1、Contents lists available at ScienceDirectSeminars in Cancer Biologyjournal homepage: cancer stem cells and their niche:perspectives for futuretherapeutic targets and strategiesYue Zhaoa,b,1,Qiongzhu Dongc,1,Jiahui Lia,Kaili Zhangc,Jie Qina,Jiangang Zhaoa,d,Qiye Suna,Zhefang Wanga,Thomas Wartmannb,Ka
2、rl Walter Jauchd,Peter J.Nelsone,LunXiu Qinc,Christiane Brunsa,aGeneral,Visceral and Cancer Surgery,University Hospital of Cologne,Cologne,GermanybDepartment of Surgery,Otto-von-Guericke University,Magdeburg,GermanycDepartment of General Surgery,Huashan Hospital&Cancer Metastasis Institute&Institute
3、s of Biomedical Sciences,Fudan University,Shanghai,ChinadDepartment of General,Visceral und Vascular Surgery,Ludwig-Maximilian-University(LMU),Munich,GermanyeMedizinische Klinik und Poliklinik IV,Ludwig-Maximilian-University(LMU),Munich,GermanyA R T I C L E I N F OKeywords:Cancer stem cellsMicroenvi
4、ronmentMetastasisStem cell nicheTherapy resistanceA B S T R A C TA small subpopulation of cells within the bulk of tumors share features with somatic stem cells,in that,they arecapable of self-renewal,they differentiate,and are highly resistant to conventional therapy.These cells havebeen referred t
5、o as cancer stem cells(CSCs).Recent reports support the central importance of a cancer stem cell-like niche that appears to help foster the generation and maintenance of CSCs.In response to signals provided bythis microenvironment,CSCs express the tumorigenic characteristics that can drive tumor met
6、astasis by theinduction of epithelial-mesenchymal-transition(EMT)that in turn fosters the migration and recolonization of thecells as secondary tumors within metastatic niches.We summarize here recent advances in cancer stem cellresearch including the characterization of their genetic and epigenetic
7、 features,metabolic specialities,andcrosstalk with aging-associated processes.Potential strategies for targeting CSCs,and their niche,by regulatingCSCs plasticity,or therapeutic sensitivity is discussed.Finally,it is hoped that new strategies and relatedtherapeutic approaches as outlined here may he
8、lp prevent the formation of the metastatic niche,as well ascounter tumor progression and metastatic growth.1.IntroductionMost malignant tumors persist as an exceptionally complexed eco-system comprised of normal cells of host tissue with different cell typesof reactive tumor stroma that helps drive
9、the diverse phenotypic het-erogeneity and malignancy of solid tumors 1.Part of this tumorheterogeneity is represented by a class of cells that are referred to ascancer stem cells(CSCs).CSCs are thought to display high metastaticpotential and help impart resistance to conventional anti-cancertherapy.
10、CSC are thought to be relatively rare immortal tumor cells thatcan both self-renew,and also give rise to the tumor cell heterogeneitythat characterizes the complex architecture of solid tumors.CSCs havebeen identified in various human cancers and are thought to representimportant targets for the eff
11、ective treatment of cancer 2.CSCs havebeen linked to tumor survival.These cells are thought to be dormant inunfavorable environments,but are activated in response to appropriateconditions 3.These unique attributes underscore how CSCs can con-tribute to tumor growth,the formation of metastases,and tu
12、mor re-currence following therapy 4.Recent findings have provided in-formationconcerningthesignalingpathwaysandspecificmicroenvironments that contribute to metastasis,stem cell survival andthe resistance to conventional therapy mediated by CSCs 5.The interaction between tumor cells and the tumor mic
13、roenviron-ment(TME)influences the phenotype of tumor cell types 6.The TMEis comprised of various cell types including fibroblastic cells,immunecells,endothelial and perivascular cells,as well as extracellular matrix(ECM)components,cytokines,growth factors and extracellular ve-sicles.CSCs are thought
14、 to reside within,or adjacent to the tumor en-vironment,in anatomically specialized regions referred to as the CSC“niche”that maintain the distinct properties of CSCs.The CSC nicheplays an important role in maintenance of the stem cell pool 7.It isthought to help induce the generation of CSCs,mainta
15、in the CSCs in thehttps:/doi.org/10.1016/j.semcancer.2018.08.002Received 30 April 2018;Received in revised form 30 July 2018;Accepted 2 August 2018Corresponding authors at:General,Visceral and Cancer Surgery,University Hospital of Cologne,Cologne,Germany.1Contribute equally.E-mail addresses:yue.zhao
16、uk-koeln.de(Y.Zhao),christiane.brunsuk-koeln.de(C.Bruns).Seminars in Cancer Biology 53(2018)139155Available online 03 August 20181044-579X/2018 The Authors.Published by Elsevier Ltd.This is an open access article under the CC BY-NC-ND license(http:/creativecommons.org/licenses/BY-NC-ND/4.0/).Tstem l
17、ike state,protect them from the immune system,and contributeto the induction of epithelial-to-mesenchymal transition(EMT),leadingto enhanced migration and recolonization as secondary tumors.This review highlights recent findings detailing the complex biologyof CSCs and their interaction with the tum
