Med Oncol (2015) 32:170 DOI 10.1007/s12032-015-0619-6

REVIEW ARTICLE

Therapeutic potential of cancer stem cells Chunguang Yang1 • Kunlin Jin2 • Yangping Tong3 • William Chi Cho4

Received: 7 April 2015 / Accepted: 10 April 2015 Ó Springer Science+Business Media New York 2015

Abstract Cancer stem cells (CSCs) play an important role in cancer growth, self-renewal, metastasis, recurrence and radio/chemotherapy. However, the underlying mechanisms remain elusive. In this review, we explore the roles of CSCs in cancer’s relapse and progression and discuss the biomarkers of CSCs to predict clinical outcome and their diagnostic potential. The different approaches of CSC therapies are also reviewed, including cytotoxic, radiation, differentiation and targeting signaling pathways. We also discuss the challenge of targeting CSCs in cancer therapy. In addition, non-coding RNAs in CSC therapies are also discussed. Keywords Cancer stem cells
Signaling pathway
Therapeutics
Epithelial–mesenchymal transition

Introduction CSCs are able to be isolated from either the primary cancers or sphere in the serum-free cell culture medium with supplement of cell growth factors, such as epidermal

& William Chi Cho [email protected] 1

Department of Otorhinolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

2

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA

3

Department of Neurology, Changsha Central Hospital, Changsha, Hunan, China

4

Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong

growth factor (EGF), basic fibroblast growth factor (bFGF) and/or B27 in vitro. Studies have shown that as few as 100 CSCs injected into immunocompromised mice form a tumor similar to its parental tumor, whereas more than 1 9 105 non-CSCs remain nontumorigenic. Some CSCs have a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, such as in colonic cancer, acute leukemia, ovarian cancer, brain cancer and so on [1–4]. Some biomarkers are identified as markers of the CSCs, such as CD133, CD44, aldehyde dehydrogenase 1 (ALDH1) [4–6]. However, these biomarkers cannot uniformly mark the CSCs. Some scientists argue that tumorpropagating cells (TPCs) [7] and circulating tumor cells (CTCs) [8] are also kinds of CSCs, including prostate cancer and hepatocellular cancer. During the conventional treatments, the majority of cells in the tumor bulk are killed, but the sparse CSCs in cancer can regenerate the whole tumor. Some CSCs are quiescent in the cell cycle, while some are active or activated by some stimulating substances in the proliferative phase. CSCs enhanced resistance to traditional therapies compared with non-CSCs, including radio- and chemotherapies [3, 9]. Even more, some low-dose chemotherapy or radiotherapy could induce some cancers to form or enhance CSCs [10]. Apart from conventional treatments, how should we treat cancer? Maybe, there are some strategies to give the new avenue to block or eradicate CSCs so that to wipe out cancer. Though CSCs have strong capability of resistance to therapy, they are sensitive to some rare chemotherapeutic drugs and signaling inhibitors. Adikrisna et al. [11] identified that quercetin was specifically toxic to CSCs in pancreatic cancer. When Notch signaling pathway was blocked by c-secretase inhibitors (GSIs), brain cancer cell’s colony formation

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and spheroid rates decreased efficiently and the expression of CSC markers, such as CD133, NESTIN, BMI1 and OLIG2, was reduced in vitro. When the cells pretreated by GSI injected subcutaneously into nude mice did not form tumors, the vehicle CSCs not pretreated by GSI could form tumors [12]. Similar results were found in the breast cancer stem cells (BCSCs). When using picropodophyllin, specific inhibitor of the IGF-1R, suppressed phospho-AktSer473 ALDH? BCSCs preferentially decreased and CD44?CD24BCSCs easily tended to epithelization [13].

