Advances in Biochemistry and Biotechnology (ISSN: 2574-7258)

Article / review article

"Cancer Stem Cells: An Overview"

Radhika Manukonda, Varsha Prabhu, Revu VL Narayana, Geeta K Vemuganti*

School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India

*Corresponding author: Geeta K Vemuganti, School of Medical Sciences, University of Hyderabad, Prof.C.R.Rao Road, Gachibowli, 500 046, Hyderabad, India

Received Date: 21 January, 2020; Accepted Date: 10 February, 2020; Published Date: 14 February, 2020

Abstract

Cancer Stem Cells (CSCs) are drug-refractory subgroup of cells within a tumor having proliferative autonomy, differentiation potential, and can recapitulate the primary tumor heterogeneity after transplanting into an immunocompromised host. The intra-tumor heterogeneity caused by these immortal cells poses a challenge for cancer therapy. Understanding the genetic and epigenetic anomalies, and multifaceted mechanisms involved in immune evasion, cellular plasticity, role of extracellular vesicle cargo in the crosstalk between tumor niche and CSCs, would facilitate designing novel therapeutic strategies that exclusively target this quiescent and metabolically distinct subgroup from the heterogeneous tumors. This review summarizes models for tumor heterogeneity, effectors for cellular plasticity, CSC characteristics responsible for therapeutic refractoriness, isolation and novel approaches for targeting this subgroup from rest of the tumor for improving patient’s survival.

Keywords

Cancer stem cells; Cellular plasticity; Therapeutic refractoriness; Tumor heterogeneity

Introduction

Cancer is a disease characterized by abnormal proliferation of cells with malignant behavior and is one of the leading causes of death globally. Since the last few decades, there have been outstanding developments in anticancer drug research, novel drug delivery approaches and treatment modalities to cure cancer. Despite these, cancer relapses due to therapeutic refractoriness and hence continues to be a major obstacle for cancer cure. The therapeutic resistance of tumors owes to the existence of cellular heterogeneity within them. Tumors, though start as single clone, subsequently develop into a heterogeneous group of cells composed of multiple clones with varied genetic mutations and epigenetic alterations including distinct promoter methylation patterns leading to genotypic heterogeneity within them [1].

Cancer Stem Cells (CSCs) are suggested to be one of the decisive factors accountable for tumor heterogeneity and relapse [2]. CSCs possess stemness properties such as self-renewability and differentiation characteristics similar to normal stem cells/progenitor cells. They can differentiate into different lineages of tumor cells through symmetrical or asymmetrical divisions [3,4]. The daughter cells from asymmetric division possess varied fates due to the differences in its morphology, gene expression patterns and succeeding cell divisions endured by them [5]. The hierarchical nature of tumor cell mass is orchestrated via CSCs and is responsible for cancer progression, relapse and poor prognosis [6]. These cells are distinguished from the rest of the tumor mass in which they can stimulate tumor growth and promote metastasis [7]. The quiescent nature of CSCs confers resistance to conventional therapies and cause cancer relapse [8]. Understanding the properties of CSCs, molecular mechanisms responsible for conferring therapeutic resistance to CSCs, and enrichment methods for this population of cells, we believe would pave way for the development of effective therapeutic strategies and identification of novel drug targets to eliminate CSCs, without affecting normal cells. This review presents an overview of the concept of tumor heterogeneity, CSC properties, comprehensive mechanisms by which CSCs attain resistance to chemo- and radiotherapy, enrichment methods used and therapeutic modalities for targeting the CSC subgroup.

Origin of CSCs

Accumulating data obtained from previous studies propose that depending on the tumor type, CSCs might originate from a) bone marrow stem cells/tissue-specific adult stem cells; b) trans-differentiation processes of somatic cells; c) dedifferentiation of progenitor cells; d) reprogramming of differentiated cancer cells e) horizontal gene transfer or cell fusion of cancer cells and normal stem cells [9-13]. These molecular variations are elicited either through activation of oncogenes, inactivation of tumor suppressor genes or as a consequence of the accumulated additional genetic and epigenetic anomalies. Additional factors that regulate CSCs maintenance for tumor initiation, growth and progression are the components of the microenvironment termed as stem cell niche and CSC niche such as stromal cells, hypoxic niche, inflammatory cells etc. Cytokine loops also play a critical role in reprogramming specified cells into CSCs [14].

Two models, the stochastic model (clonal evolution model) and the hierarchical model (CSC model) were proposed to describe the tumor origin, progression and heterogeneity [15,16].

The Stochastic model

The stochastic model proposes that each cell within a tumor own equal potential to generate new homogeneous cell mass [17]. The function of an individual cell is affected by both extrinsic factors (tumor microenvironment) and intrinsic factors (transcription factors and signaling pathways) [9,18]. The tumorigenic ability of any of these cells is attained by acquiring oncogenic mutations stochastically/randomly as a consequence of genomic instability, hyperplasia and irregular proliferation [19]. These genetic and molecular changes confer clonal growth of novel cell types, different from old cells. As a result, cancer cells within the same patient have different functional and phenotypic characteristics [20,21].

The hierarchical model

The hierarchical model illustrates that the structured diverse cell subsets and only a small number of cells, positioned on the top are decisive and have the clonogenic potential in vitro and tumor-inducing capability in vivo after transplantation into immunocompromised animal models. These cells were later termed as CSCs. The hierarchical model was first elucidated in Acute Myeloid Leukemia (AML), in which a subset of cells expressing CD34+CD38– markers on their surface-initiated leukemia upon transplantation into Severe Combined Immunodeficiency (SCID) mice. These cells showed normal stem cell properties such as self-renewing capacity and multi-lineage differentiation [13,22,23]. The occurrence of CSCs in several solid tumors such as lung [24-27], colon [26], liver [26], prostate [24,26], head & neck [26], ovarian [28], brain [26,29], bladder [30-32], melanoma [33-35], hepatocellular carcinoma [36,37] and retinoblastoma [38,39] has also been reported. Some cancer types like B cell lymphoblastic leukemias are not hierarchically organized and possess homogeneous histopathological features. These cancers gain heterogeneity in response to therapy through clonal evolution [40].

Characteristics of CSCs

CSCs and normal stem cells share similar stemness properties such as self-renewal ability and multi-lineage differentiation. Stem-like properties of CSCs are due to (epi) genetic alterations, changes in cell metabolism and dysregulated signaling pathways. The list of CSC characteristics is given in Table 1.

Self- renewability & differentiation

The prominent characteristics of CSCs is their ability to self-review and undergo differentiation into multiple cell types that are present in the primary tumor from which they are originated [41,42]. CSCs share both these properties with normal stem cells, but the proliferation of the former group is affected by genetic, epigenetic variations and stress (hypoxia, starvation, and inflammation) [13]. CSC theory postulates that cancer cells derived as a result of CSC differentiation process is accountable for tumor growth and metastasis. Dick and colleagues in 1997 demonstrated that CD34+/CD38- cells from AML patients undergo differentiation into leukemia cells in vivo [22].

