Cancer stem cell

Recently it is considered that there is a small population of cells with stem cell property not only in leukemia but also in solid cancer.These cells show the ability of self-renewal and multi-potential differentiation, and can initiate and maintain a tumor. The origin of cancer stem cells might be their normal stem cells, progenitor cells, or bone marrow-derived cells. It is still difficult to isolate cancer stem cells in solid cancer. There are three possible methodologies to isolate or identify cancer stem cells; the use of a surface marker, use of cells cultured in a specific condition (sphere), or the use of side population cells identified by FACS. The gold standard assay that fulfills the definition of cancer stem cell may be serial transplantation in animal models. Cancer stem cells are likely to be responsible for disease relapse or metastasis, and also for resistance to radiation or conventional chemotherapy. The stem cell niche plays an important role on maintaining cancer stem cells. The novel promising therapies against cancer stem cells are considered, including antibody-based therapy, signal inhibitors, overcoming radiation and drug resistance, or differentiation therapy. Another interesting therapy targeting the niche may also be considered.     

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.     

Engineering nanotheranostic strategies for liver cancer

The incidence and mortality of hepatocellular carcinoma have continued to increase over the last few years, and the medicine-based outlook of patients is poor. Given great ideas from the development of nanotechnology in medicine, especially the advantages in the treatments of liver cancer. Some engineering nanoparticles with active targeting, ligand modification, and passive targeting capacity achieve efficient drug delivery to tumor cells. In addition, the behavior of drug release is also applied to the drug loading nanosystem based on the tumor microenvironment. Considering clinical use of local treatment of liver cancer, in situ drug delivery of nanogels is also fully studied in orthotopic chemotherapy, radiotherapy, and ablation therapy. Furthermore, novel therapies including gene therapy, phototherapy, and immunotherapy are also applied as combined therapy for liver cancer. Engineering nonviral polymers to function as gene delivery vectors with increased efficiency and specificity, and strategies of co-delivery of therapeutic genes and drugs show great therapeutic effect against liver tumors, including drug-resistant tumors. Phototherapy is also applied in surgical procedures, chemotherapy, and immunotherapy. Combination strategies significantly enhance therapeutic effects and decrease side effects. Overall, the application of nanotechnology could bring a revolutionary change to the current treatment of liver cancer.     

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。     

肿瘤干细胞疫苗的研究进展

目前已知的绝大多数癌症治疗方法如化疗、放疗、免疫靶向治疗等主要以肿瘤细胞为靶目标,但很多肿瘤并不能被完全治愈且治疗后伴随很多并发症。一群高度耐药的肿瘤细胞能够使肿瘤重新聚集并转移到新的部位,使肿瘤继续发生发展。如果可以基于它们的表型或功能特征来鉴定具有干细胞样特征的癌细胞,从而找到肿瘤干细胞特异性抗原制成干细胞疫苗,进而激活机体内特异的免疫应答,以达到靶向清除肿瘤干细胞的目的,就能一定程度上控制肿瘤的复发及转移,杀灭肿瘤干细胞甚至可以消除肿瘤对放化疗的拮抗性及耐药性。因此肿瘤干细胞疫苗即靶向肿瘤干细胞的主动免疫疗法的研究与发展对恶性难治性肿瘤的治疗有着重要意义,本篇综述将对近年来肿瘤干细胞及其疫苗的发现、发展与研究结果进行概述。     

乳腺癌干细胞的调控及作用

乳腺癌是威胁妇女健康的重要疾病之一,由于其病因尚不完全清楚,目前还没有确切的预防方法,手术和放化疗是其主要的治疗办法,但其风险大且具有一定不良反应。研究发现,从实体肿瘤中分离出来的具有自我更新和多向分化能力的乳腺癌干细胞,能够介导肿瘤的侵入、转移和复发等过程,并且能够抵抗传统的放化疗,这对研究以乳腺癌干细胞为靶点的治疗方法具有重要的理论价值和实践意义。本文对乳腺癌干细胞的调控及作用的最新进展作一综述。     