Biomarkers of CSCs in cancer progression and recurrence Increasing evidence has confirmed that CSC is the initial driving force of cancer cell self-renewal that driving tumorigenesis and promoting progression in many cancer types, although it remains unclear [14]. Chan et al. identified that Skp2 (F-box protein, constituting one of the Skp1-Cullin-1-F-Box (SCF) ubiquitin E3 ligase complex) positively regulated CSC populations and self-renewal ability through high-throughput silico screening. A specific Skp2 inhibitor had antitumor potential to reduce cancer cell survival. They proved that Skp2 might be a target for inhibiting CSC and cancer progression [15]. Although many biomarkers have been identified to mark CSCs, their correlation with patient prognosis has not been clearly established. In patient cohort with glioblastoma, CD133 mRNA expression is demonstrated as a CSC marker and is a significant prognostic factor for progression and overall survival [16]. CD44 gene expression is an important factor influencing relapse in postoperative patients, as higher levels of expression of ABCG2 have more frequently present in colon cancer patients with unfavorable CSC gene profile tumors, those with worse prognosis [17]. Higher levels of CD133 expression are associated with shorter times of relapse-free interval and overall survival. Multivariate analyses revealed that CD133 emerged as a preference prognostic marker in colorectal cancer [18]. In basaloid lung carcinoma, Cox proportional hazards regression analysis showed a sixfold increased risk of relapse and a 4.2-fold increased risk of disease-related mortality in stage-specific embryonic antigen-4 (SSEA-4)-positive patients [19]. Epithelial–mesenchymal transition (EMT) is known as one of the properties of CSC and a key factor in cancer metastasis and relapse. In gastric cancer, telomerase reverse transcriptase (hTERT) positively correlates with EMT marker expression. In addition, hTERT stimulates EMT and cancer cells to CSCs, and promotes cancer metastasis and recurrence [20].

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Diagnosis of CSCs The different biomarkers can represent large parts of CSCs, although not all CSCs, such as CD44, CD133, ALDH1. The positive biomarker cancer cells may be used to diagnose the cancers or for therapies. Mustjoki et al. [21] investigated the proportion of Philadelphia chromosomepositive leukemic stem cells (LSCs, Ph?CD34?CD38-) and progenitor cells (LPCs, Ph?CD34?CD38?) from 46 chronic myeloid leukemia (CML) patients, of which both were by imatinib or dasatinib therapy. The LSCs were associated with leukocyte count, hemoglobin, and spleen size and blast percentage. A low initial LSC percentage was correlated with less therapy-related hematological toxicity. After tyrosine kinase inhibitors (TKIs) therapy to patients with CML, the LPCs and LSCs decreased significantly in both groups, but 3 months after therapy, the median LPC level was lower in dasatinib group than in imatinib patients. These results showed that LSC burden might be a target of TKI therapy and diagnostic significance to rapidly eradicate the majority of them to treat patients. Pollard et al. [22] analyzed adherent cell lines of malignant glioma through chemical and genetic screens and found that glioma neural stem (GNS) cell lines from different tumors displayed different gene expression signatures and differentiation behavior, which were associated with specific neural progenitor subtypes. The purity and stability of adherent GNS cell lines had more significant advantages than ‘‘sphere’’ cultures, which were good for studies of CSC behavior and be useful for clinical diagnosis of the CSCs in oncology. Zhao et al. compared non stem tumor cells (NSTCs) and CSCs in order to find whether chromosomal aberrations could work as diagnostic markers and/or therapeutic targets. As a result, they found that the chromosomal changes were different between the two kinds of cancer cells and might represent new markers for anti-CSC therapies [23]. In breast cancer, Pece et al. used PKH26, PKH26positive cells having all the properties of human normal mammary stem cells (hNMSCs), to isolate the stem cells from the normal gland and from breast tumor. They found that CSCs enriched in poorly differentiated (G3) cancer compared to well-differentiated (G1) cancer. Therefore, the proportion of the positive biomarker cancer cells may have the diagnostic potential in oncology [24]. If a biomarker can diagnose the early stage of the cancer, it will be good for patients. Lgr5 has been identified as a marker for intestinal CSCs. Lgr5 is demonstrated as a promising biomarker for early diagnosing premalignant lesions before polyp formation in colon tumors [25]. However, we know that some biomarkers not only can detect CSCs but also

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detect the normal stem cells. So, to diagnose the cancer cells or CSCs in patient with normal state, borderline tumor or cancer is difficult. Yilmaz et al. found that hematopoietic stem cells (HSCs) could not maintain themselves when deleted tumor suppressor gene Pten compared with leukemia-initiating cells. Mammary target of rapamycin (mTOR) inhibitor rapamycin was able to restore normal HSC function but depleted leukemia-initiating cells [26]. Besides, it is found that small molecule thioridazine, an antipsychotic drug, selectively targeted CSCs while having no impairment on normal blood SCs. This may be also used to differentiate CSCs from cancer cells and normal SCs [27].

