Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma

Cancer stem cells (CSCs) represent a subpopulation of tumor cells endowed with self-renewal capacity and are considered as an underlying cause of tumor recurrence and metastasis. The metabolic signatures of CSCs and the mechanisms involved in the regulation of their stem cell-like properties still remain elusive. We utilized nasopharyngeal carcinoma (NPC) CSCs as a model to dissect their metabolic signatures and found that CSCs underwent metabolic shift and mitochondrial resetting distinguished from their differentiated counterparts. In metabolic shift, CSCs showed a greater reliance on glycolysis for energy supply compared with the parental cells. In mitochondrial resetting, the quantity and function of mitochondria of CSCs were modulated by the biogenesis of the organelles, and the round-shaped mitochondria were distributed in a peri-nuclear manner similar to those seen in the stem cells. In addition, we blocked the glycolytic pathway, increased the ROS levels, and depolarized mitochondrial membranes of CSCs, respectively, and examined the effects of these metabolic factors on CSC properties. Intriguingly, the properties of CSCs were curbed when we redirected the quintessential metabolic reprogramming, which indicates that the plasticity of energy metabolism regulated the balance between acquisition and loss of the stemness status. Taken together, we suggest that metabolic reprogramming is critical for CSCs to sustain self-renewal, deter from differentiation and enhance the antioxidant defense mechanism. Characterization of metabolic reprogramming governing CSC properties is paramount to the design of novel therapeutic strategies through metabolic intervention of CSCs.     

Abnormal lipid synthesis as a therapeutic target for cancer stem cells

Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.     

Energy metabolism in cancer stem cells

Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.     

Unraveling the journey of cancer stem cells from origin to metastasis

Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs.     

综述: 肿瘤干细胞微环境与靶向干预策略

肿瘤干细胞具有自我更新和可塑性的潜能,能够维持肿瘤生长和异质性的能力．肿瘤干细胞是肿瘤产生、转移、耐药和复发的根源,肿瘤干细胞学说逐渐被肿瘤研究者所接受,因此,对肿瘤干细胞的深入理解有重大的科学和临床意义．肿瘤干细胞的微环境是肿瘤微环境的组成部分,包括细胞-细胞接触、分泌型因子等．肿瘤非干细胞和肿瘤干细胞本身都可以作为肿瘤干细胞的微环境．肿瘤干细胞的微环境可以维持肿瘤干细胞的可塑性,保护肿瘤干细胞免受免疫系统攻击,也可以促进其转移．肿瘤干细胞对其微环境的塑造、肿瘤干细胞的微环境对肿瘤干细胞自我更新的影响,以及针对肿瘤干细胞微环境的靶向干预等问题,已成为肿瘤干细胞研究的前沿问题．本文就肿瘤干细胞的发现、自我更新维持机制、肿瘤干细胞的微环境,及其肿瘤干细胞及微环境的干预策略等研究进展进行了综述．     

线粒体与多潜能干细胞功能

线粒体是细胞内重要的细胞器,主要功能是通过氧化磷酸化为细胞生命活动提供能量。近年来,研究表明,在多潜能干细胞（Pluripotent stem cells, PSCs）中线粒体表现出独有的特征,即在多能性状态下,PSCs主要依靠糖酵解提供能量,其分化期间线粒体氧化磷酸化代谢能力逐渐增强。相反,体细胞重编程为多潜能干细胞期间,线粒体氧化磷酸化向糖酵解途径的转变是其成功重编程必需的代谢过程。另外,线粒体通过生物合成和形态结构的动态重塑维持了PSCs多能性、诱导分化及诱导多能干细胞（Induced pluripotent stem cells, iPSCs）的重编程。因此,本文综述了PSCs线粒体形态结构及其在调控PSCs多能性、合成代谢、氧化还原状态的平衡、分化及重新编程中的作用,为深入了解线粒体调控PSCs功能的作用提供理论基础。     

Mitochondria as therapeutic targets for cancer stem cells

Cancer stem cells(CSCs) are maintained by theirsomatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondriatargeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer-specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondriatargeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer.     

Hypoxia-resistant profile implies vulnerability of cancer stem cells to physiological agents,which suggests new therapeutic targets

We have previously shown that peculiar metabolic features of cell adaptation and survival in hypoxia imply growth restriction points that are typical of embryonic stem cells and disappear with differentiation. Here we provide evidence that such restrictions can be exploited as specific antiblastic targets by physiological factors such as pyruvate, tetrahydrofolate, and glutamine. These metabolites act as powerful cytotoxic agents on cancer stem cells (CSCs) when supplied at doses that perturb the biochemical network, sustaining the resumption of aerobic growth after the hypoxic dormant state. Experiments were performed in vivo and in vitro using CSCs obtained from various anaplastic tumors: human melanoma, leukemia, and rat hepatoma cells. Pretreatment of melanoma CSCs with pyruvate significantly reduces their self-renewal in vitro and tumorigenicity in vivo. The metabolic network underlying the cytotoxic effect of the physiological factors was thoroughly defined, principally using AH130 hepatoma, a tumor spontaneously reprogrammed to the embryonic stem stage. This network, based on a tight integration of aerobic glycolysis, cellular redox state, and folate metabolism, is centered on the cellular NADP/NADPH ratio that controls the redox pathway of folate utilization in purine synthesis. On the whole, this study indicates that pyruvate, FH₄, and glutamine display anticancer activity, because CSCs are committed to survive and maintain their stemness in hypoxia. When CSC need to differentiate and proliferate, they shift from anaerobic to aerobic status, and the few mitochondria available makes them susceptible to the injury of the above physiological factors. This vulnerability might be exploited for novel therapeutic treatments.     

Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy

Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.     

Epigenetics of cancer stem cells: Pathways and therapeutics

BackgroundEpigenetic alterations including DNA methylation and histone modifications are the key factors in the differentiation of stem cells into different tissue subtypes. The generation of cancer stem cells (CSCs) in the process of carcinogenesis may also involve similar kind of epigenetic reprogramming where, in contrast, it leads to the loss of expression of genes specific to the differentiated state and regaining of stem cell-specific characteristics. The most important predicament with treatment of cancers includes the non-responsive quiescent CSC.Scope of reviewThe distinctive capabilities of the CSCs make cancer treatment even more difficult as this population of cells tends to remain quiescent for longer intervals and then gets reactivated leading to tumor relapse. Therefore, the current review is aimed to focus on recent advances in understanding the relation of epigenetic reprogramming to the generation, self-renewal and proliferation of CSCs.Major conclusionCSC-targeted therapeutic approaches would improve the chances of patient survival by reducing the frequency of tumor relapse. Differentiation therapy is an emerging therapeutic approach in which the CSCs are induced to differentiate from their quiescent state to a mature differentiated form, through activation of differentiation-related signalling pathways, miRNA-mediated alteration and epigenetic differentiation therapy. Thus, understanding the origin of CSC and their epigenetic regulation is crucial to develop treatment strategy against not only for the heterogeneous population of cancer cells but also to CSCs.General significanceCharacterizing the epigenetic marks of CSCs and the associated signalling cascades might help in developing therapeutic strategies against chemo-resistant cancers.     

Overlapping Genes May Control Reprogramming of Mouse Somatic Cells into Induced Pluripotent Stem Cells (iPSCs) and Breast Cancer Stem Cells

Recent findings suggest the possibility that tumors originate from cancer cells with stem cell properties. The cancer stem cell (CSC) hypothesis provides an explanation for why existing cancer therapies often fail in eradicating highly malignant tumors and end with tumor recurrence. Although normal stem cells and CSCs both share the capacity for self-renewal and multi-lineage differentiation, suggesting that CSC may be derived from normal SCs, the cellular origin of transformation of CSCs is debatable. Research suggests that the tightly controlled balance of self-renewal and differentiation that characterizes normal stem cell function is dis-regulated in cancer. Additionally, recent evidence has linked an embryonic stem cell (ESC)-like gene signature with poorly differentiated high-grade tumors, suggesting that regulatory pathways controlling pluripotency may in part contribute to the somatic CSC phenotype. Here, we introduce expression profile bioinformatic analyses of mouse breast cells with CSC properties, mouse embryonic stem (mES) and induced pluripotent stem (iPS) cells with an emphasis on how study of pluripotent stem cells may contribute to the identification of genes and pathways that facilitate events associated with oncogenesis. Global gene expression analysis from CSCs and induced pluripotent stem cell lines represent an ideal model to study cancer initiation and progression and provide insight into the origin cancer stem cells. Additionally, insight into the genetic and epigenomic mechanisms regulating the balance between self-renewal and differentiation of somatic stem cells and cancer may help to determine whether different strategies used to generate iPSCs are potentially safe for therapeutic use.     

Mitochondrial metabolism in cancer stem cells: a therapeutic target for colon cancer

It has been proposed that the selective elimination of cancer stem cells (CSCs) using targeted therapy could greatly reduce tumor growth, recurrence, and metastasis. To develop effective therapeutic targets for CSC elimination, we aimed to define the properties of CSC mitochondria, and identify CSC-mitochondria-specific targets in colon cancer. We found that colon CSCs utilize mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. We also found that forkhead box protein 1 (FOXM1)-induced peroxiredoxin 3 (PRDX3) maintains the mitochondrial function, and the FOXM1/PRDX3 mitochondrial pathway maintains survival of colon CSCs. Furthermore, FOXM1 induces CD133 (PROM1/prominin 1) expression, which maintains the stemness of colon CSCs. Together, our findings indicate that FOXM1, PRDX3, and CD133 are potential therapeutic targets for the elimination of CSCs in colon cancer. [BMB Reports 2015; 48(10): 539-540]     

The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells

Cancer stem cells (CSCs) are proposed to drive tumor initiation and progression. Yet, our understanding of the cellular and molecular mechanisms that underlie CSC properties is limited. Here we show that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast CSCs. TAZ protein levels and activity are elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value. Gain of TAZ endows self-renewal capacity to non-CSCs. In epithelial cells, TAZ forms a complex with the cell-polarity determinant Scribble, and loss of Scribble--or induction of the epithelial-mesenchymal transition (EMT)--disrupts the inhibitory association of TAZ with the core Hippo kinases MST and LATS. This study links the CSC concept to the Hippo pathway in breast cancer and reveals a mechanistic basis of the control of Hippo kinases by cell polarity.     