Genetic & epigenetic variations

Emerging literature and data asserts that cancer stemness is directed by genetic (loss of tumor suppressor function & oncogene activation) and epigenetic deviations (aberrant methylation patterns and chromatin remodeling) [43]. Genetic changes in genes encoding DNA methyltransferases also drive CSC formation. Among DNMT1, DNMT3A and DNMT3B; DNMT3A is the most commonly mutated enzyme especially in AML patients [44]. Abnormal methylation patterns have also been observed in solid tumors during the initial stages of carcinogenesis [45].

The role of chromatin in inducing CSC formation through attaining self-renewal ability was evident by genome sequencing data in which gain-of-function mutations in H3F3A gene encoding histone H3 and K27M substitution was observed in pediatric Glioblastoma (GBM) patients [46]. Several other studies have reported that mutated epigenetic regulators such as enzymes involved in chromatin-remodeling, transfer of histone acetyl and methyl groups stimulate the gain of CSCs stemness properties and initiate the tumorigenic process [43]. For instance in leukemias (AML and Acute Lymphoblastic Leukemia (ALL), Leukemia Stem Cell (LSC)) formation is activated by oncogenic Mixed-Lineage Leukemia (MLL) fusion proteins generated by translocations [47]. Notably, MLL fusion proteins can initiate the tumorigenic process in progenitor cells along with hematopoietic stem cells, which clues that committed cells can reprogram to attain stemness property (self- renewability) [48,49].

The process of CSCs development can also be initiated by interactions between non-coding RNAs, specifically microRNA (miRNA) and other epigenetic machinery by targeting its components or reciprocally regulated by epigenetic mechanisms [50].

CSC specific cell surface and functional markers

Cell surface and functional markers such as Epithelial Cell Adhesion Molecule (EpCAM), CD133, CD44, CD24, Thy-1 cell surface antigen (THY1), ATP binding cassette subfamily B member 5 (ABCB5) and ATP-Binding Cassette Super-Family G Member 2 (ABCG2) specific for CSCs were identified for numerous solid tumors and leukemias [39,51]. Combinations of two or three markers are employed to isolate CSC fraction from tumors. They were first identified and isolated from breast cancer based on CD44+CD24-/low marker expression, side population and aldehyde dehydrogenase+ (ALDH+) subpopulations detection. The enriched fraction exhibited higher tumor-initiating capacity after transplanting into immunodeficient host [52]. In AML, a subset of cells expressing CD34+CD38- markers showed tumorigenic potential [23,53]. CSCs from brain cancers were identified based on the expression of CD133, Epidermal Growth Factor Receptor (EGFR), Stage-Specific Embryonic Antigen 1 (SSEA-1) and CD44 [54]. Various studies reported that cells expressing alternate phenotypes of CD133 marker show varied tumorigenic potential in vitro and in vivo. Both CD133+ and CD133- cells have the tumorigenic potential in several gliomas, whereas CD133+ brain tumor cells does not induce tumors [55]. In metastatic colon cancer, both CD133+ and CD133- cells can generate tumors and CD133- cells could form more aggressive tumors [56]. In another study on Rb primary tumors, CD133lo (FSClo/SSClo) population sorted by Fluorescence-Activated Cell Sorting (FACS) exhibited CSC properties, which was additionally proven by their ability to form better and larger colony, augmented invasive potential and showed resistance to therapeutic drug carboplatin when compared to CD133hi cells (non-CSCs) [8,39,57]. Rb CSCs were identified in both mouse and human Rb and they share normal stem cell-like characteristics [38,58,59]. Tumor specific cell surface markers are represented in Table 2.

Altered signaling pathways in CSCs

Common signaling pathways involved in CSCs are Janus kinase (JAK), Signal Transducer and Activator of Transcription (STAT) proteins, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB), wingless-related integration site (Wnt) β-catenin. Among all, Hedgehog and Notch are considered as important regulators of CSCs. Normal stem cells and CSCs share almost similar type of signaling pathways, however because of the irregularities in the signaling cascade of the latter group they acquire survival properties such as self-renewability, differentiation through abnormal regulation of transcriptional factors and proapoptotic genes [60-62] resulting in therapeutic resistance towards cancer therapies. Notch signaling is an evolutionary conserved and the most activated signaling pathways in almost all cancer types and play a key role in cell differentiation and cell cycle progression [63]. Canonical and noncanonical pathways of Wnt signaling cascade regulate cell polarity, survival, proliferation and migration [64]. Hedgehog pathway helps in gaining stemness properties through EMT [60]. By understanding the molecular mechanisms involved in deregulated pathways would pave way for designing novel therapeutic strategies for targeting CSCs.

Therapeutic resistance of CSCs

The quiescent nature of CSCs

A small subset of tissue-specific adult stem cells persists in quiescent state (G0) to compensate tissue loss, to survive under metabolic stress and to maintain genomic integrity throughout the lifespan of an organism [65]. Similarly, for CSCs, quiescent state is necessary for maintaining their self-renewal ability and is a critical factor for these cells to develop therapeutic resistance [66]. In several malignancies like breast and colon, the tumor can relapse after many years due to the survival of quiescent CSCs [18]. Stem cell quiescence is regulated by various intrinsic molecules like reactive oxygen species (FoxO group), transcription factors (HIF-1α & NFATc1 poietin-1) and extrinsic molecules such as TGF-β, thrombopoietin, osteopontin, adhesion proteins (N-cadherin & β1- integrins) that are found within the niche which are critical for the long-term maintenance of stem cells in quiescence. Understanding the regulatory mechanisms (ATM, mTOR and Wnt/β-catenin signaling) involved in quiescence in stem cells is important for the development of novel therapeutic strategies to target quiescent CSCs [67].

ABC transporters and Drug efflux pathways in the maintenance of drug resistance in CSCs

ATP Binding Cassette (ABC) transporters are highly conserved transmembrane proteins, which are classified into seven gene subfamilies, designated ABCA–G. Their normal physiological functions are detoxification system, defense against oxidative stress, xenobiotics and lipid metabolism [68]. High expression of ABC transporters has been described in numerous cancers and the chemo resistance for CSCs is attributed to members of this group of proteins called Multi Drug Resistant Proteins (MDR), which are responsible for MDR phenomenon, in which cancers become resistant to numerous drugs that have little structural and functional similarity. These proteins transport cytotoxic drugs as well as signaling molecules out of the cells and promote tumorigenesis [69,70]. Among all, ABCB1 (MDR1 or P-glycoprotein), ABCC1 (multidrug resistance-associated protein 1, MRP1) and ABCG2 (breast cancer resistance protein, BCRP) are the most studied proteins in the MDR family as these transporters are expressed in majority of drug resistant tumors. As compared to normal cells and cancer cells, some MDR transporters are expressed more highly in CSCs. For instance, ABCG2 is overexpressed in breast CSCs [71], ABCB1 in ovarian CSCs [72] and ABCB5 in malignant melanoma initiating cells (MMIC) [73].