Cytotoxicity-directed CSC therapy There are many potential mechanisms of CSCs resistant to drug treatments. ABCB, ATP-binding cassette box, enhancing drug efflux is one of the mechanisms for multidrug resistance. ABCB5, one of the ABCB gene family and expressing in oral squamous cell carcinoma (OSCC), is associated with tumor formation, metastasis and a putative CSC compartment. It explains why putative CSCs can survive and may lead to tumor relapse [28]. ABCB5 mediates doxorubicin efflux transport, and ABCB5 inhibition significantly enhances intracellular drug accumulation, suggesting that ABCB5 may be a novel molecular marker to enhance cytotoxic efficacy for treating melanoma [29]. Several drugs that selectively inhibit CSCs do not constrain or nearly effect disadvantage to non-CSCs. Metformin, a drug for type 2 diabetes, is proved to possess selective anticancer properties. It reduces the proliferation rate of tumor-initiating cells isolated from human glioblastomas and has a higher reduction in proliferation of CD133-positive cells compared with CD133-negative cells. The effects are associated with inhibition of Akt pathway, which also confirmed lack of significant inhibition of normal human stem cells [30]. Compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8) can induce cell death of primary acute myeloid leukemia (AML), blast crisis CML (bcCML), acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). It also selectively has cytotoxic effect on colonyforming progenitors and LSCs in vitro and in xenotransplantation model. In contrast, there is no significant toxicity to normal hematopoietic progenitor and stem cells [31].

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Glioblastoma multiforme (GBM), an aggressive brain cancer, is resistant to chemotherapy and radiotherapy and incurable now. CD133 is a brain CSC marker, and CD133? tumor cells are resistant to radiation. CSCs preferentially activate the DNA damage checkpoint when they expose to radiation, and more effectively repair radiation-induced DNA damage compared with non-CSCs. When the checkpoint kinase 1 (Chk1) and Chk2 are inhibited, the specificity of CD133? glioma stem cells is reversed. Therefore, targeting cell-cycle Chks may overcome CSCs’ resistance to radiation therapy and give a therapeutic implication for malignant cancers [32]. CD44, a major cell surface hyaluronan receptor regulating the matrix metalloproteinase, is a biomarker of CSCs that has been investigated in a variety of cancer types. Xu et al. [33] found that CD44 functioned upstream of the mammalian Hippo signaling pathway and downregulating the Hippo signaling pathway promoted cancer cell resistance to cytotoxic agent and reactive oxygen stress. Therefore, inhibition of CD44 may enhance the efficacy of chemotherapy and radiotherapy.

Notch signaling pathway-directed CSC therapy Notch signaling regulates and maintains both murine somatic and human embryonic stem cells [34, 35]. Notch signaling activation inhibits oligodendrocyte precursor differentiating toward oligodendrocytes [36]. In addition, Notch signaling is also associated with cancer. Nicolas et al. [37] first documented that NOTCH1 was a tumor suppressor gene in mammalian skin. Tonon et al. [38] proved that Notch signaling functioned as a dominant oncogene. Furthermore, Notch signaling modulated growth and proliferation of CSCs and targeting Notch signaling pathway might thus inhibit selectively CSCs [39]. For example, Hovinga et al. found that c-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity of glioblastoma stem cells [40] and accompanied putative CSC marker CD133 downexpression. Notch pathway also plays a critical role in regulating radioresistance of glioma stem cells. Blockade of Notch signaling pathway made the glioma stem cells more sensitive to radiotherapy [41]. Thereby, targeting Notch signaling pathway of CSCs is an efficient strategy to treat cancer.

Radiation-directed CSC therapy

Wnt/b-catenin signaling pathway-directed CSC therapy

A number of hypotheses have been proposed to explain why CSCs are resistant to radiotherapy. However, the specific mechanism has not been elucidated yet.

