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.     

Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer

Previously regarded as simple fat storage particles, new evidence suggests that lipid droplets (LDs) are dynamic and functional organelles involved in key cellular processes such as membrane biosynthesis, lipid metabolism, cell signalling and inflammation. Indeed, an increased LD content is one of the most apparent features resulting from lipid metabolism reprogramming necessary to support the basic functions of cancer cells. LDs have been associated to different cellular processes involved in cancer progression and aggressiveness, such as tumorigenicity, invasion and metastasis, as well as chemoresistance. Interestingly, all of these processes are controlled by a subpopulation of highly aggressive tumoral cells named cancer stem cells (CSCs), suggesting that LDs may be fundamental elements for stemness in cancer. Considering the key role of CSCs on chemoresistance and disease relapse, main factors of therapy failure, the design of novel therapeutic approaches targeting these cells may be the only chance for long-term survival in cancer patients. In this sense, their biology and functional properties render LDs excellent candidates for target discovery and design of combined therapeutic strategies. In this review, we summarise the current knowledge identifying LDs and CSCs as main contributors to cancer aggressiveness, metastasis and chemoresistance.     

肿瘤干细胞表面标志物及主要信号通路

肿瘤干细胞是存在于肿瘤组织中的具有自我更新、增殖、分化的部分细胞群,对肿瘤的发生、发展有十分重要的作用. 肿瘤干细胞特异的表面分子及其异常活化的信号通路,是其区别于其他肿瘤细胞的特性.寻找和鉴定特异的肿瘤干细胞的表面标志物,从而识别肿瘤组织中的肿瘤干细胞,并进行相关信号调控机制研究,是肿瘤早期诊断及肿瘤干细胞靶向治疗的关键. 本文简要概述了肿瘤干细胞相关的表面标志物及信号通路的研究进展,旨在为进一步开展针对肿瘤干细胞的抗体靶向治疗提供新思路.     

Thoughts about cancer stem cells in solid tumors

Cancer chemotherapy efficacy is frequently impaired by either intrinsic or acquired tumor resistance.A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells.In recent years,the cancer stem cell(CSC) theory has changed the classical view of tumor growth and therefore the therapeutic perspective.Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers.On the other hand,the identification of CSCs in vivo and in vitro relies on specific surface markers that should allow the sorting cancer cells into phenotypically distinct subpopulations.In the present review,recent papers published on CSCs in solid tumors(breast,prostate,brain and melanoma) are discussed,highlighting critical points such as the choice of markers to sort CSCs and mouse models to demonstrate that CSCs are able to replicate the original tumor.A discussion of the possible role of aldehyde dehydrogenase and CXCR6 biomarkers as signaling molecules in CSCs and normal stem cells is also discussed.The author believes that efforts have to be made to investigate the functional and biological properties of putative CSCs in cancer.Developing diagnostic/prognostic tools to follow cancer development is also a challenge.In this connection it would be useful to develop a multidisciplinary approach combining mathematics,physics and biology which merges experimental approaches and theory.Biological models alone are probably unable to resolve the problem completely.     

Cancer stem cell markers as potential targets for epithelial cancers

In recent years, the role of tumor-initiating cells (popularly known as cancer stem cells) in tumor development and availability of novel cancer stem cell/tumor initiating cell markers promises a new arena in understanding their role in developing novel targeted molecules. It is important to identify and understand the relevance of cancer stem cells (CSC)/tumor initiating cells (TIC) in tumor development and to design appropriate strategies for CSCs and TICs elimination, which is crucial to future cancer prevention and treatment. In this review, we attempt to define various potential markers of cancer stem cells and potential exploration as therapeutic targets for epithelial cancer prevention and treatment.     