The efficacy of anticancer drugs can be elevated by inhibiting members of ABC transporter family of proteins that are regulated by various signaling pathways which are involved in stem cell renewal and differentiation. For instance, Lapatinib inhibits receptor tyrosine kinase 2 (ERBB2) and doxorubicin sensitizes breast CSCs by inhibiting ABCB1 and ABCG2 [74].

The ALDH1 mediated drug detoxification systems

Aldehyde Dehydrogenase (ALDH) is a superfamily of phase I oxidizing and NAD(P)+-dependent enzymes that protect living organisms against oxidative stress and lipid peroxidation [75] and are essential for the biosynthesis of Retinoic Acid (RA), γ-aminobutyric acid, and betaine  [76,77]. Other than these functions, ALDH members such as ALDH1A1 and ALDH1A3 are studied as metabolic stem cell markers as they regulate cellular function in both normal stem cells and CSCs [78-80]. The higher activity by ALDH members has been implicated in cellular resistance against radiation in breast cancer cells [79,81] and in prostate cancer progenitor cells [76,82]. Several studies have reported that, within a tumor cell population ALDHbr cells are more clonogenic and tumorigenic than ALDHdim cells [83] and the presence of ALDHbr cells has been associated with poor outcomes in a number of cancers [80].

Immune evasion

The first line of defense against growth of tumor cells under normal physiological conditions is the activation of innate immunity of the organism. Fundamental molecules involved in this mechanism are interferon-gamma, Interleukin-12 (IL-12), perforin, TNF-Related Apoptosis-Inducing Ligand (TRAIL), Death Receptors (DR4 and DR5) and the Recombination Activating Genes (RAG1, and RAG-2) which are also required for cell development [84]. The capability of cells to escape from the immune system is thus recognized as a hallmark of cancer metastasis and is one of the distinct properties of CSCs. This phenomenon is caused by three different mechanisms: a) by down regulating the components of the antigen processing and presentation pathways such as transporter (TAP)1, TAP2, Major Histocompatibility (MHC)I and/or MHC-II, which prevent the exposure of neo-antigens [85]; b) either by low expression of T-cell activation co-stimulatory molecules or by elevated expression of T-cell inhibitory molecules, as well as Programmed Death-Lignad1 (PD-L1) [86]; c) by promoting the expansion of pro-tumorigenic immune phenotypes [87,88]. This phenomenon of immune evasion was detected in CSCs of head and neck squamous cell carcinoma, melanoma, glioblastoma and colorectal cancer, where they have decreased expression of MHC and/or TAP molecules [88]. These properties make CSCs poor targets for the cell-mediated immune response of T cells and contribute to the immune privileged status of CSCs within the tumor microenvironment.

Cellular plasticity through Epithelial to Mesenchymal Transition (EMT)

One of the possible mechanisms responsible for attaining chemo résistance by CSCs is cellular plasticity through EMT, which is a complex and reversible phenotypic process. In this process epithelial cells lose their differentiated features and acquire mesenchymal characteristics and contribute to invasiveness, metastatic propagation and acquisition of high resistance to apoptosis resulting in therapeutic resistance of cancer cells towards conventional therapies [3,89]. This switch might be induced by the tumor microenvironment that secretes EMT-inducing growth factors (Transforming Growth Factor Beta (TGFβ) family of cytokines), activation of signaling pathways (Wnt, Notch, Receptor Tyrosine Kinases (RTKs), NF-κB and Hedgehog) and the interaction with the extracellular matrix and is closely associated with the acquisition of stem cell-like characteristics in tumors [90-92] . Some of the well-known EMT markers are E-cadherin, β-catenin, N-Cadherin, vimentin, fibronectin, snail, slug, twist and ZEB1. The reversal of EMT, i.e MET (Mesenchymal to epithelial) transition seem to happen through subsequent dissemination and leads to the consequent development of distant metastases. Recent reports have suggested that a new concept of a hybrid Epithelial/Mesenchymal (E/M) state exists, which has higher tumor‐initiating potential than their individual states “E” and “M” and its expression was correlated with tumor aggressiveness in triple negative breast cancer patients [93-95]. This hybrid state was also observed in ovarian, lung and renal cell carcinoma cell lines, where both epithelial and mesenchymal markers were co-expressed at the same time [96,97].  The process of EMT, factors responsible for EMT and MET transitions, and epithelial and mesenchymal cell properties are elucidated in figure 2.

Understanding the complex physiological processes involved in EMT and MET transitions and subsequent cellular plasticity to acquire stemness properties by CSCs will help to design targeted drugs against these cells [93].

Resistance to Apoptosis

One of the important characteristic of CSCs that contribute to therapeutic resistance is their reduced apoptosis potential [98,99]. CSCs acquire this property by multiple mechanisms such as up regulation of antiapoptotic Bcl-2 family proteins, drug resistance proteins like Interleukin (IL)-4, Inhibitors of Apoptosis Proteins (IAPs), activation of Phosphoinositide 3-Kinsae (PI3K) or serine-threonine protein kinase (AKT) signaling cascade, down regulation of death receptors such as Fas and TRAIL and paucity in mitochondrial- mediated apoptosis contribute to enhanced resistance to apoptosis initiation in numerous cancers [100,101]. Novel approaches that can be used to target CSCs by inducing apoptosis are through a) activating cell death pathways using synthetic Fas ligands like Apo010 (a hexameric FAS-L), b) triggering the extrinsic apoptosis pathways using proteasome inhibitor bortezomib, which will increase surface expression of DR5, c) using unique delivery methodologies of DR ligands, d) inhibiting Bcl-2 and Inhibitor Apoptotic (IAP) family of proteins with small RNA molecules and e) disrupting mitochondrial energy metabolism [102].

Elevated telomerase activity

Telomerase is a RNA-dependent DNA polymerase enzyme that uses catalytic subunit, Telomerase Reverse Transcriptase (TERT) and plays a key role in adding 5′ - TTAGGG - 3′ repeated sequence to the terminal ends of the human chromosomes as they lose telomeric repeats with each cell division. Expression of telomerase is observed in 90% of human cancers, but is inactive in normal somatic cells [103-105]. Numerous studies have reported that, the expression of telomerase is higher in CSCs compared to non-CSCs, and its expression is critical for the self-renewal, progression and immortalization of CSCs [106-108].

CSCs & Tumor microenvironment

Tumor Microenvironment (TME) is composed of two components: cellular and non-cellular. Along with malignant cells, the cellular portion constitutes mesenchymal stem cells, endothelial cells, Cancer Associated Fibroblasts (CAFs), immune cells, adipocytes, myeloid cells, Natural Killer (NK) & NKT cells and pericytes [109]. The non-cellular component of TME includes Extracellular Matrix (ECM), which constitutes of collagen, glycoproteins, proteoglycans and integrins [110]. Number of studies have reported that stromal cells such as CAFs support the stemness of CSCs by releasing cancer cell derived secretory molecules, which further activates Wnt/β-catenin and Notch signaling pathways [111] and cancer progression is mediated via a feedback mechanism, where CSC influences CAF activity through activation of Hedgehog signaling cascade [112]. In addition, the metastatic latency of CSCs is attributed to TME, as it provides the signals that regulates self-renewal, EMT, inflammation, hypoxia and angiogenesis which will either regulate entry of CSCs into quiescent state or stimulate the reactivation of CSCs that initiate metastasis and modulates the ability of CSCs to escape the innate immune response and survive in the metastatic niche [9].

