Therapeutic strategies targeting cancer stem cells

Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self‐renewal, and a multilineage differentiation potential. Cancer stem cells are responsible for the development of tumor cell heterogeneity, a key feature for resistance to anticancer treatments including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Furthermore, minimal residual disease, the major cause of cancer recurrence and metastasis, is enriched in CSCs. Cancer stem cells also possess the property of “robustness”, which encompasses several characteristics including a slow cell cycle, the ability to detoxify or mediate the efflux of cytotoxic agents, resistance to oxidative stress, and a rapid response to DNA damage, all of which contribute to the development of therapeutic resistance. The identification of mechanisms underlying such characteristics and the development of novel approaches to target them will be required for the therapeutic elimination of CSCs and the complete eradication of tumors. In this review, we focus on two prospective therapeutic approaches that target CSCs with the aim of disrupting their quiescence or redox defense capability.     

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.     

靶向miRNA的肿瘤干细胞治疗策略

肿瘤干细胞学说认为,肿瘤组织中存在一小部分具有无限增殖、自我更新、放化疗耐受以及高致瘤能力等干细胞特性的肿瘤干细胞(cancer stem cells,CSCs),它们是肿瘤无法治愈并不断进展的重要原因。微小RNA(microRNAs,miRNAs)是一类短链非编码RNA,通过降解mRNA或抑制mRNA翻译的方式调控着众多基因的表达。研究显示,miRNA在多种肿瘤的CSCs中异常表达,CSCs的恶性表型维持需要众多miRNA的参与。近年来,靶向miRNA的CSCs治疗实验研究已经初步展现出良好的安全性和疗效。针对miRNA的治疗策略将成为CSCs治疗的一个新的研究方向,最大限度地清除CSCs将使治愈肿瘤逐渐成为可能。     

Molecular identification and targeting of colorectal cancer stem cells

Tumor initiating or cancer stem cells (CSCs) are suggested to be responsible for tumor initiation and growth. Moreover, therapy resistance and minimal residual disease are thought to result from selective resistance of CSCs. Isolation of CSCs from colon carcinomas can be accomplished by selection of a subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer stemness, like CD133, CD44, CD24, CD29, CD166 and Lgr5. Identification of colon CSCs will lead to a better rational for new therapies that aim to target this fraction specifically. In this review, we analyze known markers used for selection of colon CSCs and their potential function in CSC biology. Moreover, we discuss potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies as well as to address more fundamental questions like the actual role of CSCs in tumor growth.     

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

Background

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are characterized by high self-renewal and multi-lineage differentiation capacities. CSCs are thought to play indispensable roles in the initiation, progression and metastasis of many types of cancer. Leukemias are thought to be initiated and maintained by a specific sub-type of CSC, the leukemia stem cell (LSC). An important feature of LSCs is their resistance to standard therapy, which may lead to relapse. Increasing efforts are aimed at developing novel therapeutic strategies that selectively target LSCs, while sparing their normal counterparts and, thus, minimizing adverse treatment-associated side-effects. These LSC targeting therapies aim to eradicate LSCs through affecting mechanisms that control their survival, self-renewal, differentiation, proliferation and cell cycle progression. Some LSC targeting therapies have already been proven successful in pre-clinical studies and they are now being tested in clinical studies, mainly in combination with conventional treatment regimens.

Conclusions

A growing body of evidence indicates that the selective targeting of LSCs represents a promising approach to improve disease outcome. Beyond doubt, the CSC hypothesis has added a new dimension to the area of anticancer research, thereby paving the way for shaping a new trend in cancer therapy.

     

Chemotherapy targeting cancer stem cells

Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cancer stem cell hypothesis inspired our search for a novel chemotherapy targeting cancer stem cells. In this review, we summarize cancer stem cell enrichment methods, the search for new efficient drugs, and the delivery of drugs targeting cancer stem cells. We also discuss cancer stem cell hierarchy complexity and the corresponding combination therapy for both cancer stem and non-stem cells. Learning from cancer stem cells may reveal novel strategies for chemotherapy in the future.     