Enrichment for Chemoresistant Ovarian Cancer Stem Cells from Human Cell Lines

Cancer stem cells (CSCs) are defined as a subset of slow cycling and undifferentiated cells that divide asymmetrically to generate highly proliferative, invasive, and chemoresistant tumor cells. Therefore, CSCs are an attractive population of cells to target therapeutically. CSCs are predicted to contribute to a number of types of malignancies including those in the blood, brain, lung, gastrointestinal tract, prostate, and ovary. Isolating and enriching a tumor cell population for CSCs will enable researchers to study the properties, genetics, and therapeutic response of CSCs. We generated a protocol that reproducibly enriches for ovarian cancer CSCs from ovarian cancer cell lines (SKOV3 and OVCA429). Cell lines are treated with 20 µM cisplatin for 3 days. Surviving cells are isolated and cultured in a serum-free stem cell media containing cytokines and growth factors. We demonstrate an enrichment of these purified CSCs by analyzing the isolated cells for known stem cell markers Oct4, Nanog, and Prom1 (CD133) and cell surface expression of CD177 and CD133. The CSCs exhibit increased chemoresistance. This method for isolation of CSCs is a useful tool for studying the role of CSCs in chemoresistance and tumor relapse.     

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.     

Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.     

Cancer stem cell impact on clinical oncology

Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo-and radio-resistance. Several mechanisms have been studied to explain chemo-and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells(CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.     

The role of NUMB/NUMB isoforms in cancer stem cells

Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs.     

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.     

An overview of the role of cancer stem cells in spine tumors with a special focus on chordoma简

Primary malignant tumors of the spine are relatively rare, less than 5% of all spinal column tumors. However, these lesions are often among the most difficult to treat and encompass challenging pathologies such as chordoma and a variety of invasive sarcomas. The mechanisms of tumor recurrence after surgical intervention, as well as resistance to radiation and chemotherapy, remain a pervasive and costly problem. Recent evidence has emerged supporting the hypothesis that solid tumors contain a sub-population of cancer cells that possess characteristics normally associated with stem cells. Particularly, the potential for long-term proliferation appears to be restricted to subpopulations of cancer stem cells (CSCs) functionally defined by their capacity to self-renew and give rise to differentiated cells that phenotypically recapitulate the original tumor, thereby causing relapse and patient death. These cancer stem cells present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. The general objective of the current study is to discuss the fundamental concepts for understanding the role of CSCs with respect to chemoresistance, radioresistance, special cell surface markers, cancer recurrence and metastasis in tumors of the osseous spine. This discussion is followed by a specific review of what is known about the role of CSCs in chordoma, the most common primary malignant osseous tumor of the spine.     

Coaction of spheroid-derived stem-like cells and endothelial progenitor cells promotes development of colon cancer

Although some studies described the characteristics of colon cancer stem cells (CSCs) and the role of endothelial progenitor cells (EPCs) in neovascularization, it is still controversial whether an interaction exists or not between CSCs and EPCs. In the present study, HCT116 and HT29 sphere models, which are known to be the cells enriching CSCs, were established to investigate the roles of this interaction in development and metastasis of colon cancer. Compared with their parental counterparts, spheroid cells demonstrated higher capacity of invasion, higher tumorigenic and metastatic potential. Then the in vitro and in vivo relationship between CSCs and EPCs were studied by using capillary tube formation assay and xenograft models. Our results showed that spheroid cells could promote the proliferation, migration and tube formation of EPCs through secretion of vascular endothelial growth factor (VEGF). Meanwhile, the EPCs could increase tumorigenic capacity of spheroid cells through angiogenesis. Furthermore, higher microvessel density was detected in the area enriching cancer stem cells in human colon cancer tissue. Our findings indicate that spheroid cells possess the characteristics of cancer stem cells, and the coaction of CSCs and EPCs may play an important role in the development of colon cancer.     