18、or microenvironment,therole CSCs play in tumor metastases,and how they foster resistance tocancer therapies.By understanding these processes,we are beginning toidentify novel strategies to better target this important cancer cellsubtype.2.CSC genetics and epigeneticsCSCs are characterized by their a
19、bility to self-renew,a limited dif-ferentiation capacity,and ability to foster malignant tumor growth 8.When compared to normal stem cells,the self-renewal capacity of CSCscan be seen as enhanced,but lacking the growth control seen in normalcells;the differentiation capacity of CSCs is limited,and p
20、rogeny cellsare not fully functional as tumor cells.There are two theories regardingthe potential origins of CSCs:The first suggests that CSCs are derivedfrom normal stem cells,or progenitor cells,that have undergonetransformation or reprogramming;the second proposes that CSCs aregenerated from full
21、y differentiated cells via reprogramming 9.Evi-dence supporting a stem cell origin for CSCs includes the activation ofWNT signaling seen in the crypt stem cells that lead to adenomas 10.By contrast,Schwitalla,et al.reported that intestinal tumors are formedby the dedifferentiation of mature intestin
22、al epithelial cells into a stemcell-like state 11.Moreover,Friedmann-Morvinski,et al.observedthat post-mitotic neurons can be dedifferentiated to form malignantgliomas in mice 12.It is thus possible that what we refer to as CSCscan be derived from both stem/progenitor cells,or from fully differ-enti
23、ated cells(Fig.1).Importantly,CSCs can be seen as a term de-scribing a special cellular phenotype in cancer.The pool of CSCs isthought to interconvert with non-CSCs in a dynamic fashion,driven bygenetic and epigenetic events 1315.Genomic instability is a hallmark of cancer cells.It is accepted thata
24、n accumulation of genetic mutations represents the major cause forneoplasia 16.Gain of function mutations in oncogenes(e.g.KRAS),and loss of function mutations in tumor suppressor genes(e.g.TP53),endow cancer cells with an enhanced self-renewal capacity that helpthem outcompete neighboring cells,thu
25、s contribute to tumor initiation13,17.As tumors progress,they accumulate more somatic mutations.In pancreatic ductal adenocarcinoma(PDAC),four predominant geneticmutations(KRAS activation,CDKN2A inactivation,TP53 inactivationand SMAD4 inactivation)occur in a temporal pattern from low-gradepancreatic
26、 intraepithelial neoplasias(PanINs)to high-grade PanINs18.Do the genetic lesions differ between CSCs and non-CSCs withinthe tumor?Klevebring D.,et pared whole genome sequencingdata of CSCs(CD44+/ALDH1+)with paired primary tumor samples,and found that CSCs share the majority of somatic mutations foun
27、dwithin the bulk tumor 19.This study suggests the presence of dy-namic reversible events moderating the phenotypes between CSCs andnon-CSCs.However,the genetics of CSC biology is still poorly under-stood.Genetic mosaicism is an area that is beginning to be studied athigher resolution using single-ce
28、ll genome sequencing.A more in-depthunderstanding of this biology will require the broad and systematicapplication of single cell analysis.To date,the relevant studies are stilllacking,but will benefit from as this technology is more widely applied.These and related studies should help address centr
29、al questions such asif specific somatic mutations are linked to metastatic CSCs or therapyresistant CSCs.Epigenetic events have also been strongly associated with CSCbiology.Liu C.C.,et al.showed that lung cancer CSC populations wereincreased as a result of hypermethylation of the TP53 and P21 genes
30、 byDNA methyltransferase 1(DNMT1)20.In acute myeloid leukemia(AML),histone modifications(H3K4me3 and/or H3K27me3)were re-ported to be significantly involved in gene expression regulation duringFig.1.The architecture of stem cell-and cancer stem cell niche.Y.Zhao et al.Seminars in Cancer Biology 53(2
31、018)139155140CSCs to non-CSCs transition 21.In studies of prostate cancer,thehistone demethylase family has been shown to be activated in responseto hypoxia leading to the demethylation of repressive H3K9me3 sites inandrogen receptor genes,thus promoting the self-renewal capacity ofthe tumor cells 2
32、2.Loss of DNA methylation(hypomethylation),or aloose chromatin structure,which is thought to facilitate the dediffer-entiation process,has been described in CSCs 9,23.Feinberg,et al.identified a subgroup of genes that act as“epigenetic mediators”,whichare seldom found to be mutated,but frequently re
33、present a target ofepigenetic modification.These include the genes OCT4,NANOG,SOX2and KLF4 9.These epigenetic mediators also play important roles ingenetic reprogramming,and have been proposed to be responsible forCSCs initiation 9.In pediatric malignancy,where it is often difficult toidentify somat