The observed interactions between CSCs and TME provides critical insights into the mechanism of cancer drug resistance and recurrence.

CSCs & Hypoxia

Impaired vascularization within a primary tumor results in hypoxic condition, which is an important characteristic feature of locally advanced solid tumors. In cancer patients, tumor hypoxia is positively correlated with poor prognosis, aggressive tumor behavior and resistance to therapy [113,114]. Heddleston, et al. demonstrated that between the two transcriptional hypoxic signatures hypoxia inducible factor (HIF)-1α and HIF2α, the former is known to express in normal neural progenitors and cancer cells. Its expression is critical for the proliferation and survival of these two cell types, whereas HIF2α is expressed only in cancer stem cells and not expressed by normal neural progenitors indicating its role as a specific target for CSCs [7].

Role of Extracellular Vesicles in crosstalk between tumor niche and CSCs

Extracellular Vesicles (EVs) are a diverse group of membrane-bound vesicles, first identified in plasma by Wolf, who referred to them as “Platelet dust” [115]. Three main types of EVs have been described based on their subcellular origin, type of release and size: exosomes (30–100 nm in diameter), micro vesicles (100–1,000 nm) and ectosomes or shedding vesicles (larger than 100nm) [116]. EVs are considered as a new mode of intercellular communication and tumor-derived EVs play a significant role in various cancers via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells [117]. CSC derived EVs reprogram the local cells genetically and affect the immune cells of TME, which influences the tumor cell fate. Recent studies have demonstrated that, EVs particularly exosomes derived from various solid tumors such as prostate [118-120], breast [121-123], lung [124,125] and colorectal cancers [126-128] could influence the components of the microenvironment such as macrophages, mesenchymal stromal cells, CAFs, osteoclasts etc., and alter the tumor niche through a cargo of microRNAs like miR-409, miR-21, miR-378e, miR-143, miR-125a, miR-126 and by activation of AKT, IL6/STAT3 signaling pathways [117]. The released exosomes also have the ability to travel to distant organs and form a pre-metastatic niche [125]. However, other in vitro and in vivo studies have reported the anti-tumor effect of EVs derived from stem cells by obstruction of cell proliferation and induction of apoptosis in gliomas, lympho blastomas and liver carcinomas [129-131]. In addition, EVs derived from human liver stem cells improved the efficacy of Tyrosine Kinase Inhibitors (TKIs) by elevating the apoptosis of CSCs isolated from renal carcinomas [117]. By understanding the role of EVs crosstalk between tumor niche, and CSCs and characterization of EVs from both normal stem cells and CSCs could help in the identification of novel tumor biomarkers and development of new therapeutic targets.

Isolation and characterization of CSCs

Compelling evidence suggests that CSCs are the core cause of tumor initiation, progression, invasion, metastasis, therapeutic resistance and relapse which therefore makes their analysis crucial for targeting and eradication of this sub group from the tumors [13,132]. Various enrichment methodologies have been developed based on CSC properties. The isolated CSC populations are further tested for their self-renewal capacity and ability to form tumors. Two in vitro assays that are being widely used for demonstrating self-renewal of CSCs are clonogenic assay and sphere formation assay [133]. The tumor seeding capability of CSCs is validated by in vivo xenotransplantation assay using immunocompromised animal models. Other CSC isolation methods are based on cell surface and functional markers, ability to efflux Hoechst 33342 dye, quiescent nature, invasion capability and in vivo tumor forming ability [134].

Therapeutic strategies for targeting CSCs

Strong evidence suggests that after the standard treatments including chemo and radiotherapy, the CSC subset remains alive, and are accountable for Minimal Residual Disease (MRD) and cancer relapse [135]. In recent years multiple mechanisms, physiological processes of CSCs have been elucidated in order to eradicate CSCs to improve patient survival [125,136,137]. Numerous CSCs-specific tactics such as ATP-Binding Cassette (ABC) transporters, obstruction of self-renewal and survival of CSCs, surface marker and functional marker specific for CSC targeted drugs delivery, molecular agents for disrupting tumor microenvironment and MDR group of enzymes have already been developed against various cancers [136,138-140]. Elevated telomerase activity was observed in CSCs of breast and lung cancer cells compared to non-CSCs, targeting these cells based on this property is an effective strategy to eliminate this subgroup [141,142]. The telomerase inhibitor, imetelstat has effectively inhibited the cancer stem-like cell proliferation in glioblastoma and prostate cancer [142,143].

The prime reason for therapeutic resistance of CSCs is due to their quiescent state which can be altered by inducing them to enter into cell cycle through the inactivation of Fbw7, a component of E3 ubiquitin ligase contribute to the cell cycle arrest evident in CSCs [144,145]. Another promising approach developed for targeting CSCs is microRNA (miR) dependent. Transfection of miR34a and ectopic expression of miR206 reduces the stemness properties of breast cancer cells in vitro and in vivo [146,147]. Mesenchymal Stem Cells (MSCs) are widely used to deliver specific miRs such as miR9 antisense oligonucleotide to control the expression of drug-resistant protein, p-glycoprotein in glioblastoma cells [148]. Along with these, novel drug delivery systems and unique secretory molecules such as exosomes have been identified to eradicate CSC subgroup from the heterogeneous tumors. The role of exosomes as information carriers and their existence in tumor microenvironment for maintaining the dynamic equilibrium state between non-CSCs and CSCs suggest that they might be an effective strategy for cancer therapeutics. For instance, molecular inhibitors such as GW4869, heparin are used to target molecules involved in exosomes regulating non-CSCs dedifferentiation pathway [149]. MSC derived exosomes are used to deliver synthetic miR122 to elevate the sensitivity of liver tumors to chemotherapeutic drug, sorafenib [150].

In addition to the above stated therapeutic approaches, numerous genomics, proteomics, bioinformatics tools and databases to integrate the genes were employed to understand the molecular mechanisms responsible for the origin of CSCs, tumor progression and metastasis in numerous cancers including lung [151] and in recurrent glioblastoma [152]. A summary of therapeutic strategies targeting CSCs are shown in Figure 3.

Future Directions

With the evolving techniques to identify and target CSCs in various tumors, it is quite logical to predict that future treatment strategies would include a combined therapy that addresses both CSCs and non-CSCs through in-vivo tracking, localization and targeting them at a microscopic level.

