‘cancer Biol Med 2016. d REVIEW 10,20892/}.icen.2095-3941.2016,0076 Properties and feasibility of using cancer stem cells in clinical cancer treatment Xiao-Mei Gao, Rui Zhang2, Qiong-Zhu Dong*2, Lun-Xiu Qin}? Ins Hospital and Cancer Meta les of Biomedical Sciences, Fuclan University, Shanghai 200032, China: “Department of General Surgery, Huashan is Institute, Fudan University, Shanghai 200040, China ABSTRACT (Cancer treatment lure, dg resistance, oe rstvtaic recurrence ate tot tobe cased mainly by the eastenceof« very sl spumberofeancer stem cells (CSC¢), The characterises of this subgroup of elle include valfxeneval, tumorigenesis, mliple ferentiation and high invusiveness, metastasis, and drug resistance potential, Many studies have demonstrated that CSCé play {important roles in tumor growth spread and metaslaterelapee aller treatment, and are losey related to the prognosis of patients From a theapeutie viewpoint, deep insights inte the CSCs biology, development of specie therapeutic siategies for targeting csi KEYWoRDS: and characterization of hee microenvironment could beanies! way to combat cance. Cancer tem cells; cancer; treatment ulre metastasis cancer therapy Introduction As one of the most serious diseases that afllet humans, ‘cancer accounts for 15% of global mortality each year, Furthermore, 90% of patients with solid tumor die of metastasis, which consists of multiple processes associated with many factors, including epithelial-mesenchymal tansition (EMT) and cancer stem cells (CSCs)!. Even in a hematopoietic system, where the cancers can be eradicated, cancer relapse always occurs’. Although patients are diagnosed as disease-free after cancer treatment, cancer frequently recurs several months or years later because of the redifferentiation and colonization of a small group of CSC. "Thus, at present, C$Cs are considered as the cause of tumor initiation, relapse, metastasis, and drug resistance. The exploration of CSCs can be traced back to the ‘experiment on teratomas in the 18th century. At present, CSCs are widely considered as the root of tumors Hematopoietic malignancies are the focus of basic research and clinical tris on CSCs, However, over the past several decades, with respect to stem cell biology, an effective and satisfactory cure for cancer has not been developed yet. From Correspondence to: Lun-Xiu Qin small gink@tudaneducn Raceived September 62016; accepted October 24,2016 ‘Available at wor cancerbiomed.org Copyright © 2016 by Cancer Biology & Medicine this perspective, the complexity of CSCs is considered as the sain barrier for curing cancer, Thus, the origins, functions uring tumor metastasis, and differentiation of CSCs should be revealed with urgency. Cutting-edge studies on CSCs have already progressed from secking and screening related biomarkers to placing greater emphasis on the mechanism of ‘molecular regulation and clinical transformation, Until today, some CSCs biological features, which are regarded as distinct from the group's parental counterparts, continue to be revealed. CSCs always remain quiescent to suppress their own outgrowth and to maintain their long- rm survival until the stress from extra- or intra-tumor cells interferes and induces them to enter the eell cycle from GJG, phase to aberrant rapid proliferation’, Moreover, some signal pathways, such as phosphatidylinositol 3-kinase (PBI)/AKT, interleukin 6 (IL6)/stat3*, and Wavp-catenin’, which are closely associated with drug resistance, are abnormally activated, After CSCs or non-CSCs transform via an EMT and enter into circulation to become circulating samor eclls( ‘many proteins are ectopically expressed for the purposes of anti-apoptosis, immune escape, and even dormancy”. Currently, many clinical trials and pre-clinical experiments that target CSCs are ongoing. Molecular and pharmacological targeting of proline-rich tyrosine kinase 2 specifically induces cell death in aldehyde dehydrogenase (ALDH)-positive myeloma CSC”, However, CSCe could not be completely destroyed, and they allow the regrowth of tumor because of uncovered complicated characteristics.‘Therefore, CSCs are the cause of cancer treatment failure; on. the other hand, CSCs could be promising clinical targets for improving future cancer therapy! In this review, we discuss the role of CSCs in seeding ‘tumor and the possible strategies for using them in clinical ‘cancer treatment (Figure 1) Overview of CSCs ‘The theory on CSCs was proposed in 1967 by Bergsagel” who discovered that leukemic stem cells might exist in Philadelphia chromosome positive chronic myelogenous leukemia (CML). This observation challenged the traditional Darwinian “clonal selection theory, ” which advocates that tumor cells are derived from a single cell in the subelone”. During the past decades, more researchers have mentioned. that when a group of sub-clonal cells are on the verge of extermination, about 5% of these cells narrowly escape apoptosis and acquire more malignant phenotypic properties such as tumorigenesis, metastasis, self-renewal, and drug resistance, Eventually, in 1997, Bonnet et al! ascertained for the first time the existence of CSCs with the marker for (CD34"/CD38- in acute myeloid leukemia (AML). In 2008, Al-lajj et al successfully obtained CSCs from breast carcinoma by using the marker for CD44*/CD24-. Thereafter, CSCs were found in other kinds of solid malignancies, including those ofthe brain'* and the liver”. Although increasing evidence has indicated the existence ‘of CSCs, the origin of CSCs remains unknown. At present, three hypotheses are used to explain the origin of CSCs!