Wnt/b-catenin signaling contributes to physiology and pathology of tissues by regulating cellular development and homeostasis, including proliferation, differentiation,

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survival, oxidative stress, morphogenesis, and others [42], and is associated with diseases, such as familial exudative vitreoretinopathy, osteoporosis, myeloma [43]. Willert et al. investigated the Wnt/b-catenin signaling functions in self-renewal and proliferation of stem cell. It has been found that purified Wnt3a protein regulates self-renewal of haematopoietic stem cells and pluripotency of embryonic stem cells. Therefore, Wnt signaling in cell-cycle progression has potential use in regenerative medicine [44– 46]. It has been reported that Wnt signaling plays an important role in regulating cancer progression, growth, especially the gene APC in colorectal cancer [47] and is targeted to cancer therapy [48, 49]. Because cancer is resistant to conventional therapies, finding the signaling target points to wipe out cancer becomes a challenging issue. Importantly, CSCs hold an important status in cancer metastasis, recurrence and radio/chemotherapy resistance; therefore, targeting signaling pathways of CSCs to treat cancer may be a feasible way [50]. Wnt/b-catenin signaling is accumulated in cancer stem-like cells [11], and therapeutic target to CSCs may reach the aim to treat cancer [51]. Several studies have proved that Wnt/bcatenin signaling blockade in CSCs leads to the inhibition of cancer growth, such as in gastric cancer. Mao et al. [52] used salinomycin to inhibit gastric tumor growth through suppressing Wnt signaling in CSCs. This may have efficacy of clinical applications in cancer therapy. Another study reports that Wnt/b-catenin signaling regulates stem-like transition and EMT, which may be treating cancers through modulating the CSCs transition [53].

PI3 K/Akt/mTOR signaling pathway-directed CSC therapy PI3 K/Akt/mTOR signaling pathway has an important role in regulating CSCs. For example, targeting PTEN to inhibit the Akt/PKB pathway could reverse EMT and phenotype of CSCs [54]. Li and Zhou [55] found that blockade of the Akt signaling pathway could significantly suppress the EMT and expression of CSC marker CD44. Some phosphoinositide 3-kinase inhibitors, including 2-(4-morpholinyl)-8-phenylchromone, LY29400, quercetin, analogs of quercetin, could inhibit proliferation of normal cells, such as smooth muscle cell, but not inhibit phosphoinositide 4-kinase or tested protein and lipid kinases [56]. Quercetin, a naturally occurring bioflavonoid, is able to inhibit phosphoinositide 3-kinase and more importantly could especially inhibit CSCs, but nearly not affect non-CSCs [11]. This gives us an option that inhibiting certain one signaling pathway might eradicate CSCs to treat cancer.

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Many signaling pathways have crosstalk with each other to communicate signals for proliferation, self-renewal and radiochemotherapy resistance (Fig. 1). In T cell lymphoblastic leukemia, Notch signaling and the PI3 K-AKT pathway synergize to inhibit leukemia cell tumorigenesis and mutation of lost PTEN is associated with the cells resistant to NOTCH1 inhibition [57]. It has shown that VEGF signaling has correlation with AKT/mTOR signaling in human epithelial ovarian cancer, in which VEGF-A signaling could activate the AKT/mTOR pathway of tumor cells [58]. Furthermore, mTOR inhibitor, rapamycin could inhibit prostate cancer cell secretion of IL-8 or VEGF levels and reduce CSC marker CD44 expression [59]. Hence, combination of different signaling pathways might be an efficient method to inhibit cancer cells and CSCs.

EMT-directed CSC therapy Some signaling pathways exhibit important roles in the process of cancer cell EMT. For example, Akt activation is coupled to the onset of differentiation of embryonal carcinoma cells through coordinating phosphorylations of pluripotency/differentiation factors, including downregulation of stem marker Oct4, Klf4 and Nanog [60]. Aldaz et al. [61] demonstrated the terminal differentiation and senescence of GBM-initiating cells (GICs) through blocking NF-jB pathway. They also discovered that dynamic expression of the microRNA changed during differentiation of GICs. b-catenin signaling regulates the cancer stem-like EMT [53]. In addition, it is found that Notch signaling is inhibited in Wnt-induced differentiation of CD133-positive GBM cells and that crosstalk between HIF-1a, Wnt, and Notch signaling mediated the pro-differentiating effects of GBM cells [62]. Wnt/b-catenin signaling alone modulates the delicate balance between differentiation and stemness of adult stem cell and prompts tumor growth and malignant behavior [50]. The biomarkers of CSCs are reduced after CSCs differentiate, and growth and proliferation are also inhibited. For example, in breast cancer, picropodophyllin inhibit CD24-CD44? BCSCs to undergo the EMT process; meanwhile, the mesenchymal markers downregulated [13]. In high-grade gliomas, when the stem cells differentiate, the expression levels of both CD90 and CD133 are reduced [63]. But, it is required that find some drugs which just target CSCs rather than impair other cells. Gupta et al. used high-throughput screening to investigate the biomarkers of the cancer cells, knockdown of E-cadherin, which acquired typical CSC features of low CD24, high CD44 and the capacity of forming mammospheres. They also demonstrated that salinomycin could induce the metastasis cancer cells, using 4T1 murine carcinoma cells constructed an