Summary

Compelling evidence demonstrates that the CSC population is accountable for the origin and development of cellular heterogeneity in tumors ensuing therapeutic resistance and cancer relapse. The effective strategy to improve cancer patient survival is through complete eradication of both CSCs and non-CSC populations. Comprehensive understanding of cellular heterogeneity in tumors, cellular plasticity and reprogramming mechanisms responsible for generating CSCs from different cell types offer new insights to develop effective methodologies to exterminate already existing CSCs and avert the generation of new diverse CSC subtypes. The therapeutic strategies that would be useful for targeting CSCs are based on surface marker, involving signaling cascades, epigenetic alterations or mechanisms that modulate CSC reprogramming and differentiation, molecules involved in immune evasion, tumor microenvironment, and tumor niche. Identification of unique dissimilarities owned by normal and CSCs can help in designing novel agents for targeting CSCs alone. Thus, targeting CSCs, the under bunker enemies, which are well protected in their niche and are resistant to chemo and radio-therapy would be crucial for cancer regression and for improving patient survival.

Acknowledgements

The authors acknowledge UGC-UKIERI funding agency for financial support.

Conflict of interests

No conflicting relationship exists for any author.


Figure 1: Molecular mechanisms that contribute to therapeutic resistance in CSCs.



Figure 2: Epithelial-Mesenchymal Transition. During metastasis “CSCs undergo EMT”, which involves functional transition of stationary epithelial cells into motile mesenchymal cells through an intermediate state where the cells exhibit both the properties of epithelial and mesenchymal cells under the influence of growth and transcription factors, adhesion molecules and tumor microenvironment. The mesenchymal cells migrate to adjacent stromal tissues and invade blood or lymph vessels. The properties of epithelial and mesenchymal cells are cited here.



Figure 3: Strategies for targeting CSCs based on repressing surface marker expression, inhibiting the signaling pathways, promoting cell death pathways including apoptosis, inhibiting telomerase activity and drug efflux pumps, interfering the tumor microenvironment and epigenetic mechanisms, targeting self-renewal ability and cell differentiation process.

Characteristics of CSCs

Self –renewal capability

Differentiation ability into heterogeneous lineages of cells, which makes up the original tumor.

Ability to survive for a long time - Quiescent nature (G0 Stage of cell cycle)

Resistance to damaging agents

Active membrane transporter activity (MDR1 and ABCG2 responsible for chemo-resistance)

Anchorage –independent growth and metastasizing capacity through EMT

Active telomerase expression

Expression of cell surface proteins

Altered gene expression profile (genetic & epigenetics variations)

Altered signaling pathways (Wnt, Notch, Hedghog)

Expression of EMT gene signatures

Protective autophagy system

Immune evasion

Cancer stem cell plasticity through EMT

Sphere forming ability

Tumorigenicity

Metabostemness

Tumor invasion

Resistant to apoptosis (ROS scavenging, DNA Repair, Anti apoptosis signaling pathways


Table 1: List of CSCs Characteristics.

Cancer type

Markers

Reference

AML

CD34+/CD38-

[22]

Breast

CD44+/CD24−/low/EpCAM+

[52]

CD44+/CD24-/ESA+

[153]

ALDH1+/CD44+/CD24−/low

[154]

Pancreatic cancer

CD44+/CD24+/ESA+

[155]

CD133+/CD44+/CD24+/ESA+

[156]

Ovarian

CD133+, CD44+, ALDH1+

[157,158]

Lung

CD133+, ALDH+

[159,160]

Colon cancer

EpCAM+/CD44+/CD166+

[161]

CD133+/EpCAM+/CD44+/CD166+

[162]

Liver

CD133+, CD49f+, CD90+

[163,164]

CD133+, CD49f+, CD90+  

Multiple myeloma CD138 - Multiple myeloma   

CD138

[165]

 Retinoblastoma (Y79 cells)

 FSClo/ SSClo/CD133lo/CD44hi

[8,57]

CD133+, Nestin+ and OCT4+

[166]

ABCG2+

[58]


Table 2: Tumor specific cell surface markers.