MicroRNAs and cancer stem cells: Therapeutic approaches and future perspectives

Cancer stem cells (CSCs) are a sub-population of cancer cells that possess characteristics associated with normal stem cells but with the peculiarity that they are tumourigenic. This property allows them to persist in the tumour population, causing relapse and metastasis by giving rise to new tumours. Accordingly, if the CSCs were eliminated, then the tumour would simply regress due to differentiation and cell death. By selectively targeting CSCs, it may be possible to treat patients with aggressive, non-resectable tumours and prevent the tumour from metastasising. MicroRNAs are involved in all biological processes, and several studies have demonstrated their function in human tumourigenesis. Importantly, microRNAs have been implicated in the regulation of stem cells and CSCs. The most important concept to emerge with regard to CSC therapy is still controversial because a number of signalling pathways unique to normal stem cells may also be operating in CSCs, and these offer new targets for therapy. This article reviews how the modulation of microRNAs may revert tumour proliferation in vivo and in vitro and how this approach could be transferred to the clinic. Although the delivery of therapeutic microRNAs to target cells is a challenge that still needs to be overcome, microRNAs offer the advantage that they are small molecules that can be easily transported by body fluids, which makes them good candidates for cancer therapy.     

靶向肿瘤干细胞治疗肿瘤

具有独特的分子表达、表面标志物、干性相关信号通路和代谢模式等方面特征的肿瘤干细胞（cancer stem cell, CSC） 因其具有高致瘤、高转移、高治疗抵抗能力,可能是多种类型恶性肿瘤生长、转移、治疗抵抗的关键因素,也是肿瘤发生和复发的 重要根源。正常干细胞在产生了第一个致癌突变之后将逐步发展成为癌前干细胞和CSC,随后在突变和微环境的共同作用下进 一步积累突变增加异质性,并与CSC可塑性转变交织在一起推动肿瘤的发生和进展,促进肿瘤的复发、转移及治疗抵抗。为了更 好地治疗肿瘤,现已研发了多种类型的靶向CSC的治疗策略,包括靶向CSC的细胞表面标志物、信号转导途径、微环境、代谢模式 等,以及促CSC分化、靶向CSC的免疫治疗等其他策略。多个靶向CSC治疗肿瘤的新药在临床试验中已经展现出良好的治疗效 果,然而,也有一些抗肿瘤新药的失败为未来研发提供了值得注意的教训。未来肿瘤治疗中,特异地靶向患者肿瘤中所有异质性 的CSC,并同时清除癌前干细胞和子代肿瘤细胞,将会更好地抑制肿瘤生长、转移和复发,从而为治愈肿瘤带来新的希望。     

The Wnt signaling pathway: implications for therapy in osteosarcoma

Osteosarcoma is the most common primary bone malignancy, with a high propensity for local invasion, early metastasis and relapse. While the molecular mechanisms behind osteosarcoma development and metastasis have not yet been fully elucidated, research has highlighted an important role for Wnt signaling. Several Wnt ligands, receptors and coreceptors are highly expressed in osteosarcoma cell lines, while Wnt inhibitors are downregulated. As a result, research has begun to identify mechanisms with which to inhibit Wnt signaling. The use of Wnt pathway inhibitors and the targeting of c-Met, a Wnt regulated proto-oncogene, may be two possible mechanisms for treatment of osteosarcoma. In addition, as the Wnt signaling pathway is a regulator of stem cells, reagents that function as Wnt inhibitors are currently under investigation as inhibitors of cancer stem cell proliferation. Research involving the Wnt signaling pathway and cancer stem cells holds promise for novel treatment options in the future.     

The emerging role of exosome and microvesicle‐ (EMV‐) based cancer therapeutics and immunotherapy

There is an urgent need to develop new combination therapies beyond existing surgery, radio‐ and chemo‐therapy, perhaps initially combining chemotherapy with the targeting specificities of immunotherapy. For this, strategies to limit inflammation and immunosuppression and evasion in the tumour microenvironment are also needed. To devise effective new immunotherapies we must first understand tumour immunology, including the roles of T cells, macrophages, myeloid suppressor cells and of exosomes and microvesicles (EMVs) in promoting angiogenesis, tumour growth, drug resistance and metastasis. One promising cancer immunotherapy discussed uses cationic liposomes carrying tumour RNA (RNA‐lipoplexes) to provoke a strong anti‐viral‐like (cytotoxic CD8⁺) anti‐tumour immune response. Mesenchymal stem cell‐derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumours, have also been used. As tumour EMVs clearly exacerbate the tumour microenvironment, another therapy option could involve EMV removal. Affinity‐based methods to deplete EMVs, including an immunodepletion, antibody‐based affinity substrate, are therefore considered. Finally EMV and exosome‐mimetic nanovesicles (NVs) delivery of siRNA or chemotherapeutic drugs that target tumours using peptide ligands for cognate receptors on the tumour cells are discussed. We also touch upon the reversal of drug efflux in EMVs from cancer cells which can sensitize cells to chemotherapy. The use of immunotherapy in combination with the advent of EMVs provides potent therapies to various cancers.     

Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation,progression, and targeted therapy

The discovery of rare tumor cells with stem cell features first in leukemia and later in solid tumors has emerged as an important area in cancer research. It has been determined that these stem-like tumor cells, termed cancer stem cells, are the primary cellular component within a tumor that drives disease progression and metastasis. In addition to their stem-like ability to self-renew and differentiate, cancer stem cells are also enriched in cells resistant to conventional radiation therapy and to chemotherapy. The immediate implications of this new tumor growth paradigm not only require a re-evaluation of how tumors are initiated, but also on how tumors should be monitored and treated. However, despite the relatively rapid pace of cancer stem cell research in solid tumors such as breast, brain, and colon cancers, similar progress in lung cancer remains hampered in part due to an incomplete understanding of lung epithelial stem cell hierarchy and the complex heterogeneity of the disease. In this review, we provide a critical summary of what is known about the role of normal and malignant lung stem cells in tumor development, the progress in characterizing lung cancer stem cells and the potential for therapeutically targeting pathways of lung cancer stem cell self-renewal.     

EMT,CTCs and CSCs in tumor relapse and drug-resistance

Tumor relapse and metastasis are the primary causes of poor survival rates in patients with advanced cancer despite successful resection or chemotherapeutic treatment. A primary cause of relapse and metastasis is the persistence of cancer stem cells (CSCs), which are highly resistant to chemotherapy. Although highly efficacious drugs suppressing several subpopulations of CSCs in various tissue-specific cancers are available, recurrence is still common in patients. To find more suitable therapy for relapse, the mechanisms underlying metastasis and drug-resistance associated with relapse-initiating CSCs need to be identified. Recent studies in circulating tumor cells (CTCs) of some cancer patients manifest phenotypes of both CSCs and epithelial-mesenchymal transition (EMT). These patients are unresponsive to standard chemotherapies and have low progression free survival, suggesting that EMT-positive CTCs are related to co-occur with or transform into relapse-initiating CSCs. Furthermore, EMT programming in cancer cells enables in the remodeling of extracellular matrix to break the dormancy of relapse-initiating CSCs. In this review, we extensively discuss the association of the EMT program with CTCs and CSCs to characterize a subpopulation of patients prone to relapses. Identifying the mechanisms by which EMT-transformed CTCs and CSCs initiate relapse could facilitate the development of new or enhanced personalized therapeutic regimens.     

卵巢癌肿瘤干细胞耐药性及其治疗的研究进展

肿瘤干细胞是肿瘤组织内具有自我更新能力及无限增殖潜能的一群细胞,对外源细胞毒性药物耐受。卵巢癌肿瘤干细胞在卵巢癌发生、化疗耐药和复发过程中起重要作用。传统治疗对减小肿瘤体积有效,但是治疗后残留的卵巢癌干细胞成为卵巢癌复发和难治的根源,针对卵巢癌肿瘤干细胞的靶向治疗可能在抗卵巢癌治疗中具有重要作用,为临床彻底治愈卵巢癌带来希望。     

Radiation resistance in breast cancer: are CD44+/CD24-/proteosomelow/PKH26+ cells to blame?

Identification and characterization of cancer-initiating cells (CICs) enriched for stem cell-like functions and the establishment of a link between CICs and tumor recurrence, chemotherapy resistance and radiation resistance, and metastasis have been the focus of cancer research for the last eight years. Although this field has its share of controversies, it is becoming apparent that cells isolated from recurrent or residual tumors or both are enriched for cancer cells that have a specific phenotype compared with heterogeneous cells in the primary tumor. Enrichment of CICs in tumors subjected to radiation therapy could be due in part to the delivery of sublethal doses of treatment and the efficient radical scavenging system within CICs. Sublethal doses of radiation are sufficient to induce senescence of non-CICs while forcing CICs to gain several new properties related to cell cycle progression in addition to maintaining or enhancing stem cell characteristics of pre-treatment CICs. Characterizing pathways responsible for the increase in CICs after therapy and exploiting the unique characteristics of therapy-resistant CICs for developing targeted therapies are becoming a central focus of research in the rapidly evolving field of CICs.     

Understanding the cancer stem cell

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents.     

