Loureiro-2017-Mitochondrial biology in cancer.pdf

Contents lists available at ScienceDirectSeminars in Cancer Biologyjournal homepage: biology in cancer stem cellsRute Loureiroa,1,Katia A.Mesquitab,1,Silvia Magalhes-Novaisb,Paulo J.Oliveirab,Ignacio Vega-Naredob,c,aMax-Planck Institute for Metabolism Research,50931 Cologne,GermanybCNC-Center for Neuroscience and Cell Biology,University of Coimbra,UC Biotech Building,Biocant Park,3060-197 Cantanhede,PortugalcDepartment of Morphology and Cell Biology,University of Oviedo,33006 Oviedo,SpainA R T I C L E I N F OKeywords:MitochondriaCancer stem cellsMetabolismChemotherapyCell deathA B S T R A C TCancer stem cells(CSCs)have been suggested to be responsible for tumor re-growth and relapse.Physiologicaland morphological knowledge of CSCs may be essential for the development of new therapeutic strategiestargeting cancer development,progression,and recurrence.Current research is focused on a deeper under-standing of CSCs metabolic profiles,taking into consideration their energy demands.Energy metabolism andmitochondrial function are important factors operating on stemness maintenance and cell fate specification.Dueto the role of mitochondria as central hubs in the overall cell metabolism and death and survival pathways,research on their physiology in CSCs is of paramount importance to decipher mechanisms underlying theirtherapy-resistant phenotype.In this review,we focus on CSCs mitochondrial biology and mitochondria-relatedsignaling pathways that contribute to CSCs survival and maintenance,thereby representing possible therapeutictargets.1.IntroductionThe existence of different tumor types and the concept of tumorheterogeneity were proposed decades ago,being now widely accepted1.Such heterogeneity is represented by differential tumor cell po-pulations with distinct proliferative and differentiation capacitieswithin the same tumor bulk.Pioneering studies from Hewitt et al.2together with a later work from Lapidot et al.3 supported the idea oftumor heterogeneity,and suggested the hypothesis of cancer stem cells(CSCs)as tumor-initiating cells.Further studies by John Dick and col-leagues 4 replicated and transferred these findings to different tumortypes such as glioblastomas 5,breast 6 and colorectal tumors,among other neoplastic lesions 7,convincingly demonstrating theexistence of CSCs.Two models were proposed to explain tumor heterogeneity:theclonal evolution model(or stochastic model)based on the accumulationof mutations which leads to the loss of normal cell traits,and the CSCsmodel(or hierarchical model).In contrast with the stochastic model,the CSCs hypothesis suggests the existence of hierarchical and hetero-geneous cell populations within a tumor.Given their ability to in-definitely proliferate,the stem-like counterparts of those cell popula-tions would generate an entire tumor 810.It is noteworthy that thesetwo models are not exclusive,as showed in leukemic CSCs whichundergo clonal evolution 8.In fact,a publication from Tomasetti andVogelstein 11 proposed that CSCs could be mostly originated fromstochastic events occurring during DNA replication in normal adultstem cells.The authors claimed that cancer risk is strongly correlatedwith abnormal number of divisions in normal stem-cells.Random mu-tations during DNA replication would induce differential replicationprofiles which disrupt homeostatic balance of tissues,promoting tumororigin and development.Therefore,two hypotheses have been pro-posed regarding the origin of CSCs:one pointing out that a normalstem-progenitor suffering a hit mutation acquires tumorigenic potentialand self-renewal abilities,and the second suggesting that CSCs can arisefrom cells that undergone epithelial-mesenchymal transition(EMT)inwhich epithelial cells transform and acquire the capacity to disseminateand migrate through different tissues,suffering latter additional ded-ifferentiation events 12,13.Currently,CSCs are described as being a subset of tumor cellshaving unlimited self-renewal ability and the capacity to differentiateand generate cell diversity comprising a whole tumor.Specific CSCsphenotypes have been reported as clinically relevant to design strate-gies in order to prevent cancer initiation and relapse.This particulargroup of cells is highly tumorigenic,having high cell plasticity asso-ciated to the multiplicity of cell fate paths they can undertake,known as“dynamic stemness”1416.It is possible to identify CSCs through thehttp:/dx.doi.org/10.1016/j.semcancer.2017.06.012Received 29 October 2016;Received in revised form 24 June 2017;Accepted 27 June 2017Corresponding author at:Department of Morphology and Cell Biology,Faculty of Medicine,University of Oviedo,Julin Clavera 6,33006 Oviedo,Spain.1Both authors contributed equally to this work.E-mail address:(I.Vega-Naredo).Seminars in Cancer Biology 47(2017)1828Available online 30 June 20171044-579X/2017 Elsevier Ltd.All rights reserved.Tspecific expression patterns of markers 17,which vary within