References

  1. Mazor T, Pankov A, Song JS, Costello JF (2016) Intratumoral heterogeneity of the epigenome 29: 440-451.
  2. Kreso A, Dick JE (2014) Evolution of the cancer stem cell model 14: 275-291.
  3. Mitra A, Mishra L, Li S (2015) EMT, CTCs and CSCs in tumor relapse and drug-resistance 6: 10697.
  4. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, et al. (2009) EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. 136: 1012-1024.
  5. Horvitz HR, Herskowitz I (1992) Mechanisms of asymmetric cell division: two Bs or not two Bs, that is the question 68: 237-255.
  6. Kai K, Arima Y, Kamiya T, Saya H (2010) Breast cancer stem cells 17: 80-85.
  7. Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB, et al. (2010) Hypoxia inducible factors in cancer stem cells 102: 789.
  8. Nair RM, Balla MMS, Khan I, Kalathur RKR, Kondaiah P, et al. (2017) In vitro characterization of CD133 lo cancer stem cells in Retinoblastoma Y79 cell line. BMC cancer 17: 779.
  9. Plaks V, Kong N, Werb Z (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? 16: 225-238.
  10. Baccelli I, Trumpp A (2012) The evolving concept of cancer and metastasis stem cells. 198: 281-293.
  11. Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ (2005) The origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 5: 899.
  12. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, et al. (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell stem cell 7: 403-41
  13. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414: 105.
  14. Eun K, Ham SW, Kim H (2017) Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep 50: 117.
  15. Gerdes MJ, Sood A, Sevinsky C, Pris AD, Zavodszky MI, et al. (2014) Emerging understanding of multiscale tumor heterogeneity. Front Oncol 4: 366.
  16. Michor F, Polyak Kv(2010) The origins and implications of intratumor heterogeneity. Cancer Prev Res (Phila) 3: 1361-1364.
  17. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194: 23-28.
  18. Dick JE (2008) Stem cell concepts renew cancer research. Blood 112: 4793-4807.
  19. Foo J, Leder K, Michor F (2011) Stochastic dynamics of cancer initiation. Phys Biol 8: 015002.
  20. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194: 23-28.
  21. Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9: 138-141.
  22. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730.
  23. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, et al. (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645.
  24. Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH (2013) Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Protoc Pharmacol Chapter 14: Unit 14.25.
  25. Codony-Servat J, Rosell R (2015) Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res 4: 689-703.
  26. Moharil RB, Dive A, Khandekar S, Bodhade A (2017) Cancer stem cells: An insight. J Oral Maxillofac Pathol 21: 463.
  27. Toledo-Guzmán ME, Bigoni-Ordóñez GD, Hernández MI, Ortiz-Sánchez E (2018) Cancer stem cell impact on clinical oncology. World J Stem Cells 10: 183-195.
  28. Al-Alem LF, Pandya UM, Baker AT, Bellio C, Zarrella BD, et al. (2019) Ovarian cancer stem cells: What progress have we made? Int J Biochem Cell Biol 107: 92-103.
  29. Cho DY, Lin SZ, Yang WK, Lee HC, Hsu DM, et al. (2013) Targeting cancer stem cells for treatment of glioblastoma multiforme. Cell Transplant 22: 731-739.
  30. Chan KS, Volkmer JP, Weissman I (2010) Cancer stem cells in bladder cancer: a revisited and evolving concept 20: 393.
  31. Tran MN, Goodwin Jinesh G, McConkey DJ, Kamat AM (2010) Bladder cancer stem cells. Curr Stem Cell Res Ther 5: 387-395.
  32. Yin B, Zeng Y, Liu G, Wang X, Wang P, et al. (2014) MAGE-A3 is highly expressed in a cancer stem cell-like side population of bladder cancer cells. Int J Clin Exp Pathol 7: 2934.
  33. Brinckerhoff CE (2017) Cancer Stem Cells (CSCs) in melanoma: There's smoke, but is there fire?. J Cell Physiol 232: 2674-2678.
  34. Parmiani G (2016) Melanoma cancer stem cells: markers and functions. Cancers (Basel) 8: 34.
  35. Shakhova O1, Sommer L (2013) Testing the cancer stem cell hypothesis in melanoma: the clinics will tell. Cancer Lett 338: 74-81.
  36. Dang HT, Budhu A, Wang XW (2014) The origin of cancer stem cells. J Hepatol 60: 1304-1305.
  37. Ji J, Wang XW (2012) Clinical implications of cancer stem cell biology in hepatocellular carcinoma. in Seminars in oncology. Semin Oncol 39: 461-472.
  38. Seigel GM (2005) Evidence for Cancer Stem Cells in Retinoblastoma. Cancer Stem Cells: 87.
  39. Balla MMS, Vemuganti GK, Nair R, Honavar S (2013) Evaluation of response to Carboplatin in putative Cancer Stem Cells of Retinoblastoma Y79 cell line. 54: 1256-1256.
  40. Williams RT, Besten WD, Sherr CJ (2007) Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev 21: 2283-2287.
  41. Ayob AZ, Ramasamy TS (2018) Cancer stem cells as key drivers of tumour progression. J Biomed Sci 25: 20.
  42. Desai A, Yan Y, Gerson SL (2019) Concise reviews: Cancer stem cell targeted therapies: toward clinical success. Stem Cells Transl Med 8: 75-81.
  43. Wainwright EN, Paola Scaffidi (2017) Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer 3: 372-386.
  44. Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368: 2059-2074.
  45. Kim MS, Kim YR, Yoo NJ, Lee SH (2013) Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers. APMIS 121: 85-94.
  46. Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, et al. (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44: 251.
  47. Shilatifard A (2012) The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 81: 65-95.
  48. Cozzio A, Passegué E, Ayton PM, Karsunky H, Cleary ML, et al. (2003) Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 217: 3029-3035.
  49. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, et al. (2006) Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Nature 442: 818.
  50. Wang F, Ma Y, Wang H, Qin H (2017) Reciprocal regulation between microRNAs and epigenetic machinery in colorectal cancer. Oncology Letters 13: 1048-1057.
  51. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8: 755.
  52. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100: 3983-3988.
  53. Clarke MF, Hass AT (2006) Cancer stem cells.
  54. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, et al. (2004) Identification of human brain tumour initiating cells. Nature 432: 396.
  55. Cheng JX, Liu BL, Zhang X (2009) How powerful is CD133 as a cancer stem cell marker in brain tumors?. Cancer Treat Rev 35: 403-408.
  56. Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, et al. (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133–metastatic colon cancer cells initiate tumors. J Clin Invest 118: 2111-2120.
  57. Balla MM, Vemuganti GK, Kannabiran C, Honavar SG, Murthy R (2009) Phenotypic characterization of retinoblastoma for the presence of putative cancer stem-like cell markers by flow cytometry. Investigative ophthalmology & visual science 50: 1506-1514.
  58. Seigel GM, Campbell LM, Narayan M, Gonzalez-Fernandez F (2005) Cancer stem cell characteristics in retinoblastoma. Mol Vis 11: 729-737.
  59. Dyer MA, Bremner R (2005) The search for the retinoblastoma cell of origin. Nat Rev Cancer 5: 91.
  60. Koury J, Zhong L, Hao J (2017) Targeting signaling pathways in cancer stem cells for cancer treatment. Stem Cells Int.
  61. Dandawate PR, Subramaniam D, Jensen RA, Anant S (2016) Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. in Seminars in cancer biology. Semin Cancer Biol.
  62. Samadani AA, Norollahi SE, Rashidy-Pour A, Mansour-Ghanaei F, Nemati S, et al., Cancer signaling pathways with a therapeutic approach: An overview in epigenetic regulations of cancer stem cells. Biomed Pharmacother 108: 590-599.
  63. Salem ML, El-Badawy AS, Li Z (2015) Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy. Cytotechnology 67: 749-759.