以肿瘤干细胞为靶的免疫治疗

肿瘤干细胞(cancer stem cell,CSC)是肿瘤发生和转移的种子细胞,CSC具有自我更新、增殖和不完全分化的能力。CSC对化疗/放疗的抵抗以及免疫逃逸成为肿瘤复发的根源,要提高肿瘤治愈率必须彻底清除CSC。认识CSC的标记特征和"干性"调节关键分子才能有效和特异地攻击CSC。免疫治疗具有抗原识别的靶向性和时空效应性,是以CSC为靶的治疗的基础;以单克隆抗体和致敏的免疫细胞为主要治疗技术的免疫治疗清除CSC具有可实践性和挑战性。     

Heterogeneity and targeting of pancreatic cancer stem cells

Cancer stem cells (CSC) have been identified in an ever-increasing number of human malignancies on the basis of their ability to recapitulate tumors in the ectopic setting and maintain long-term tumorigenic potential. In addition, in pancreatic adenocarcinoma, CSCs may display additional properties, such as relative drug resistance and enhanced invasive and migratory potential that implicate a role in disease pathogenesis spanning initial tumor formation to metastatic disease progression. Importantly, these findings also indicate that the development of novel therapeutic strategies capable of inhibiting or eliminating CSCs will improve clinical outcomes. Preclinical studies have already described a wide array of potential approaches that target CSC-specific surface antigens and cellular pathways involved in cell survival, adhesion, self-renewal, and differentiation. Further, progress in this area should continue to move forward as the unique biology of CSCs is better understood. All preclinical studies to date have focused on targeting specific and phenotypically defined CSCs, but multiple cell populations with the ability to form tumors and self-renew have been identified in pancreatic carcinoma. As the clinical efficacy of CSC-directed therapies will depend on the inhibition of all sources of tumor self-renewal, better understanding of how specific CSC populations are related to one another and whether each possesses specific functional properties will be critical. In this CCR Focus article, we discuss the potential relationships between different pancreatic CSC populations and strategies to identify novel targeting approaches.     

Emerging role of Notch in stem cells and cancer

The Notch signaling pathway is known to be responsible for maintaining a balance between cell proliferation and death and, as such, plays important roles in the formation of many types of human tumors. Recently, Notch signaling pathway has been shown to control stem cell self-renewal and multi-potency. As many cancers are thought to be developed from a number of cancer stem-like cells, which are also known to be linked with the acquisition of epithelial-mesenchymal transition (EMT); and thus suggesting an expanding role of Notch signaling in human tumor progression.     

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。     

New therapeutics targeting colon cancer stem cells

The recent identification of tumor-initiating colorectal cancer (CRC) stem cells in the pathogenesis of CRC has provided a potential target for novel therapeutics. Many details about CRC stem cells, however, remain poorly understood. Several potential markers of CRC stem cells have been proposed, including CD133, CD44, and, recently, Lgr5. Attention also has been drawn to control of stem cell self-renewal, proliferation, and differentiation by the Wnt and transforming growth factor (TGF)-β pathways. Disruption of Wnt signaling, via loss of APC (adenomatous polyposis coli), is among the earliest events in the multistage progression of CRC and likely occurs in basal crypt stem cells, generating a neoplastic cell population that then expands upward to occupy the rest of the crypt. TGF-β signaling is a key tumor suppressor pathway, and mutations in the type II receptor and Smad4 are observed in CRC specimens and are associated with more aggressive disease in tumors with disrupted Wnt signaling. Loss of the TGF-β adaptor protein β₂-spectrin is associated with loss of colonic cell polarity and architecture, and its expression parallels that of Smad4. This review suggests rational approaches to target CRC stem cells as a novel and effective way to treat advanced and difficult-to-treat CRC.     

Breast cancer chemoresistance: Emerging importance of cancer stem cells

Cancer stem cells (CSCs) have recently been documented in solid tumours. Evidence has suggested that CSCs are involved in carcinogenesis, tumour invasion and metastases, and resistance to various forms of therapies, including chemotherapy. Breast CSCs are characterised by the expression of CD44 but lack of CD24 (CD44⁺/CD24^? cells). The mechanisms involved in chemoresistance of breast CSCs are complex and not clearly defined. Overexpression of ABC transporters, detoxification enzymes (aldehyde dehydrogenase), low cell turn over rate and the ability to activate the DNA check point response are possibly all involved. Innovative therapies, based on a better understanding of CSCs, should lead to enhanced and long-term cure rates in breast cancer.     