™, First, adult stem cells or progenitor cells from normal tissues become CSCs because of somatic mutation accumulation at ‘Genetic oF epigenetic change F Progenitor cel Matured cole # ee as °— ae ‘Cancer stem cells Gao et al. Targeting cancer stem cells isa ideal therapeutic strategy the genetic or epigenetic level", or differentiated tumor cells become CSCs through EMT, This hypothesis attracts more researchers to exert effort on discovering the differences between CSCs and transformed cells. Learning about such differences may help modify curzent cancer treatments more precisely or even develop a completely, effective cure for cancer. Second, the differentiated cell and tissue stem cel fuse into a euploidy cell. The euploidy cell has an unstable genome, which is prone to mutating, and it ean finally transform into CSCs. This phenomenon is a rare event, but it might contribute to tumor progression. Third, the normal cells absorb exogenous DNA from nearby tumor cells and integrate the genetic material into their own genomes, resulting in the supprestion or ectopic expression of some genes and ultimately leading to the transformation of CSCs. This process is not easily recognized. Given the diversity ofthe hypotheses, the origin of CSCs still remains a fundamental issue to be addressed, CSCs: controversial biomarkers in solid tumor ‘The CSCs hypothesis contradicts the classical theory of clonal selection in which only CSCS is considered as the origin and seed of tumors. However, the heterogeneity of CSCs is universal. Thus, selecting a single specific CSCs biomarker for a certain type of cancer is arduous. For example, CD138, ALDHI* %, and side population cells have been used to identify multiple myeloma stem cells. CD13323, CD24", CD90", and CD47 are all approved to be the markers in hepatic CSCs; leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), CD133*, and CD44°* are used in colonic carcinoma, These markers indicate that distingui- ‘Therapeti strategies % Biomarkers targeting therapy mm) Signaing pathy targeting therapy §ok Microenvonment targeting therapy Figure 1 Origin, regulating mechanisms, and possible targeted therapy for CSCS.‘cancer Biol Med 3113, No 4 December 2016 shing CSCs from other kinds of cancer cells by surface biomarkers lone is difficult, This confusion may result from. the limitation of the current detection techniques and understanding of CSCs, The transformation of CSCs can be more suitably described as the clonal evolution of CSCs to survive in their changing microenvironment. The different biomarkers indicate that different potentials of CSCs emerge under certain conditions, including the accumulation of mutation, which maintains the long-term survival of CSCs, Thus, the (CSCs model and clonal evolution mode in cancers could co- exist. In fact, in some cancers, CSCs hypothesis is not considered because among cancer cells, the intrinsic differences, which are characterized as genetic and epigenetic differences among tumorigenic cancer cells that lack hierarchical organization”, can be explained by clonal evolution, In CML patients who relapsed after sequential treatment with the ABL inhibitors, imatinib and dasatinib, resistant BCR-ABL kinase domain mutations, including "T3LSI, are revealed in the CSC”. CSCs: seeds of metastasis Given the strong potential of the group, CSCs are regarded as the seeds of metastasis. When CSCs disseminate into ‘circulation, they may become a part of CTCs. Recently, many studies suggest that the portion of CTCs that can successfully form metastases may as well be CSCs or have some characteristics of CSCs. In breast cancer, a part of epithelial cell adhesion molecule (EpCAM)* CTCs expresses CD133* ‘or ATP-binding cassette sub-family G member 2°, hinting that CSCs could be the major functional cells in all CTCs, or only the CTCs with the characteristics of CSCs could survive ‘metastasis, Moreover, the patients who have CTCs with the phenotype or molecular type of CSCs have a more dismal prognosis", When metastasis progresses, CSCs in circulation, prepare to enter self-driven quiescence and decrease the ‘expression of ligands recognized by the immune system to survive. In breast cancer, metastatic stem celle highly express sex-determining region Y-box (SOX)2 or SOX9 and vupregulate dickkopf-related protein 1, inhibiting the Wnt signaling pathway and downregulating the natural killer cell, ligands”, In colorectal