The roles of Linc-ROR in the regulation of cancer stem cells

Cancer stem cells (CSCs) are considered to be a kind of tumor cell population characterized by self-renewal, easy to metastasize and drug resistance, which play an indispensable role in the occurrence, development, metastasis and drug resistance of tumors, and their existence is an important reason for high metastasis and recurrence of tumors. Long non-coding RNAs (LncRNAs), which are more than 200 nucleotides in length, have a close relationship with the malignant progression of cancer.In recent years, abundant studies have reavling that LncRNAs are beneficial to the regulation of various cancer stem cells. Linc-ROR, as a newly discovered intergenic non-protein-coding RNA in recent years, is considered to be a key regulator affecting the development of human tumors. Dysregulation of Linc-ROR is related to stemness phenotype and functional regulation of cancer stem cells. For that, Linc-ROR has the potential to be used as a diagnostic biomarker for cancer patients and can serve as a clinically meaningful potential therapeutic target. In this review, we generalize the existing research results on the important role of Linc-ROR in regulation of CSCs.     

Emerging role of exosome signalling in maintaining cancer stem cell dynamic equilibrium

Cancer stem cells (CSCs) are a small subset of heterogeneous cells existed in tumour tissues or cancer cell lines with self‐renewal and differentiation potentials. CSCs were considered to be responsible for the failure of conventional therapy and tumour recurrence. However, CSCs are not a static cell population, CSCs and non‐CSCs are maintained in dynamic interconversion state by their self‐differentiation and dedifferentiation. Therefore, targeting CSCs for cancer therapy is still not enough,exploring the mechanism of dynamic interconversion between CSCs and non‐CSCs and blocking the interconversion seems to be imperative. Exosomes are 30‐100 nm size in diameter extracellular vesicles (EVs) secreted by multiple living cells into the extracellular space. They contain cell‐state‐specific bioactive materials, including DNA, mRNA, ncRNA, proteins, lipids, etc. with their specific surface markers, such as, CD63, CD81, Alix, Tsg101, etc. Exosomes have been considered as information carriers in cell communication between cancer cells and non‐cancer cells, which affect gene expressions and cellular signalling pathways of recipient cells by delivering their contents. Now that exosomes acted as information carriers, whether they played role in maintaining dynamic equilibrium state between CSCs and non‐CSCs and their mechanism of activity are unknown. This review summarized the current research advance of exosomes’ role in maintaining CSC dynamic interconversion state and their possible mechanism of action, which will provide a better understanding the contribution of exosomes to dedifferentiation and stemness acquisition of non‐CSCs, and highlight that exosomes might be taken as the attractive target approaches for cancer therapeutics.     

An overview of the role of cancer stem cells in spine tumors with a special focus on chordoma

Primary malignant tumors of the spine are relatively rare, less than 5% of all spinal column tumors. However, these lesions are often among the most difficult to treat and encompass challenging pathologies such as chordoma and a variety of invasive sarcomas. The mechanisms of tumor recurrence after surgical intervention, as well as resistance to radiation and chemotherapy, remain a pervasive and costly problem. Recent evidence has emerged supporting the hypothesis that solid tumors contain a sub-population of cancer cells that possess characteristics normally associated with stem cells. Particularly, the potential for long-term proliferation appears to be restricted to subpopulations of cancer stem cells(CSCs) functionally defined by their capacity to self-renew and give rise to differentiated cells that phenotypically recapitulate the original tumor, thereby causing relapse and patient death. These cancer stem cells present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. The general objective of the current study is to discuss the fundamental concepts for understanding the role of CSCs with respect to chemoresistance, radioresistance, special cell surface markers, cancer recurrence and metastasis intumors of the osseous spine. This discussion is followed by a specific review of what is known about the role of CSCs in chordoma, the most common primary malignant osseous tumor of the spine.     