Immune therapeutic targeting of glioma cancer stem cells

Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to radiotherapy and chemotherapy. Glioma cancer stem cells (gCSCs) have been shown to recapitulate the characteristic features of GBM and to mediate chemotherapy and radiation resistance. Immunotherapeutic targeting of this cell population holds therapeutic promise but must be considered in the context of the immunosuppressive properties mediated by the gCSC. Recent findings have indicated that this goal will be challenging because the gCSC can suppress both the innate and adaptive immune systems by a variety of gCSC-secreted products and cell-membrane interactions. In this review article, we will attempt to reconcile the disparate research findings regarding the potential of immune targeting of the gCSC and propose several novel solutions.     

乳腺癌干细胞的分选鉴定

乳腺癌干细胞是一群未分化,具有自我更新、多向分化潜能的细胞。化疗及放疗抵抗性、缺氧耐受性、高致瘤性、高侵袭转移性是这群细胞的特征,成为乳腺癌难以根除、日后复发的一个重要原因。因此正确分选鉴定乳腺癌干细胞是乳腺癌干细胞研究的关键。本文简要介绍了侧群细胞分选技术、细胞表面分子标记的筛选技术、ALDEFLUOR分析法、原位检测法等乳腺癌干细胞分选技术和体外细胞的微球体培养法、有限稀释法及体内动物模型等鉴定技术的研究进展,为后续相关研究提供重要的参考方法,从而探索治疗乳腺癌的新方法。     

Pancreatic cancer stem cells: Emerging target for designing novel therapy

In the past few years, there have been significant advances in the research on cancer stem cells (CSCs). The emerging evidences have demonstrated that CSCs and epithelial–mesenchymal transition (EMT)-type cells, which share molecular characteristics with CSCs, play critical roles in drug resistance, invasion, and metastasis. Pancreatic cancer (PC) has a high mortality due to both intrinsic (de novo) and extrinsic (acquired) drug resistance, leading to increased invasive and metastatic potential of PC cells. Therefore, targeting pancreatic CSCs and EMT-type cells could be a novel therapeutic strategy for the treatment of PC. In this article, we will review the current state of our knowledge on the role of pancreatic CSCs and EMT-type cells, and summarize the novel therapeutic strategies that could target pancreatic CSCs and EMT-type cells, leading to the reversal of EMT phenotype, the induction of drug sensitivity, and the inhibition of invasion and metastasis of PC, which is expected to yield better treatment outcome.     

Emerging nanomedical strategies for direct targeting of pediatric and adult diffuse gliomas

High-grade gliomas, in particularly diffuse midline glioma, H3K27-altered in children and glioblastoma in adults, are the most lethal brain tumour with a dismal prognosis. Developments in modern medicine are constantly being applied in the search for a cure, although finding the right strategy remains elusive. Circumventing the blood–brain barrier is one of the biggest challenges when it comes to treating brain tumours. The cat and mouse game of finding the Trojan horse to traverse this barrier and deliver therapeutics to the brain has been a long and hard-fought struggle. Research is ongoing to find new and feasible ways to reach specific targets in the brain, with a special focus on inoperable or recurring brain tumours. Many options and combinations of options have been tested to date and continue to be so in the search to find the most effective and least toxic treatment paradigm. Although improvements are often small and slow, some of these strategies have already shown promise, shining a light of hope that finding the cure is feasible. In this review, we discuss recent findings that elucidate promising but atypical strategies for targeting gliomas and the implications that this work has on developing new treatment regimens. Subject terms: CNS cancer, Targeted therapies     

ALDH1与干细胞和肿瘤干细胞的分选鉴定

乙醛脱氢酶1( aldehyde dehydrogenase 1,ALDH1)是一种可以将醛类氧化为乙酸的胞质溶酶,其在胚胎干细胞和成体干细胞中表达增高,对维持干细胞( stem cell,SC)的“干性”中起着重要作用.近年发现,ALDH1在肿瘤干细胞(cancer stem cell,CSC)中表达也升高.基于AL...     

Therapeutic strategies to eliminate breast cancer stem cells

Recent studies have identified markers that can be used to prospectively identify cells with a tumor-initiating phenotype when transplanted into the cleared fat pads of immunocompromised mice. The technical capability to identify cells that meet the functional criteria of putative cancer stem cells has led to investigations of their biological importance and an expanding interest in developing therapeutic strategies to target the stem cell population. It is believed that strategies targeting cancer stem cells may complement traditional therapies, which are effective at eliminating the rapidly proliferating differentiated population but less effective at treating the cancer stem cell populations, which may then seed metastasis or local recurrence. This article reviews potential targets and targeting strategies for selective cancer stem cell therapies.