dif-ferent lineages.For instance,CD133 is normally associated with brain18,prostate 19 and colorectal 20 tumors,while CD24 and CD44are linked to breast 6 and pancreatic ones 20.In the same direction,aldehyde dehydrogenase(ALDH)21,the epithelial cell adhesionmolecule(EpCAM,ESA,TROP1)22 and microRNAs(miRNA)specificexpression 23 are others examples of specific markers allowing for theidentification of CSCs.CSCs have the capacity to re-colonize either in the primary tumorbulk or in other distant sites from the primary tumor 2426.AmongCSCs hallmarks,one can mention a slow cell-cycle kinetics 27,a highresistance to DNA damage and an increased capacity to repair suchdamage 28,29,together with a distorted telomerase function whichwas described to prompt cell immortality 30.Moreover,CSCs alsoshow an overexpression of multiple drug resistance transporters31,32,and a higher resistance to mitochondria-mediated cell deathmechanisms 33.Their specific microenvironment,based in hypoxicconditions with low pH values,contributes to stemness maintenance,and leads to the acquisition of new phenotypes through natural re-sistant clone selection 34,35.An important imprint on CSCs is theiraltered cell metabolism and related-signaling pathways which grantstheir resistant profiles,contributing to the failure of anticancer treat-ments.Mitochondria are key organelles involved in several processes re-lated to cell proliferation and survival.Mitochondrial functions in livingcells include,between others,the regulation of calcium homeostasis,cell signaling and fatty acid oxidation.Overall,their most importantfunction is the generation of ATP,which holds cell metabolism.Mitochondria have a central role in cell life and death decisions andrecent research points out a strong interplay between mitochondrialfunction and pluripotency states 36,37.Thus,a specific metabolicprogram involving mitochondrial remodeling appears to be intrinsicallyrequired to fullfil the demands of a pluripotency stage.It has beenpreviously described that during stem cell differentiation,higheramounts of energy are needed,supporting a proper remodelling of thebioenergetic machinery in order to increase mitochondrial oxidation ofsubstrates 3840.Given the central role of these organelles in cell lifeand death decisions,we will focus on mitochondrial physiology in CSCsbiology.2.Mitochondria in non-neoplastic stem cellsStem cells are classified into three broad categories:embryonic stemcells(ESCs)arising from the inner mass of early blastocysts and sharingthe ability to differentiate into cells from all three germ layers;somatic(or adult)stem cells(SSCs)that can be found in different adult tissues,and include cells such as mesenchymal stem cells(MSCs)and hema-topoietic stem cells(HSCs);and finally induced pluripotent cells(iPSCs)that are somatic cells(e.g.fibroblasts)artificially reprogrammed backinto an embryonic-like state through overexpression of stemness tran-scription factors.Although self-renewal and differentiation capacity diverge amongthe different types of stem cells,current evidence has demonstrated thatthe regulation of energy metabolism takes part in determining stemcells fate,especially by playing a critical role in stem cell maintenanceand differentiation 41.Thus,a large amount of data suggests a closeconnection between stemness and mitochondrial morphology andfunction.Mitochondrial ultrastructure presents clear alterations overthe entire span of the cell differentiation process.Mitochondria fromESCs are more immature,rare and globular,presenting poorly devel-oped cristae and a perinuclear localization 42,43.The differentiationof ESCs results in more mature mitochondrial cristae in a more fila-mentous mitochondrial network.Beyond these morphological altera-tions,mitochondrial biogenesis,DNA content and energy metabolismare also changed over the differentiation process 43,44.Mitochon-drial DNA instability,including mutations and/or altered copy number,has been described to specifically affect stem cells viability,functionand differentiation potential 45.Interestingly,increased levels ofmitochondrial DNA copy number and mitochondrial biogenesis wereassociated with cell differentiation 44,46,suggesting that decreasedmitochondrial activity is favorable to a stemness phenotype.The glycolytic pathway is preferred in ESCs that present low rates ofmitochondrial respiration and high lactate production.Therefore,andsimilarly to cancer cells,ESCs exhibit the Warburg effect,in whichglycolytic ATP production is preferred even in the presence of oxygen47,48.Although glycolysis is less proficient in terms of energy pro-duction,the generation of ATP is faster than by OXPHOS.Moreover,such preference for glycolytic-generated ATP is associated with lowerreactive oxygen species(ROS)production 49 that accounts forstemness maintenance either on hypoxia or normoxia.Nevertheless,ESCs have the capacity to switch between anaerobic glycolysis andmitochondrial OXPHOS.This metabolic switch is frequently