Tracing and targeting cancer stem cells: New venture for personalized molecular cancer therapy

Tumors consist of a mixture of heterogeneous cell types. Cancer stem cells(CSCs) are a minor sub-population within the bulk cancer fraction which has been foundto reconstitute and propagate the disease and to be frequently resistant to chemotherapy, irradiation, cytotoxic drugs and probably also against immune attack. CSCs are considered as the seeds of tumor recurrence, driving force of tumorigenesis and metastases. This underlines the urgent need for innovative methods to identify and target CSCs. However, the role and existence of CSCs in therapy resistance and cancer recurrence remains a topic of intense debate. The underlying biological properties of the tumor stem cells are extremely dependent on numerous signals, and the targeted inhibition of these stem cell signaling pathways is one of the promising approaches of the new antitumor therapy approaches. This perspective review article summarizes the novel methods of tracing CSCs and discusses the hallmarks of CSC identification influenced by the microenvironment or by having imperfect detection markers. In addition, explains the known molecular mechanisms of therapy resistance in CSCs as reliable and clinically predictive markers that could enable the use of new targeted antitumor therapy in the sense of personalized medicine.     

Designing precision medicine panels for drug refractory cancers targeting cancer stemness traits

Cancer is one amongst the major causes of death today and cancer biology is one of the most well researched fields in medicine. The driving force behind cancer is considered to be a minor subpopulation of cells, the cancer stem cells (CSCs). Similar to other stem cells, these cells are self-renewing and proliferating but CSCs are also difficult to target by chemo- or radio-therapies. Cancer stem cells are known to be present in most of the cancer subgroups such as carcinoma, sarcoma, myeloma, leukemia, lymphomas and mixed cancer types. There is a wide gamut of factors attributed to the stemness of cancers, ranging from dysregulated signaling pathways, and activation of enzymes aiding immune evasion, to conducive tumor microenvironment, to name a few. The defining outcome of the increased presence of CSCs is tumor metastasis and relapse. Predictive medicine approach based on the plethora of CSC markers would be a move towards precision medicine to specifically identify CSC-rich tumors. In this review, we discuss the cancer subtypes and the role of different CSC specific markers in these varying subtypes. We also categorize the CSC markers based their defining trait contributing to stemness. This review thus provides a comprehensive approach to catalogue a predictive set of markers to identify the resistant and refractory cancer stem cell population within different tumor subtypes, so as to facilitate better prognosis and targeted therapeutic strategies.     

Cancer stem cell, niche and EGFR decide tumor development and treatment response: A bio-computational simulation study

Recent research in cancer biology has suggested the hypothesis that tumors are initiated and driven by a small group of cancer stem cells (CSCs). Furthermore, cancer stem cell niches have been found to be essential in determining fates of CSCs, and several signaling pathways have been proven to play a crucial role in cellular behavior, which could be two important factors in cancer development. To better understand the progression, heterogeneity and treatment response of breast cancer, especially in the context of CSCs, we propose a mathematical model based on the cell compartment method. In this model, three compartments of cellular subpopulations are constructed: CSCs, progenitor cells (PCs), and terminal differentiated cells (TCs). Moreover, (1) the cancer stem cell niche is, considered by modeling its effect on division patterns (symmetric or asymmetric) of CSCs, and (2) the EGFR signaling pathway is integrated by modeling its role in cell proliferation, apoptosis. Our simulation results indicate that (1) a higher probability for symmetric division of CSC may result in a faster expansion of tumor population, and for a larger number of niches, the tumor grows at a slower rate, but the final tumor volume is larger; (2) higher EGFR expression correlates to tumors with larger volumes while a saturation function is observed, and (3) treatments that inhibit tyrosine kinase activity of EGFR may not only repress the tumor volume, but also decrease the CSCs percentages by shifting CSCs from symmetric divisions to asymmetric divisions. These findings suggest that therapies should be designed to effectively control or eliminate the symmetric division of CSCs and to reduce or destroy the CSC niches.     

The role of cancer stem cells in cancer metastasis: New perspective and progress

Recent studies have identified the important role of cancer stem cells (CSCs) in carcinogenesis and relapse. However, with respect to multistage cancer metastasis, the role of CSCs has not been well-defined. In several human cancers, data showed that some phenotypic subsets of CSCs were responsible for cancer metastasis. In this review, we surveyed recent advances in the role and mechanism of metastatic CSCs.