乳腺癌干细胞研究的新进展

肿瘤是由肿瘤干细胞异常增殖、分化而形成,常规放化疗仅能消灭增殖期的非致瘤性肿瘤细胞,使肿瘤缩小甚至消失。然而,肿瘤干细胞和普通干细胞一样,对放化疗等方法具有较高的抵抗能力,当治疗停止后,肿瘤干细胞可再次增殖形成肿瘤。目前研究已证实乳腺癌中存在乳腺癌干细胞,并且乳腺癌干细胞在乳腺癌的发生、发展中起着关键作用。乳腺癌干细胞不但介导乳腺癌组织对放化疗的抵抗,还关系到乳腺癌的转移和复发,所以有必要针对乳腺癌干细胞进行深入研究。因此,本文就乳腺癌干细胞的分离鉴定、相关信号通路的调控及其治疗方面的新进展作一综述。      

Cell volume regulation in cancer cell migration driven by osmotic water flow

Cancer metastasis is the most frequent cause of death for patients with cancer. The main current treatment for cancer metastasis is chemotherapy targeting cancer cells’ ability to proliferate. However, some types of cancer cells show resistance to chemotherapy. Recently, cancer cell migration has become the subject of interest as a novel target of cancer therapy. Cell migration requires many factors, such as the cytoskeleton, cell‐matrix adhesion and cell volume regulation. Here, we focus on cell volume regulation and the role of ion/water transport systems in cell migration. Transport proteins, such as ion channels, ion carriers, and aquaporins, are indispensable for cell volume regulation under steady‐state conditions and during exposure to osmotic stress. Studies from the last ~25 years have revealed that cell volume regulation also plays an important role in the process of cell migration. Water flow in accordance with localized osmotic gradients generated by ion transport contributes to the driving force for cell migration. Moreover, it has been reported that metastatic cancer cells have higher expression of these transport proteins than nonmetastatic cancer cells. Thus, ion/water transport proteins involved in cell volume regulation and cell migration could be novel therapeutic targets for cancer metastasis. In this review, after presenting the importance of ion/water transport systems in cell volume regulation, we discuss the roles of transport proteins in a pathophysiological context, especially in the context of cancer cell migration.     

Molecular treatment strategies and surgical reconstruction for metastatic bone diseases

Molecular mechanism of bone metastasis development is extremely complex. It is determined by intrinsic properties of cancer cells or cancer stem cells (CSCs) and intricate bone microenvironment. Therefore, molecular treatment strategies have been suggested to directly induce cancer cells apoptosis and to target vascular and bone microenvironment as well, thus inhibiting vicious cycles established between osteoblasts/osteoclasts and metastatic cancer cells. Chemokine/chemokine receptor pathway, adhesion molecules, and proteinases are crucial for bone metastatic process, including migration, adhesion and invasion into bone, angiogenesis and cell proliferation, which could provide potential targets for prevention and treatment of bone metastasis. Restoration of metastasis suppressor genes and microRNAs inhibits bone metastasis. Furthermore, targeting the bone marrow endothelium around cancer cells by use of both antiangiogenic inhibitors and vascular disrupting agents is another promising and valid therapeutic approach. On the other hand, many antitumor drugs/small molecules are limited in reaching tumor site due to a very complex vasculature. Nanotechnology aids in the targeted delivery of antitumor drugs/small molecules. For severe bone lesion, multifunctional implants integrating with antitumor drugs/small molecules and bone forming factors could be effective to reconstruct bone defects and to improve the quality of life in patients with bone metastasis.     

MicroRNAs在乳腺癌干细胞中的作用研究进展

乳腺癌干细胞（breast cancer stem cells,BCSCs）是导致乳腺癌发生、转移、耐药、复发等的重要原因。MicroRNAs（miRNAs）是近年来发现的一种非编码小分子RNA,可通过与靶标基因的3 '-非翻译区（3'-UTR）的完全或不完全配对,抑制靶标基因的翻译或降解靶标基因,从而发挥多种生物学功能。miRNAs在BCSCs中的异常表达可调控BCSCs的自我更新、抗凋亡、上皮间质转化（epithelial-mesenchymal transition,EMT）等生物学行为,从而促进乳腺癌的复发、转移。以miRNAs为研究靶点,为乳腺癌的诊断、预后及治疗提供了全新的思路。本文就近年来该方面的研究进展简要综述。     

乳腺癌干细胞及其临床应用

乳腺癌干细胞(BCSC)是乳腺癌细胞中一类具有自我更新能力和多向分化潜能的细胞.这类细胞具有高度的致瘤性和侵袭转移性,在乳腺癌的转移和复发以及放化疗抵抗中都起着重要作用.针对BCSC进行靶向治疗对提高乳腺癌疗效具有重要意义.