and metastasis as they re‐enter the cell cycle after a period of latency. Targeting of the switch between quiescence and proliferation in CSCs is therefore a potential strategy for preventing the reinitiation of malignancy, underscoring the importance of elucidation of the mechanisms by which these cells are maintained in the quiescent state. The fundamental properties of CSCs are thought to be governed cooperatively by internal molecules and cues from the external microenvironment (stem cell niche). Several such intrinsic and extrinsic regulators are responsible for the control of cell cycle progression in CSCs. In this review, we address two opposite approaches to the therapeutic targeting of CSCs – wake‐up and hibernation therapies – that either promote or prevent the entry of CSCs into the cell cycle, respectively, and we discuss the potential advantages and risks of each strategy.     

Tumour stem cell-targeted treatment: elimination or differentiation.

A wide range of studies suggest that most cancers are clonal and may represent the progeny of a single cell, a cancer stem cell (CSC) endowed with the capacity to maintain tumour growth. The concept of a cancer stem cell emerged decades ago, and the haematopoietic system is where it has mostly gained ground. More recently, CSC have been described in breast cancer and brain tumours. Growing evidence suggests that pathways regulating normal stem cell self-renewal and differentiation are also present in cancer cells and CSC. Malignant tumours can be viewed as an abnormal organ in which a small population of tumourigenic cancer stem cells have escaped the normal limits of self-renewal giving rise to abnormally differentiated cancer cells that contribute to tumour progression and growth. This new model has important implications for the study and treatment of cancer. Understanding the molecular circuitry which contributes to the maintenance of stem cells may provide an insight into the molecular mechanisms of cancer and thus new approaches for elimination or differentiation therapy. Therapies targeting CSC should focus on pathways such as Wnt, Shh and Notch which are required for the maintenance of cancer stem cells, but also on the ABC transporter family and other specific properties of cancer stem cells.     

Stem cells, quiescence and rectal carcinoma: an unexplored relationship and potential therapeutic target

Stem cells are responsible for maintaining differentiated cell numbers during normal physiology and at times of tissue stress. They have the unique capabilities of proliferation, self-renewal, clonogenicity and multi-potentiality. It is a widely held belief that stem-like cells, known as cancer stem cells (CSCs), maintain tumours. The majority of currently identified intestinal stem cell populations appear to be rapidly cycling. However, quiescent stem cell populations have been suggested to exist in both normal intestinal crypts and tumours. Quiescent CSCs may have particular significance in the modern management of colorectal cancer making their identification and characterisation a priority. In this review, we discuss the current evidence surrounding the identification and microenvironmental control of stem cell populations in intestinal crypts and tumours as well as exploring the evidence supporting the existence of a quiescent stem and CSC population in the gut and other tissues.     

Stem cells in gastrointestinal cancers: a matter of choice in cell fate determination

Cancerous stem cells share the same properties of self-renewal and differentiation as normal stem cells, and have a similar phenotype to adult stem cells isolated from the same tissue. Some believe that cancer stem cells are derived from mutation of normal stem cells, whereas others suspect them to have different origins. Although complicated and controversial, the stem cell as the progenitor of cancer has found support in leukemia research, and subsequently in some solid tumors. It was first accepted that both stem and progenitor cells could acquire genetic abnormalities that would lead to uncontrolled replication and dysregulated differentiation, causing them to transform into cancerous stem cells that might then initiate and maintain a tumor. In this article, we discuss recent progress in the studies of stomach and intestinal cancer stem cells, while focusing on the complex molecular pathways underlying stem cell transformation and gastrointestinal tumorigenesis. This understanding provides a basis for promising new therapies that may specifically target gastrointestinal cancer stem cells.     

肿瘤干细胞标志物与胃癌关系的研究进展

肿瘤干细胞（cancer stem cell,CSCs）是理论认为肿瘤中存在一小部分细胞具有自我更新和多向分化的潜能,具有特异性表面标志的细胞.目前已经从乳腺癌、结直肠癌、皮肤癌等多种恶性肿瘤中鉴定分离出了各自的肿瘤干细胞标志物.本文就与胃癌相关的干细胞标志物进行综述.     