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Fig. 1 Signaling pathways in cancer stem cell

orthotropic mouse model of lung metastasis, to express plasma membrane-E-cadherin, so especially targeting the CSCs to kill cancer cells rather than targeting non-CSCs. In the contrast, paclitaxel induced more cancer cells metastasizing in lung. So, salinomycin might eradicate CSCs by inducing their differentiation instead of cytotoxicity [64]. Retinoic acid, a potent modulator that coordinates proliferation and differentiation of normal stem cells, was applied in inducing stem-like glioma cell (SLGC) differentiating, which had antiangiogenic, antitumorigenic and anti-invasive traits. After SLGCs were differentiated by retinoic acid, their chemosensitizing and radiosensitizing effects increased [65]. Other factors modulating the differentiation of CSCs also affect tumorigenic of CSCs. For example, IL-15 directly acts the epithelial differentiation of renal CSCs by CSC pool depletion and differentiates to nontumorigenic cells that make the cells sensitive to chemotherapeutic agents [66].

Therapeutic potential of non-coding RNAs for CSC therapy Non-coding RNAs (ncRNA) locating in intron are a kind of RNAs from gene transcription, containing small ncRNAs (\200 nucleotides, such as microRNA, piRNA) and long ncRNAs ([200 nucleotides, such as lncRNA), which cannot code proteins [67]. In recent years, scientists find that

ncRNA plays great role in cells’ posttranscriptional regulation such as cancer cells’ self-renewal, migration, metastasis and recurrence [68]. MicroRNAs acting on CSCs In recent years, microRNAs have predominately played a great role in cancer cells or CSCs. On the one hand, microRNAs could regulate the self-renewal and differentiation of CSCs. Yu et al. found that overexpression of let-7 reduced proliferation, mammosphere formation and the proportion of mammosphere formation and undifferentiated cells in breast tumor-initiating cells (BT-IC), while depletion of let-7 could enhance non-T-IC self-renewal [69]. Shimono et al. also detected the expression of microRNAs in BCSCs and nontumorigenic cancer cells, in which 37 microRNAs existed in different levels. What is more, they also found that the expression of BMI1 was modulated by miR-200c which strongly restrained BCSCs to form mammary ducts and tumor formation in vivo [70]. On the other hand, some microRNAs can modulate the cancer cells’ EMT, considered as one characteristic of CSCs. Song et al. confirmed that miR22 played very important roles in modifying epigenetic and promoting EMT and metastasis of BCSCs [71]. They also investigated that miR-22 enhanced hematopoietic stem cell self-renewal with defective differentiation, while inhibition of it leads to proliferation blocked in both mouse and human leukemic cells [72]. Moreover, microRNAs have the

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function of signal transduction or interacting with signals. In colorectal cancer, miR-146a inhibited the MEK or Wnt activity to reduce the symmetrical division of colorectal cancer stem cells (CRCSCs) by interfering with the Snail-miR146a-beta-catenin loop [73]. In ovarian cancer, miR-101 takes part in regulating CSC stemness and increasing metastatic and tumorigenic potential through myeloidderived suppressor cells (MDSCs)-miR-101-C-terminal binding protein-2 (CtBP2)–stem cell core genes [74]. Furthermore, microRNAs affect EMT-associated CSCs by interacting with important gene such as miR-200c interacting with p53 [75]. Long non-coding RNAs and CSC therapy Scientists have been focusing on the emerging role of lncRNAs, especially when these RNAs have great roles in many biological processes, which contain modulating gene repression and apoptosis, reprogramming pluripotent stem cells [76, 77]. In breast cancer, large intervening non-coding RNA (lincRNA): HOTAIR, a kind of lncRNAs, enforces epithelial cancer cells translate to fibroblasts, which leads to cancer gene expression alteration and strengthens cancer invasiveness and metastasis in a manner dependent on Polycomb repressive complex 2 (PRC2) [78]. More importantly, long non-coding RNAs regulate the CSCs’ growth, self-renewal and differentiation. For example, in non-small cell lung cancer (NSCLC), BRAF-activated non-coding RNA (BANCR) overexpresses and regulates EMT to affect NSCLC metastasis [79]. LncRNA H19 levels were found significantly increased in bladder cancer tissues, and upregulation of lncRNA H19 was closely related to bladder cancer cell migration accompanying with EZH2 change and E-cadherin expression inhibition [80].