  64. Liskova A, Kubatka P, Samec M, Zubor P, Mlyncek M, et al. (2019) Dietary Phytochemicals Targeting Cancer Stem Cells. Molecules 24: 899.
  65. Cheung TH, Rando TA (2013) Molecular regulation of stem cell quiescence. Nature reviews Molecular cell biology 14: 329.
  66. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, et al. (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12: 445-64.
  67. Li L, Bhatia R (2011) Stem cell quiescence. Clinical cancer research 17: 4936-4941.
  68. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B (2004) The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv 1: 27-42.
  69. Mukhopadhyay A, Chakraborty A, Mukhopadhyay S, Basak J (2014) Cancer stem cells and multiple drug resistance in breast cancer. Science and culture: 80.
  70. Begicevic RR, Falasca M (2017) ABC transporters in cancer stem cells: beyond chemoresistance. Int J Mol Sci 18: 2362.
  71. Chuthapisith S, Eremin J, El-Sheemey M, Eremin O (2010) Breast cancer chemoresistance: emerging importance of cancer stem cells. Surg Oncol 19: 27-32.
  72. Eyre R, Harvey I, Stemke-Hale K, Lennard TW, Tyson-Capper A, et al. (2014) Reversing paclitaxel resistance in ovarian cancer cells via inhibition of the ABCB1 expressing side population. Tumour Biol 35: 9879-9892.
  73. Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, et al. (2011) VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res 71: 1474-1485.
  74. Chun SY, Kwon YS, Nam KS, Kim S (2015) Lapatinib enhances the cytotoxic effects of doxorubicin in MCF-7 tumorspheres by inhibiting the drug efflux function of ABC transporters. Biomed Pharmacother 72: 37-43.
  75. Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, et al. (2013) Aldehyde dehydrogenases in cellular responses to oxidative/electrophilicstress. Free Radic Biol Med 56: 89-101.
  76. Marchitti SA1, Brocker C, Stagos D, Vasiliou V (2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 4: 697-720.
  77. Fox SB, Fawcett J, Jackson DG, Collins I, Gatter KC, et al. (1994) Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms. Cancer research 54: 4539-4546.
  78. Alison MR, Guppy NJ, Lim SM, Nicholson LJ (2010) Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose?. J Pathol 222: 335-344.
  79. Xu X, Chai S, Wang P, Zhang C, Yang Y, et al. (2015) Aldehyde dehydrogenases and cancer stem cells. Cancer Lett 369: 50-57.
  80. Vassalli G (2019) Aldehyde dehydrogenases: Not just markers, but functional regulators of stem cells. Stem Cells Int.
  81. Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, et al. (2010) Aldehyde dehydrogenase 1–Positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16: 45-55.
  82. Moreb JS (2008) Aldehyde dehydrogenase as a marker for stem cells. Curr Stem Cell Res Ther 3: 237-246.
  83. Januchowski R1, Wojtowicz K, Zabel M (2013) The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 67: 669-680.
  84. Codony-Servat J, Rosell R (2015) Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res 4: 689.
  85. Suárez-Alvarez B, Rodriguez RM, Calvanese V, Blanco-Gelaz MA, Suhr ST, et al. (2010) Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells. PLoS One 5: e10192.
  86. Lee Y, Shin JH, Longmire M, Wang H, Kohrt HE (2016) CD44+ cells in head and neck squamous cell carcinoma suppress T-cell–mediated immunity by selective constitutive and inducible expression of PD-L1. Clin Cancer Res 22: 3571-3581.
  87. Gupta HB, Hurez V, Clark CA, Sareddy GR, Vadlamudi R, et al. (2016) Tumor B7-H1 regulates cancer stem cell generation and virulence.
  88. Sultan M, Coyle KM, Vidovic D, Thomas ML, Gujar S, et al. (2017) Hide-and-seek: the interplay between cancer stem cells and the immune system. Carcinogenesis 38: 107-118.
  89. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14: 611.
  90. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15: 178-196.
  91. Marcucci F, Stassi G, De Maria R (2016) Epithelial–mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov 15: 311.
  92. Pulkoski-Gross A, Zheng XE, Kim D, Cathcart J (2015) Epithelial to Mesenchymal Transition (EMT) and Intestinal Tumorigenesis, in Intestinal Tumorigenesis. Springer 309-364.
  93. Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends in cell biology 29: 212-226.
  94. Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29: 212-226.
  95. Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H (2016) Tumor budding: the name is EMT. Partial EMT. J Clin Med 5: 51.
  96. Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, et al. (2012) EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12: 91.
  97. Fustaino V, Presutti D, Colombo T, Cardinali B, Papoff G, et al. (2017) Characterization of epithelial-mesenchymal transition intermediate/hybrid phenotypes associated to resistance to EGFR inhibitors in non-small cell lung cancer cell lines. Oncotarget 8: 103340.
  98. Guzman ML1, Swiderski CF, Howard DS, Grimes BA, Rossi RM, et al. (2002) Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A 99: 16220-16225.
  99. Enderling H, Hahnfeldt P (2011) Cancer stem cells in solid tumors: Is ‘evading apoptosis’a hallmark of cancer? Prog Biophys Mol Biol 106: 391-399.
  100. Reed JC (1999) Mechanisms of apoptosis avoidance in cancer. Current opinion in oncology 11: 68.
  101. Fisher DE (1994) Apoptosis in cancer therapy: crossing the threshold. Cell 78: 539-542.
  102. Wang YH, Scadden DT (2015) Harnessing the apoptotic programs in cancer stem‐like cells. EMBO Rep 16: 1084-1098.
  103. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011-2015.
  104. Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, et al. (2007) Protein composition of catalytically active human telomerase from immortal cells. Science 315: 1850-1853.
  105. C M Counter, A A Avilion, C E LeFeuvre, N G Stewart, C W Greider, et al. (1992) Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11: 1921-1929.
  106. Shay JW, Wright WE (2010) Telomeres and telomerase in normal and cancer stem cells. FEBS Lett 584: 3819-3825.
  107. Ju Z, Rudolph KL (2006) Telomeres and telomerase in cancer stem cells. Eur J Cancer 42: 1197-1203.
  108. Zhang Z, Komaki R, Wang L, Fang B, Chang JY (2008) Treatment of radioresistant stem-like esophageal cancer cells by an apoptotic gene-armed, telomerase-specific oncolytic adenovirus. Clin Cancer Res 14: 2813-2823.
  109. Spaw M, Anant S, Thomas SM (2017) Stromal contributions to the carcinogenic process. Mol Carcinog 56: 1199-1213.
  110. Frantz C, Stewart KM, Weaver VM (2010) The extracellular matrix at a glance. J Cell Sci 123: 4195-4200.
  111. Fiori ME, Franco SD, Villanova L, Bianca P, Stassi G, et al. (2019) Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Molecular Cancer 18: 70.
  112. Fedele M, Cerchia L, Chiappetta G (2017) The epithelial-to-mesenchymal transition in breast cancer: focus on basal-like carcinomas. Cancers (Basel) 9: 134.
  113. Vaupel P, Harrison L (2004) Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9: 4-9.
  114. Zhou J, Schmid T, Schnitzer S, Brüne B (2006) Tumor hypoxia and cancer progression. Cancer Lett 237: 10-21.
  115. Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13: 269-288.
  116. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated Platelets Release Two Types of Membrane Vesicles: Microvesicles by Surface Shedding and Exosomes Derived From Exocytosis of Multivesicular Bodies and-Granules. Blood 94: 3791-3799.
  117. Ciardiello C, Leone A, Budillon A (2018) The Crosstalk between Cancer Stem Cells and Microenvironment Is Critical for Solid Tumor Progression: The Significant Contribution of Extracellular Vesicles.
  118. Huang H, Wang C, Liu F, Li HZ, Peng G, et al. (2018) Reciprocal network between cancer stem-like cells and macrophages facilitates the progression and androgen deprivation therapy resistance of prostate cancer. Clin Cancer Res 24: 4612-4626.