Regulation of the self-renewal ability of tissue stem cells by tumor-related genes

Stem cells are defined by both their ability to produce stem cells, a property known as self-renewal, and their ability to give rise to differentiated progeny. One of the hallmarks of tissue stem cell is its adoption of a non-dividing, undifferentiated state called quiescence. The ability to sustain quiescence is crucial for stem cell function in several tissues. In this review, we discuss how tissue stem cell properties are affected by the products of tumor-related genes such as ATM, PTEN and FOXO. Recent advances in stem cell research achieved using mouse genetics have provided novel evidence that numerous tumor-related genes, which are known to control genomic stability, cell proliferation and survival, are also closely associated with the regulation of tissue stem cell self-renewal. These findings support the notion that tissue stem cells and cancer cells share common properties. Further investigation of stem cell regulation by tumor-related genes may pave the way for successful stem cell-based approaches to regenerative medicine and cancer therapy.     

Isolation of Side Population Cells and Detection of ABCG2 from SW480

Objective:Side population cells(SP cells)are a new type of stem cells.They mainly express ABCG2/BCRP1 and have the ability to eliminate DNA dye Hoechst33342.Many studies showed that side population cells were able of self-renewal,differentiation and carcinogenesis in cancers.Our investigation aimed at isolation of side population cells and ABCG2 positive subpopulation from colon cancer cell line SW480 and identification of their characteristics of cancer stem cells.Methods:side population cells and non-side population cells of colon cancer cell line SW480 were isolated with DNA dye Hoechst33342 and their cell cycles were measured by flow cytometry.Expression of ABCG2 of SW480 was measured by immunohistochemistry and immunofluorescence,and its proportion was measured by flow cytometry.Results:SW480 contained 2.29% side population cells.The fraction of side population cells decreased greatly to 0.40% by treatment with verapamil.The fraction of side population cells in S-G2M cell cycle was 16.14%,which was much lower than the fraction(34.05%)of non-side population cells in S-G2M.In SW480,ABCG2 positive cells,which proportion was 9.66%,were small,circular or oval,lack of psuedopods,similar to poor differentiation.On the contrary,the ABCG2 negative cells were large,polygonal,with many psuedopods,similar to high differentiation.Conclusion:our assay identified that side population cells did exist in SW480 and had a quiescence characteristic of stem cells.ABCG2 positive subpopulation occupied about 9.66% of SW480 and may have the ability to promote cell self-renewal and inhibit cell differentiation.Therefore,to isolate ABCG2 positive subpopulation from side population cells may be an alternative to study colorectal cancer stem cells.     

Therapeutic strategies targeting cancer stem cells

Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy.     

干细胞niche与肿瘤干细胞产生和发展的关系

肿瘤干细胞学说认为大部分肿瘤来源于肿瘤干细胞。肿瘤干细胞与正常干细胞一样具有自我更新能力,能够产生肿瘤组织团块中的各种增殖和分化的细胞。肿瘤干细胞可能来源于正常干细胞或分化细胞。干细胞niche是干细胞生存的微环境,通过提供抑制细胞增殖和生长的信号来维持干细胞于静止状态。干细胞niche功能异常会导致niche的数量增加,以及干细胞功能异常和数量增加。肿瘤干细胞可能在异常的niche中存活,打破这种异常的niche就会削弱肿瘤干细胞的自我更新,从而抑制肿瘤的生长。靶向肿瘤干细胞异常微环境的治疗策略可能是癌症治疗的一个方向。     

Do stem-like cells play a role in drug resistance of sarcomas?