Challenges of CSC therapy in clinical trials Although there are many CSC biomarkers and signaling pathways and CSCs have genomic instability and may differentiate to other dormant cells, it is challenging to design clinical trials with stem cell-directed therapies [81, 82]. In addition, gene methylation is also a factor affecting the stem cell-directed therapy, such as promoter methylation of Wnt target genes, ASCL2 and LGR5, strongly predicting that CSC gene signatures may implicate differentiation status of the cancer [83]. miRNAs affect cancer growth, proliferation and progression. Among them, let-7 family have important role in regulating CSCs [84, 85]. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, controlled stem cell function. In prostate cancer, loss of let-7 family and overexpression of EZH2 are inversed by 3,39-diindolylmethane

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by Bio Response-DIM (Boulder, CO, USA) in experiments and ongoing phase II clinical trials [86], suggesting that targeting miRNA may also a stem cell-directing therapy. In addition, immunotherapy with autologous dendritic cells vaccine used in metastatic melanoma patients is proved to be associated with longer survival [87].

Future perspectives CSCs have very strong capability of proliferation and selfrenewal; therefore, inhibiting proliferation and self-renewal of CSCs is able to block cancer growth [88, 89]. In addition, many different signaling pathways activated in CSCs, consequently, inhibiting signaling pathways can completely block the tumorigenesis and completely wipe out cancer [90, 91]. Although monoclonal antibodies are considered to have selective property to eliminate cancers, such as anti-CD133 antibody dCD133KDEL targeting CD133-positive ovarian cancer cells, which is a selective therapy [92, 93], it is also unsuccessful because no antibodies can label and kill the CSCs. Notably, cancer cells undergoing the EMT become CSCs, so inhibiting CSCs mesenchymal transition totally removes the cancers [65], which remains under investigation. Furthermore, DNA damage, methylation and demethylation are applied to change the DNA construction of CSCs to achieve the aim to clear cancers [32, 83], but it is also not feasible. Microenvironment plays a critical role in forming a niche for cancer self-renewal and growth [94]. In pancreatic cancer, pancreatic stellate cells are important component of the tumor stroma, which secret the embryonic morphogens NODAL/activin for creating a paracrine niche for pancreatic CSCs and promote their in vitro sphere formation and invasiveness [95]. So, targeting the microenvironment may regulate the CSCs. Similarly, in brain tumor cells, endothelial cells as niche microenvironment compounds secrete factors to maintain these cells self-renewing and stem cell-like state. Therefore, targeting vascular niches might be a therapeutic approach to kill CSCs [96]. Moreover, it has been suggested that some CSCs can migrate in long distant organs, which are called migrating cancer stem cells [97]. If special biomarkers can be used to track the primary CSCs and migrating CSCs, then targeting these CSCs for therapy will be available. The biomarker, signaling and gene damage repair seem effective to treat cancer, but these methods cannot eradicate CSCs so as to cancer metastasis and recurrence. Noncoding area of gene, ncRNA, gives a new novel research way to interfere cancer. LncRNAs are also new points to treat CSCs, although they are unclear until now, lncRNA H19 being a case [80]. A new therapeutic strategy targeting

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miR-203 to regulate stem cell renewal factor Bmi-1 can control self-renewal and proliferation of esophageal cancer stem-like cells [98]. Some miRNAs play great roles in the repression of E-cadherin by zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2 to regulate EMT, including miR-200 family, its feedback loop or feedforward loop [99, 100]. These provide strong evidences to treat CSCs with targeting non-coding RNAs. As many ways of CSC therapy have crosstalk [53, 75], combination of self-renewal, radio/chemotherapy, ncRNA, signaling pathways and cell differentiation may be a powerful strategy to treat cancer.

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15. Conflict of interest The authors declare that there is no conflict of interests regarding the publication of this paper. 16.

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