34、ic mutation,a general increase in epigenetic disorder isthought to act as a driver for cancer initiation and progression.Forexample,the bi-allelic loss of SMARCB1,a chromatin remodeler gene,has been shown to contribute to highly malignant pediatric rhabdoidrenal tumor 24,25.The dynamic intersection
35、of genetic instability and epigenetic ab-normality is thought to underlie cancer initiation,progression andchemotherapy resistance 2628.Genetic mutations in epigeneticregulators have been shown to influence the epigenetic landscape oftumor cells classified as CSCs.DNA methyltransferase 3a(DNMT3A),wh
36、ich is responsible for DNA methylation,is frequently mutated inacute myeloid leukemias 29.A mouse model with a targeted deletionof DNMT3A in hematopoietic stem cells(HSCs)showed increased self-renewal capacity in conjunction with an impaired capacity for HSCdifferentiation 30.Other studies have desc
37、ribed genetic mutationevents that are induced as a consequence of epigenetic instability.O6-methylguanine-DNA methyltransferase(MGMT)belongs to the DNArepair gene family.Silencing of MGMT by DNA hypermethylation in itspromoter region leads to increased presence of G to A mutations,whichhave been obs
38、erved in the critical TP53 and KRAS genes 31.Whencomparing matched patient samples from pediatric acute lymphoblasticleukemia taken at the time of diagnosis,and after relapse,an enrich-ment of mutations in epigenetic modifiers(i.e.H3K36 methyl-transferases)was observed,suggesting a role for genetic
39、mutation andepigenetics in cancer progression 32.Suda et al.reported that anEGFR secondary mutation leading to change from threonine to me-thionine,at codon 790(T790M),is associated with epidermal growthfactor receptor(EGFR)tyrosine kinase inhibitor(TKI)resistance in non-small cell lung cancer(NSCLC
40、)33.Sharma et al.also showed thatresistance to TKI in NSCLC requires histone demethylase(KDM5A)andIGF-1R signaling 34.CSCs share genetic and epigenetic complexity with differentiatedcancer cells,but differ in the way they confront survival challenges.Forexample,cytotoxic drugs are commonly used in c
41、ancer chemotherapy.However,due to their slow cell proliferation rate,in comparison toother tumor cells,CSCs are thought to gain the time needed to generatenew survival strategies(e.g.new mutations,trans-differentiation orreprogramming),while other more rapidly growing cancer cells arekilled 35.Durin
42、g the metastasis process,CSCs are more likely toovercome the physical barriers needed to seed remote organs and po-pulate metastatic niches 24.Finding novel targets in the biology ofCSCs represents an important direction of cancer research.Under-standing this biology can further provide new potentia
43、l prognosticmarkers.3.Metabolic profiling of CSCsCell metabolism plays a critical role in determining the fate of CSCs,and ultimately cancer progression 3638.It is noteworthy that tar-geting specific metabolic pathways in CSCs may represent a promisingtherapeutic strategy.It is conventionally though
44、t that stem cells preferglycolysis rather than oxidative phosphorylation(OxPhos)for theirenergy needs.In part,this is thought to provide protection against thegenesis of reactive oxygen species(ROS).However,recent studies haveshown both metabolic patterns in different stem cell settings.Whenhematopo
45、etic stem cells(HSCs)are quiescent in their relatively hypoxicbone marrow niche,they employ glycolytic metabolism 39,40.Pro-liferation and differentiation in HSCs coincides with a switch to OxPhoswith a corresponding increase in ROS production 41.In the case ofintestinal stem cells(ISCs),OxPhos and
46、glycolysis are compartmenta-lized.Highly proliferative Lgr5+ISCs display elevated OxPhos levels,whereas adjacent paneth cells use glycolysis and supply lactate to ISCsfor the oxidative metabolism of the latter 42.Glucose is thought to bean essential nutrient for CSCs as glucose levels positively cor
47、relate withCSC numbers in cancer cell populations 43.However,there is nocommon consensus regarding an overriding use of glucose for energy.Itappears that CSCs share numerous properties with normal stem cells,including their flexibility regarding energy production.In addition totheir ability to self-
48、renew and a further differentiation into daughtercells,CSCs also show metabolic plasticity.In several studies comparingCSCs to non-CSCs,CSCs were found to be more glycolytic as evidencedby an upregulation of glycolytic enzymes,leading to more consumptionof glucose resulting in lactate production 444
49、7.In addition,recentreports have indirectly suggested that glycolysis may also play a role inthe acquisition of stemness during EMT.In a breast cancer study,thetranscriptional repressor Snail was shown to silence expression of thefructose-1,6-biphosphatase(FBP1)gene,which led to a reduction inglucon
50、eogenesis and an enhanced glycolytic metabolic state in breastcancer cells during EMT 48.A second study suggested that inhibitingthe EMT-linked transcription factor ZEB1 in pancreatic tumor cellsblocked their progression to EMT and switch to glycolytic metabolismwhen OxPhos was inhibited 49.CSCs wit