Stem cells are defined by their unique characteristics, which include their abilities to self-renew and differentiate. Normal somatic stem cells have been isolated from various tissues such as bone marrow, adipose tissue, mammary glands and the nervous system. They are considered naturally resistant to chemotherapeutic agents because they express high levels of membrane transporter molecules, detoxifying enzymes and DNA repair proteins. Several recent studies have identified the presence of side populations in various cancer tissues, the so-called ‘cancer stem cells’, which are defined as the counterparts of stem cells in tumor tissues. These cancer stem cells possess stem-like properties, such as self-renewal and differentiation abilities, as well as playing a role in tumor initiation. Most sarcomas, which are thought to originate from mesenchymal stem cells, are highly malignant and approximately 30–40% of them show local and/or distant relapse (metastasis), even in the case of relatively chemosensitive tumors such as osteosarcomas and Ewing sarcomas. Several studies have suggested the presence of stem-like cell populations in sarcomas, based on their tumorigenicity and drug resistance. This review explores the issues of drug resistance of cancer stem cells in sarcomas and the possibilities of targeting cancer stem cells for the future treatment of sarcomas.     

Expression and functional role of ALDH1 in cervical carcinoma cells

Tumor formation and growth is dictated by a very small number of tumor cells, called cancer stem cells, which are capable of self-renewal. The genesis of cancer stem cells and their resistance to conventional chemotherapy and radiotherapy via mechanisms such as multidrug resistance, quiescence, enhanced DNA repair abilities and anti-apoptotic mechanisms, make it imperative to develop methods to identify and use these cells as diagnostic or therapeutic targets. Aldehyde dehydrogenase 1 (ALDH1) is used as a cancer stem cell marker. In this study, we evaluated ALDH1 expression in CaSki, HeLa and SiHa cervical cancer cells using the Aldefluor method to isolate ALDH1-positive cells. We showed that higher ALDH1 expression correlated with significantly higher rates of cell proliferation, microsphere formation and migration. We also could demonstrate that SiHa-ALDH1- positive cells were significantly more tumorigenic compared to SiHa-ALDH1-negative cells. Similarly, SiHa cells overexpressing ALDH1 were significantly more tumorigenic and showed higher rates of cell proliferation and migration compared to SiHa cells where ALDH1 expression was knocked down using a lentivirus vector. Our data suggested that ALDH1 is a marker of cervical cancer stem cells and expand our understanding of its functional role.     

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。     

Hes1: a key role in stemness,metastasis and multidrug resistance

Hes1 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability. Recent studies have shown that Hes1 functions in the maintenance of cancer stem cells (CSCs), metastasis and antagonizing drug-induced apoptosis. Pathways that are involved in the up-regulation of Hes1 level canonically or non-canonically, such as the Hedgehog, Wnt and hypoxia pathways are frequently aberrant in cancer cells. Here, we summarize the recent data supporting the idea that Hes1 may have an important function in the maintenance of cancer stem cells self-renewal, cancer metastasis, and epithelial–mesenchymal transition (EMT) process induction, as well as chemotherapy resistance, and conclude with the possible mechanisms by which Hes1 functions have their effect, as well as their crosstalk with other carcinogenic signaling pathways.     

乳腺癌干细胞研究进展

乳腺癌干细胞是乳腺肿瘤细胞中少数具有自我更新和分化潜能,并能维持乳腺肿瘤的生长和异质性的一类细胞。越来越多的证据表明,乳腺癌干细胞在乳腺癌的发生、生长、复发、转移和抗药性等方面起决定性的作用。因此,研究乳腺癌干细胞的调控机理和开发靶向乳腺癌干细胞的新药已经成为乳腺癌研究中的热点。文章简要综述乳腺癌干细胞的概念,分离鉴定及其在乳腺癌转移和治疗中的作用,并对其分子调控进行了探讨。     

靶向肿瘤干细胞的条件增殖腺病毒研究进展

肿瘤干细胞(CSC)具有自我更新及分化潜能,是肿瘤生长和转移的源泉,与化放疗抵抗密切相关,能否彻底根除CSC决定肿瘤治疗的成败.条件增殖腺病毒(CRAd)是一类仅在肿瘤细胞内特异增殖的新型病毒载体,可同时靶向肿瘤细胞和肿瘤干细胞,为彻底治愈肿瘤带来曙光.     