observedduring ESCs differentiation,demonstrating an evident energetic plas-ticity in order to fulfill their specific energy requirements.In fact,dif-ferentiation of ESCs and iPSCs is associated with increased ATP levelsand reduced lactate production 50.Despite this,not all types of ESCsshow this energetic plasticity 51.One example was described inhuman ESCs(hESCs)which mostly meet their energy requirements viaanaerobic glycolysis 51.Zhou et al.52 mentioned that althoughhESCs present a more complex and expanded mitochondrial network,the decreased expression of cytochrome c oxidase(COX)indicates alower mitochondrial respiratory capacity.Mitochondria also play a crucial role in the reprogramming of iPSCs.The conversion from somatic OXPHOS to stem-like glycolysis pheno-type has been postulated to be required for reprogramming of cells intopluripotent stem cells.Hence,more than half of the proteins differen-tially expressed in iPSCs versus their differentiated counterparts show amitochondrial location,underlining the conservation of certain mi-tochondria-related factors which seem to be particularly important forthe maintenance of core pluripotency circuits 53.Somatic stem cells,MSCs or HSCs,also present immature mi-tochondria,although with higher mitochondrial activity when com-pared to ESCs 54.Their successful differentiation requires a furtherincrease in mitochondrial biogenesis and activity,together with a de-crease in the glycolytic flux 5557.It is undeniable that mitochondrial dynamics and biogenesis areinvolved in cell differentiation.Recent proof of concept is the studiesfrom Parker et al.58 and Khacho et al.59.Those authors demon-strated how changes in mitochondrial dynamics,namely through de-creased mitochondrial fission 58 or favored fusion processes 59,lead to the maintenance of a stem cell-like pool.All these data point out a bidirectional relationship between mi-tochondrial physiology and cell differentiation with important im-plications for regenerative medicine and cancer.3.Mitochondrial physiology in cancer stem cellsShifts on metabolic profiles have been recognized as driving forcesfor the initial stages of tumorigenesis 60.It is known that differenttumors show markers for CSCs,which are associated with tumor pro-gression and tumor migratory capacity 21,61,62.Considering tumorheterogeneity and CSCs as the hierarchical“bottom line”for cancerdevelopment and evasion 63,understanding CSCs metabolic featuresis of paramount importance to target their radio-and chemotherapeuticresistance profiles 6466.Metabolic aberrations in cancer related tomitochondrial dysfunction have been reported to be linked to the fol-lowing hallmark pathways as i)proliferative potential,ii)impairedapoptosis,iii)increased anabolism and iv)decreased autophagy67,68.Such mitochondrial alterations connect drug resistance pro-files with the blockade of cell death pathways.Regarding its metabolicprofile,CSCs share some of the characteristics described in the previoussection for ESCs.Actually,CSCs were reported by our group 43 andR.Loureiro et al.Seminars in Cancer Biology 47(2017)182819others 6971 to have a markedly glycolytic profile with increasedexpression of glycolytic enzymes,increased lactate production,togetherwith a decreased/dormant mitochondrial function.However,in con-trast to these findings,other authors evidenced the preference of CSCsfor OXPHOS metabolism,represented by increased mitochondrial massand function.De Luca et al.72 showed that inhibition of PGC1alpha,a transcription factor which stimulates mitochondrial biogenesis,de-creases CSCs markers in breast tumors.Other similar studies on pan-creatic 54 and ovary 73 tumors also pointed out the existence ofCSCs with an oxidative metabolism 45,which does not differ muchfrom that of more developed tumor cells.Despite the aforementionedreports about the involvement of mitochondrial function on the main-tenance of stem-like properties of CSCs,Liu et al.74 showed that highglucose concentrations within a tumor,increase the percentage of CSCsin the overall cancer cell population.The increased amount of CSCshappens through AMP-activated protein kinase(AMPK)suppressionand Akt activation,and is associated with an increased expression ofpyruvate dehydrogenase kinase(PDK),facilitating lactate productionand decreasing mitochondrial pyruvate oxidation.Thus,although clearevidences from the past years indicate that some CSCs isolated frombreast 75,nasopharyngeal 76 and hepatocellular carcinoma 77primarily rely on glycolysis for ATP production,CSCs from glio-blastoma 78,lung cancer 79 and pancreatic ductal adenocarcinoma80 prefer OXPHOS to generate ATP.Again,mimicking what occurs inmore differentiated tumor cells,the glycolytic Warburg-like preferenceof CSCs is being challenged by many exceptions.Actually,it is broadlyaccepted that ATP production in CSCs depends on glycolysis or OX-PHOS in a tumor type-dependent manner.Collectively,those reportsevidence the apparent heterogeneity and plasticity