Nonadhesive culture system as a model of rapid sphere formation with cancer stem cell properties

Background

Cancer stem cells (CSCs) play an important role in tumor initiation, progression, and metastasis and are responsible for high therapeutic failure rates. Identification and characterization of CSC are crucial for facilitating the monitoring, therapy, or prevention of cancer. Great efforts have been paid to develop a more effective methodology. Nevertheless, the ideal model for CSC research is still evolving. In this study, we created a nonadhesive culture system to enrich CSCs from human oral squamous cell carcinoma cell lines with sphere formation and to characterize their CSC properties further.

Methods

A nonadhesive culture system was designed to generate spheres from the SAS and OECM-1 cell lines. A subsequent investigation of their CSC properties, including stemness, self-renewal, and chemo- and radioresistance in vitro, as well as tumor initiation capacity in vivo, was also performed.

Results

Spheres were formed cost-effectively and time-efficiently within 5 to 7 days. Moreover, we proved that these spheres expressed putative stem cell markers and exhibited chemoradiotherapeutic resistance, in addition to tumor-initiating and self-renewal capabilities.

Conclusions

Using this nonadhesive culture system, we successfully established a rapid and cost-effective model that exhibits the characteristics of CSCs and can be used in cancer research.     

Cancer stem cells and angiogenesis

Cancer stem cells (CSCs) or tumor initiating cells were identified and characterized as a unique subpopulation with stem cell features in many types of cancer. Current CSC studies provide novel insights regarding tumor initiation, progression, angiogenesis, resistance to therapy and interplay with the tumor micro-environment. A cancer stem cell niche has been proposed based on these findings. The niche provides the soil for CSC self-renewal and maintenance, stimulating essential signaling pathways in CSCs and leading to secretion of factors that promote angiogenesis and long term growth of CSCs. We present evidence which has emerged over the past 5 years indicating interaction of CSCs with angiogenesis in the proposed "vascular niche". Based on these findings, targeting the "cancer stem cell niche" by combining an individualized anti-CSC approach with treatment of their microenvironment may represent a novel therapeutic strategy against solid tumor systems.     

A model of cancer stem cells derived from mouse induced pluripotent stem cells

Cancer stem cells (CSCs) are capable of continuous proliferation and self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. CSCs are considered derived from normal stem cells affected by the tumor microenvironment although the mechanism of development is not clear yet. In 2007, Yamanaka's group succeeded in generating Nanog mouse induced pluripotent stem (miPS) cells, in which green fluorescent protein (GFP) has been inserted into the 5'-untranslated region of the Nanog gene. Usually, iPS cells, just like embryonic stem cells, are considered to be induced into progenitor cells, which differentiate into various normal phenotypes depending on the normal niche. We hypothesized that CSCs could be derived from Nanog miPS cells in the conditioned culture medium of cancer cell lines, which is a mimic of carcinoma microenvironment. As a result, the Nanog miPS cells treated with the conditioned medium of mouse Lewis lung carcinoma acquired characteristics of CSCs, in that they formed spheroids expressing GFP in suspension culture, and had a high tumorigenicity in Balb/c nude mice exhibiting angiogenesis in vivo. In addition, these iPS-derived CSCs had a capacity of self-renewal and expressed the marker genes, Nanog, Rex1, Eras, Esg1 and Cripto, associated with stem cell properties and an undifferentiated state. Thus we concluded that a model of CSCs was originally developed from miPS cells and proposed the conditioned culture medium of cancer cell lines might perform as niche for producing CSCs. The model of CSCs and the procedure of their establishment will help study the genetic alterations and the secreted factors in the tumor microenvironment which convert miPS cells to CSCs. Furthermore, the identification of potentially bona fide markers of CSCs, which will help the development of novel anti-cancer therapies, might be possible though the CSC model.     

Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients

Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including ASCL2 and LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue.     

Ubiquitin ligase CHIP suppresses cancer stem cell properties in a population of breast cancer cells

Cancer stem cells (CSCs) have several distinctive characteristics, including high metastatic potential, tumor-initiating potential, and properties that resemble normal stem cells such as self-renewal, differentiation, and drug efflux. Because of these characteristics, CSC is regarded to be responsible for cancer progression and patient prognosis. In our previous study, we showed that a ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein (CHIP) suppressed breast cancer malignancy. Moreover, a recent clinical study reported that CHIP expression levels were associated with favorable prognostic parameters of patients with breast cancer. Here we show that CHIP suppresses CSC properties in a population of breast cancer cells. CHIP depletion resulted in an increased proportion of CSCs among breast cancers when using several assays to assess CSC properties. From our results, we propose that inhibition of CSC properties may be one of the functions of CHIP as a suppressor of cancer progression.