Targeted therapy for cancer stem cells: the patched pathway and ABC transporters

Data from certain leukemias as well as brain and breast cancer indicate that there is a small population of tumor cells with "stem cell" characteristics and the capacity for self-renewal. The self-renewing cells have many of the properties of normal stem cells and have been termed "cancer stem cells". These cancer stem cells make up as few as 1% of the cells in a tumor, making them difficult to detect and study. Like normal stem cells, cancer stem cells have a number of properties permitting them to survive traditional cancer chemotherapy and radiation therapy. These cells express high levels of ATP-binding cassette (ABC) drug transporters, providing for a level of resistance; are relatively quiescent; have higher levels of DNA repair and a lowered ability to enter apoptosis. Combined cancer therapy approaches targeting the cancer stem cells and the non-stem cells may be developed with increased efficacy. Efforts to target the Hedgehog/Patched pathway, critical to embryonic growth and differentiation, and the ABCG2 drug efflux transporter will be presented.     

微RNA对肿瘤干细胞自我更新的影响机制

肿瘤干细胞( CSC)的自我更新与肿瘤的形成、复发以及耐药有关.微RNA (miRNA)能够调控细胞周期,影响细胞命运.目前的研究已发现微RNA可通过直接调节相关的基因靶点作用于肿瘤干细胞的自我更新,同时可能通过影响Wnt、Notch、Hedgehog等信号传导途径参与调节肿瘤干细胞自我更新.     

To grab the stroma by the horns: From biology to cancer therapy with mesenchymal stem cells

Mesenchymal stem or stromal cells (MSCs) are precursor cells that play important roles in tumorigenesis. MSCs are recruited to tumors from local and distant sources to form part of the tumor microenvironment. MSCs influence tumor progression by interacting with cancer cells, endothelial cells, immune cells, and cancer stem cells, in a context-dependent network. This review aims to synthesize this emerging yet controversial field to identify key questions regarding the mechanisms of MSC mobilization and survival in blood; homing to tumors, metastases, and premetastatic sites; spatiotemporal organization and differentiation; and interaction with immune cells and cancer stem cells. Understanding the fundamental biology underlying mesenchymal stem cell and tumor interactions has the potential to inform our knowledge of cancer initiation and progression as well as lead to novel therapeutics for cancer. Furthermore, knowledge of endogenous mechanisms can be used to “program” exogenous MSCs for targeted chemotherapeutic delivery to tumors and metastases. Emerging studies will provide crucial insight into the mechanisms of tumor interactions with the whole organism including MSCs.     

Isolation of cancer stem-like cells from a side population of a human glioblastoma cell line,SK-MG-1

Accumulating evidence suggests that in several types of brain tumors, including glioma, only a phenotypic subset of tumor cells called brain cancer stem cells (BCSCs) may be capable of initiating tumor growth. Recently, the isolation of side population (SP) cells using Hoechst dye has become a useful method for obtaining cancer stem cells in various tumors. In this study, we isolated cancer stem-like cells from human glioma cell lines using the SP technique. Flow cytometry analysis revealed that SK-MG-1, a human glioblastoma cell line, contained the largest number of SP cells among the five glioma cell lines that were analyzed. The SP cells had a self-renewal ability and were capable of forming spheres in a neurosphere culture medium containing EGF and FGF2. Spheres derived from the SP cells differentiated into three different lineage cells: neurons, astrocytes and oligodendrocytes. RT-PCR analysis revealed that the SP cells expressed a neural stem cell marker, Nestin. The SP cells generated tumors in the brains of NOD/SCID mice at 8 weeks after implantation, whereas the non-SP cells did not generate any tumors in the brain. These results indicate that SP cells isolated from SK-MG-1 possess the properties of cancer stem cells, including their self-renewal ability, multi-lineage differentiation, and tumorigenicity. Therefore, the SP cells from SK-MG-1 may be useful for analyzing BCSCs because of the ease with which they can be handled and their yield.