eancer, CD110" intestinal CSCs have a strong potential for liver metastasis. The thrombopoietin produced by the liver isa ligand of CD110, which induces Wat pathway activation and promotes the self-renewal of CSC¥,In colon cancer, reports showed that the expression of doublecortin-like kinase 1 and Lgx5 ate upregulated in both SCs and CICS”, Thus, many scientists combine CTC: related research with the ute of CSCs. 491 The communication between CSCs and the microenvironment in primary tumor affects the stemness factors or pathways facilitating the invasiveness and metastatic abilities of CSCs ™', After the formation of pre- to g0 “home” (o specific distal tissues. Finally, the changing metabolism of CSCs and the cross-talk of the cells with the metastases, some attractors could further guide C' new environment during the formation of metastatic cells also regulate the self-renewal and settlement of CSCs, The researchers aim to find intrinsic driving factors within these processes and to perform moze effective targeted therapies. In hepatocellular carcinoma, when CD44* CSCs are co- cultured with CD14° tumor-associated macrophage (TAM), their migration and tumorigenic abilities are enhanced by 1L6 from TAM®. In breast cancer, when CD90° celle interact with TAM, EpbA¢ is upregulated to modulate the activity of, CD90* breast carcinoma celle, In addition, the exosome, which is secreted by mesenchymal cells inthe primary tumor of pancreatic cancer, reaches the targeted organ in advance to remold the microenvironment, thereby facilitating the adaptability of metastatic pancreatic cancer cells and elevating their survival rate. Treatment strategies that target CSCs After cytotoxic treatments, such as chemotherapy, radiotherapy, or targeted therapy, the tumor initially shrinks or disappears; however, relapse may occur and cause the death of cancer patients", The theory on CSCé tries to identify the reason for this phenomenon, CSCs are considered as the "beating heart” of tumors. Thus, possibly, only by exterminating CSCs could cancer be cured. Actually SCs can be targeted through various strategies, such a: by inbibiting the molecular pathway(s) of CSCs4*, targeting OSC: of the microenvironment’, combining CSC-targeted therapy with chemotherapy, or differentiating inducers to promote the differentiation of CSCs into bulk tumor cells, Which can be eradicated by chemotherapy" (Table 1). Targeted treatments always focus on the cell surface or abnormally activated signaling pathway of CSCs or the cells in the niche, CD133", CD13", and CD24* could be targets for eliminating CSCs. The embryonic signaling pathways always abnormally activate CSCs, which are inhibited by. different inhibitors, such as cyclopamine, the prototype of Hedgehog (Hh) pathway-specific inhibitors; iCGOOL, which selectively inhibits Wnt/B-catenin signaling": and y-secretase inhibitors, which block notch signaling. Adoptive therapy with ALDH family member Al (ALDHIAL)-specific CD8+ T cells eliminates ALDH bright cells, which have the492 ‘Table 1 Treatment strategies for targeting CSCs Gao at al. Targeting cancer stem cells isa ideal therapeutic strategy Cancer types herapeutc strategies samples Umitation ‘Sold tumor Targeting specie surface biomarkers Targeting abnormal signaling pathways ‘coisa, coisa, coz ‘Cyclopamine (11-deoxojervine), the prototype of Hh pathway-specific Provided that CSCé and normal stem cells share many common characteristics, the treatments for targeting CSCé could als have side effects on normal stem cele inhibitors; CGOO1, which selectively inhibits Wnt/B-catenin signaling: y- secretas inhibitors, which block notch signaling argeting the stem cel niche Inducing differentiation ‘Adoptive therapy with ALDHLAL- specife cb8~ bright celle, calls eliminates ALDH ‘Oncostatin M induces EpCAM liver {CSCS to diferentiate into a hepatocyte lineage, making CSCs more sensitive to S-fuorouracil Hematologic neoplasm Targeting specific surface biomarkers Targeting abnormal signaling pathways (¢D233, CD44, CD47, €D123, CLL-A Inhibitor of 8%, ibrtinb, inhiots WwrtiB-catenin and AKT signaling characteristics of cancer-intiating cells, The curative effect of classical treatments may be increased when combined with the targeted therapy of CSCs. CS Ce resist drugs because of their quiescent state, whercas most drug treatments target proliferating cells. This characteristic suggests that stimulating CSCs to differentiate may increase their sensitivity to drugs. Oncostatin M induces EpCAM" liver CSCs to differentiate into a hepatocytic lineage, causing the ‘CSCS to be more sensitive to 5-fluorouracil™ In a hematological system, given that CSCs were first identified in AML in 1994, eradicating the leukemia stem cells (LSCs) has been regarded as the optimal way of decreasing the possibility of relapse. Similar to the solid ‘tumor, LSCs can be targeted with two kinds of treatment strategies, such as by interfering in the abnormal signal pathways or by targeting the specific surface biomarkers of