  119. Karlsson T, Lundholm M, Widmark A, Persson E (2016) Tumor cell-derived exosomes from the prostate cancer cell line TRAMP-C1 impair osteoclast formation and differentiation. PLoS One 11: e0166284.
  120. Minciacchi VR, Spinelli C, Reis-Sobreiro M, Cavallini L, You S, et al. (2017) MYC mediates large oncosome-induced fibroblast reprogramming in prostate cancer. Cancer Res 77: 2306-2317.
  121. Baroni S1, Romero-Cordoba S2, Plantamura I1, Dugo M3, D'Ippolito E, et al. (2016) Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts. Cell Death Dis 7: e2312.
  122. Donnarumma E, Fiore D, Nappa M, Roscigno G, Adamo A, et al. (2017) Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer. Oncotarget 8: 19592.
  123. Gernapudi R1, Yao Y, Zhang Y, Wolfson B, Roy S, et al. (2015) Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer. Breast Cancer Res Treat 150: 685-695.
  124. Hsu YL, Hung JY, Chang WA, Jian SF, Lin YS, et al. (2018) Hypoxic lung-Cancer-derived extracellular vesicle MicroRNA-103a increases the oncogenic effects of macrophages by targeting PTEN. 26: 568-581.
  125. Chu J, Li Y, Fan X, Ma J, Li J, et al. (2018) MiR-4319 suppress the malignancy of triple-negative breast cancer by regulating self-renewal and tumorigenesis of stem cells. Cell Physiol Biochem 48: 593-604.
  126. Giroux Leprieur E, Tolani B, Li H, Leguay F, Hoang NT, et al. (2017) Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer. Oncotarget 8: 103744.
  127. Fang M, Li Y, Huang K, Qi S, Zhang J, et al. (2017) IL33 promotes colon cancer cell stemness via JNK activation and macrophage recruitment. Cancer Res 77: 2735-2745.
  128. Ren D, Lin B, Zhang X, Peng Y, Ye Z, et al. (2017) Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway. Oncotarget 8: 49807.
  129. Bruno S, Collino F, Deregibus MC, Grange C, Tetta C, et al. (2012) Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev 22: 758-771.
  130. Aliotta JM, Pereira M, Wen S, Dooner MS, Del Tatto M, et al. (2017) Bone marrow endothelial progenitor cells are the cellular mediators of pulmonary hypertension in the murine monocrotaline injury model. Stem Cells Transl Med 6: 1595-1606.
  131. Fonsato V, Collino F, Herrera MB, Cavallari C, Deregibus MC, et al. (2012) Human liver stem cell‐derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs. Stem Cells 30: 1985-1998.
  132. Lodestijn SC, Lenos KJ, Miedema DM, Bijlsma MF, Vermeulen L (2019) Cancer stem cells: here, there, and everywhere. Molecular & cellular oncology 6: 1540235.
  133. Kosovsky M (2012) Culture and Assay Systems Utilized for cancer stem cell research: 1.
  134. Abbaszadegan MR, Bagheri V, Razavi MS, Momtazi AA, Sahebkar A, et al. (2017) Isolation, identification, and characterization of cancer stem cells: A review. J Cell Physiol 232: 2008-2018.
  135. Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, et al. (2012) Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer 12: 767.
  136. Gao XM, Zhang R, Dong QZ, Qin LX (2016) Properties and feasibility of using cancer stem cells in clinical cancer treatment. Cancer Biol Med 13: 489.
  137. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14: 11.
  138. Chen X, Wu L, Li D, Xu Y, Zhang L, et al. (2018) Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α. 7: 3834-3847.
  139. Yun X, Zhang K, Wang J, Pangeni RP, Yang L, et al. (2018) Targeting USP22 suppresses tumorigenicity and enhances cisplatin sensitivity through ALDH1A3 downregulation in cancer-initiating cells from lung adenocarcinoma. Mol Cancer Res 16: 1161-1171.
  140. Dammacco F, Leone P, Silvestris F, Racanelli V (2019) Cancer Stem Cells in Multiple Myeloma and the Development of Novel Therapeutic Strategies, in Oncogenomics. Elsevier: 121-137.
  141. Ho MM, Ng AV, Lam S, Hung JY (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67: 4827-4833.
  142. Joseph I, Tressler R, Bassett E, Harley C, Buseman CM, et al., The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res 70: 9494-9504.
  143. Shervington A, Lu C, Patel R, Shervington L (2009) Telomerase downregulation in cancer brain stem cell. Mol Cell Biochem 331: 153.
  144. Cicenas J, Valius M (2011) The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol 137: 1409.
  145. Welcker M, Clurman BE (2008) FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer 8: 83.
  146. Ostroff JS, Burkhalter JE, Cinciripini PM, Li Y, Shiyko MP, et al. (2014) Randomized trial of a presurgical scheduled reduced smoking intervention for patients newly diagnosed with cancer. 33: 737.
  147. Samaeekia R, Adorno-Cruz V, Bockhorn J, Chang YF, Huang S, et al. (2017) miR-206 inhibits stemness and metastasis of breast cancer by targeting MKL1/IL11 pathway. Clin Cancer Res 23: 1091-1103.
  148. Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, et al. (2013) Delivery of functional anti-miR-9 by mesenchymal stem cell–derived exosomes to glioblastoma multiforme cells conferred chemosensitivity Mol Ther Nucleic Acids 2: e126.
  149. Sun Z, Wang L, Dong L, Wang X (2018) Emerging role of exosome signalling in maintaining cancer stem cell dynamic equilibrium. J Cell Mol Med 22: 3719-3728.
  150. Lou G, Song X, Yang F, Wu S, Wang J, et al. (2015) Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol 8: 122.
  151. Wu X, Chen H, Wang X (2012) Can lung cancer stem cells be targeted for therapies?. Cancer Treat Rev 38: 580-588.
  152. Bo LJ, Wei B, Li ZH, Wang ZF, Gao Z, et al. (2015) Bioinformatics analysis of miRNA expression profile between primary and recurrent glioblastoma. Eur Rev Med Pharmacol Sci 19: 3579-3586.
  153. Velasco-Velázquez MA, Homsi N, De La Fuente M, Pestell RG (2012) Breast cancer stem cells. Int J Biochem Cell Biol 44: 573-577.
  154. Shao J, Fan W, Ma B, Wu Y (2016) Breast cancer stem cells expressing different stem cell markers exhibit distinct biological characteristics. Mol Med Rep 14: 4991-4998.
  155. Shankar S, Nall D, Tang SN, Meeker D, Passarini J, et al. (2011) Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 6: e16530.
  156. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, et al. (2007) Identification of pancreatic cancer stem cells. Cancer Res 67: 1030-1037.
  157. Bapat SA, Mali AM, Koppikar CB, Kurrey NK (2005) Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res 65: 3025-3029.
  158. Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, et al. (2009) Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 8: 158-166.
  159. Eramo A1, Lotti F, Sette G, Pilozzi E, Biffoni M, et al. (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15: 504.
  160. Huang CP, Tsai MF, Chang TH, Tang WC, Chen SY, et al. (2013) ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett 328: 144-151.
  161. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, et al. (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 104: 10158-10163.
  162. Ricci-Vitiani L1, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, et al. (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445: 111.
  163. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, et al. (2008) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13: 153-166.
  164. Rountree CB, Senadheera S, Mato JM, Crooks GM, Lu SC (2008) Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A–deficient mice. Hepatology 47: 1288-1297.
  165. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, et al. (2004) Characterization of clonogenic multiple myeloma cells. Blood 103: 2332-2336.
  166. Tang Z, Ma H, Mao Y, Ai S (2019) Identification of stemness in primary retinoblastoma cells by analysis of stem-cell phenotypes and tumorigenicity with culture and xenograft models. Experimental Cell Research 379: 110-118.

Citation: Manukonda R, Prabhu V, Narayana RVL, Vemuganti GK (2020) Cancer Stem Cells: An Overview. Adv Biochem Biotechnol 5: 1097. DOI: 10.29011/2574-7258.001097

free instagram followers instagram takipçi hilesi