LCSs*2’, Along with their unique ch alterations in many signal pathways, such as Wat, Notch, NI self-renewal, proliferation, motility, stemness mai acteristics, distinct -xB, and PISK-AKT, which play important roles in cell and survival, have been identified in LSCs compared with their normal corresponding hematopoietic stem cells (HSCs). Some inhibitors, such as asbortezomib, parthenolide, and rapamycin, which target abnormally activated pathways, have been developed. Bruton tyrosine Kinase (BTK), which could govern or at least participate in ‘Wntif-catenin and AKT signaling in myeloma stemness, is not expressed in normal plasma cells, Thus, the BTK inhibitors, including ibrutinib or CGI1746, are promising therapeutic candidates". However, the major concern regarding these inhibitors is their potential toxicity to the normal hematopoietic system because these pathways are also functional in HSCs. Thus, discovering a target that could selectively impair the survival, self-renewal, or proliferation pathways of LSCs is important. ‘The discovery of the specifie surface molecules of LSCs provides some important insights. An ideal therapeutic target should be expressed on LSCs but not on the normal HSCs, Several candidate antigens, such as CD33, CD44, CD47, D123, and CLL-1, have been identified“, The monoclonal antibodies against these markers show more specificity in in vitro experiments than the inhibitors of signal pathways. However, the expression levels of certain LSCs surface markers may vary greatly in patients. Even within the same patient, more than one phenotypically distinet sub- population of LSCs might be found. This information suggests that the cell surface antigen profiles of LSCs may vary. Another challenge in the treatment of hematological malignancies is that targeted druge cannot reach the appropriate concentration in circulation to induce an yblem, the surface systems. The multifunctional delivery using targeting ligands (e.g., hyaluronic acid to target CD44) and other combination effective action. To deal with this markers are combined with nano-deliv. herapeutics (e.g, siRNA with small molecular drug) can enhance the treatment efficacy”‘cancer Bial Med 3113, No 4 December 2016 and normal stem cells share many common characteristics, including stemness-related gene expression profiles and capabilities for self-renewal, development into lineages, and proliferation, Thus, the inkibitors that target could also have side effects on normal stem cells The side effects may be due lo the inaccurate experimental methods that simply regard CSCs as adult stem cells However, non-CSCs progeny could revert to CSCs under certain conditions, implying the dynamic transition between, Cs and non-CSCs"*, In addition, multi-lineage cs, because most papers published in recent years have shown that CSCs may. only possess mono-potential, which could result in non- ESCs. However, if all of these key points are addressed, specific Largeting of CSCs is possible. Robert A. Weinberg, an expert in CSCs-targeted therapy, is taking the risk with, treatment through his Verastem Incorporated, which has over 2 uillion dollars in investment and is conducting more than 60 C$Cs-related clinical trials differentiation is not a fixed feature of Problems and prospects ‘CSCs models have been established for most types of cancer, and related discoveries have revealed important information ‘on them, However, their applications in clinical practices still face many obstacles, First, given the uncertainty of CSCs- specific biomarkers, the criteria for CSCs are not simple and accurate enough, Second, the gold standard for approving CSCS is introducing them to immuno-d various doses by injection, which is time-consuming and ficient mice at expensive, Thus, administration ie another difficulty in the study of CSCs, Third, the origin of CSCs may vary, and a dynamic transition exists between CSC: "Therefore, eradicating the existing CSCs does not guarantee that non-CSCs will never transform into CSCs. Furthermore, provided that human cancer is a systemic disease under unbalanced homeostasis, the passive attitudes demonstrate and non-CSCs. that tumors may not disappear even after CSC: are liminated. In consequence, although CSCs are promising therapeutic targets, more comprehensive studies are needed. to uncover all myths involved in CSCs and to establish a bridge between the progress in basic studies and clinical application in routine cancer diagnosis and weatment of cSCs, Acknowledgments This work is supported by the grants from the National Key Basic Research Program of China (Grant No. 2013CB910500), 493 China National Key Projects for Infectious Disease (Grant No. 20122X10002-012), and National Natural Science Foundation of China (Grant No. 81372647). Conflict of interest statement No potential conflicts of interest are disclosed References 1. Gupta GP, Massague]. Cancer metastasis bulding 2 amework cal, 2006; 127: 679-85 2 Delude C. 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