Characteristics of Cancer Stem Cells (CSCs)

Transcription

1 GENReports: Market & Tech Analysis Characteristics of Cancer Stem Cells (CSCs) > Enal Razvi, Ph.D. Biotechnology Analyst, Managing Director Select Biosciences, Inc.

2 Topic,IntroducEon,and,Scope! The,focus,of,this,GEN,Market,&,Tech,Analysis,Report,is,to,frame,the, challenging,space,of,cancer,stem,cells,(cscs), CSC,research,and,clinical,translaEon,has,been,hampered,by,the,lack,of, bona% fide% characterisecs, of, this, cellular, class, and, agreement, within, the,research,community,as,to,their,role,in,metastaec,development, Indeed,!many!have!ques?oned!the!existence!of!CSCs!in#vivo# Do! CSCs! originate! from! the! primary! tumor! and! then! traffic! within! the! circula?on!to!distal!sites!to!give!rise!to!metastases?! What! is! the! rela?onship! between! circula?ng! tumor! cells! (CTCs)! which! are! known!to!be!increased!in!number!in!the!circula?on!of!cancer!pa?ents!visoào vis!cscs?!!!!is!one!cellular!class!the!progenitor?! The,challenge,in,the,study,of,CSCs,is,compounded,by,the,fact,that,the, surface,phenotype,of,bona%fide%cscs,is,controversial, In,this,GEN,report,,we,have,sought,to,address,some,of,the,data,that,is, available,and,provide,a,view,of,this,marketplace,based,upon,primary, market,research,we,have,performed,on,researchers,studying,cscs,

3 SchemaEc,RepresentaEon,of,PotenEal,Origins,of, Precursor,Invasive,Cancer,Cells! Source:!!Industry!sources.!

4 Biology,of,CSCs, " The cancer stem cell (CSC) hypothesis states that cells with long life spans must exist within the bulk population of a cancer to sustain the multiple rounds of mutations necessary for cancer formation " According to this model, human cancers originate from tissue stem or progenitor cells, and only a small fraction of these cells (CSCs) have the capacity to proliferate indefinitely " First described in patients with acute myeloid leukemia (AML), CSCs share many of the hallmarks of normal stem cells. For example, both of these cell types have the capacity to self renew and differentiate, however, unlike the highly-regulated self-renewal and differentiation decisions of normal stem cells, it has been suggested that cancer cells undergo uncontrolled self-renewal and abnormal differentiation " Furthermore, CSCs metastasize to distant organs and tissues much like somatic stem cells migrate to distant tissues, and most importantly both cell types exhibit resistance to apoptotic stimuli CSCs Behave like Stem Cells, Exhibit Migratory Behavior, and " Any disturbance of the tightly regulated processes that control self-renewal, cell fate (proliferation vs. apoptosis) and differentiation of tissue stem or progenitor cells may favor the emergence Exhibit of CSCs and Resistance the subsequent to development Apoptosis. of cancer CSCs are Heterogeneous with Respect to Surface " While the precise identity of CSCs in a given type of cancer remains to be identified and is highly controversial at present, it appears that CSCs may arise either from the Marker Properties malignant transformation of a tissue stem or progenitor cell, or alternatively, from the abnormal re-activation of stem cell pathways in a committed progenitor cell " The seemingly distinct (from the bulk tumor) and relatively small population of CSCs possess unlimited self-renewal and proliferation capacity and ultimately potentially sustain tumor growth. However, the proportion of CSCs within the bulk population remains questionable and controversial

5 DescripEon,of,Selected,Markers,for,CSCs,, Marker, Aldehyde! dehydrogenase! Bmi1! CD24! CD44! CD90!(Thy1)! CD105! CD117!(cOkit)! CD133! CD166! EpCAM!(ESA)! Side!Popula?on! DefiniEon, ALDH!gene!superfamily!encodes!detoxifying!enzymes! Normally!measured!by!FACS!aWer!ALDEFLUOR!staining!of!live!cells! Polycomb!protein!that!suppresses!the!INK4A!and!ARF!genes! A!sialoglycoprotein!which!acts!as!a!ligand!for!POselec?n!enabling!cells!to!bind!platelets! Transmembrane!glycoprotein!that!binds!hyaluronan!(HA).! A!glycosylphospha?dylinositolOanchored!protein!(GPIOAP)! A!type!I!integral!membrane!protein! A!receptor!tyrosine!kinase!receptor!for!Stem!Cell!Factor!(SCF)! An!important!marker!for!several!classes!of!CSCs,!probably!not!a!universal!marker!for!CSCs! Ac?vated!leukocyteOcell!adhesion!molecule!(ALCAM)! Epithelial!cell!adhesion!molecule,!a!glycosylated!type!I!integral!membrane!protein.!!Involved! with!components!of!wnt!signaling!in!s?mula?ng!cell!prolifera?on!awer!cleavage!of!epcam! intracellular!domain! Side!popula?on!defines!cells!able!to!efflux!fluorescent!dyes,!appearing!fluorescent!dull!by! FACS.!!This!phenotype!is!usually!dependent!upon!the!ABC!superfamily!of!membrane! transporters!

6 Overview,of,Surface,Phenotypic,Markers,Associated,with,CSCN containing,populaeons,in,various,cancer,subntypes, Cancer Class Glioblastoma, medulloblastoma CD133 + Markers used for identification and/or purification of CSC population Colon carcinoma CD133 +, CD44 +, Lin, EpCAM(ESA) + Mammary carcinoma CD24 /low, CD44 + Lung cancer CD133 + Pancreas carcinoma CD44 +, CD24 +, EpCAM(ESA) +, CD133 + Hepatocellular cancer CD133 + Head and neck squamous cell carcinoma CD44 + Prostate carcinoma CD44 +, α 2 β 1 high, CD133 + Hematological malignancies CD34 +, CD38 " CSCs,with,Different,Surface,Phenotypes,[Surface,Marker,Expression],are,Found,in,Different, Types,of,Cancers., " There,is,SEll,Significant,Disagreement,as,to,whether,there,is,a, Universal,CSC,Phenotype.,

7 Some,Cancer,SubNTypes,and,Associated,CSC, CharacterisEcs, Cancer Sub-type CSC Characteristics Glioblastoma [Aggressive brain tumor] " Glioblastoma stem cells are enriched in a population of cells that express CD133 " Expression of this marker has been linked to poor clinical outcome for the patient " CD133 + cells reside in the perivascular niche in close contact with endothelial cells and this may drive the tumor vasculature Chronic Myeloid Leukemia [CML] " CML stem cells are implicated in disease persistence " Primitive CD34 + CD38 - CML cells have increased expression of the Bcr-Abl protein which is linked with genomic instability and resistance to kinase inhibitors Intestinal Cancer " Cells within the crypts of the stomach, small intestine, and colon that express the GPCR LGR5 are long-lived stem cells " When the tumor suppressor protein APC is lost, these cells give rise to microadenomas and adenomas Breast Cancer " Cells with CSC-like characteristics (ALDH + CD44 high CD24 low ) have been shown to be enriched in patients with breast cancer treated with chemotherapy Prostate Cancer " A subset of cells that are CD133 +, α 2 β 1+, and CD44 + with basal cell characteristics have been shown to be tumorigenic in the prostate CSCs with Different Surface Phenotypes [Surface Marker Expression] and Characteristics are Found in Various Types of Cancers

8 Colorectal,Cancer,Stem,Cells, " Colorectal,cancer,(CRC),is,one,of,the,most,commonly,diagnosed,and,lethal,cancers,worldwide, " CRC, is, a, leading, cause, of, morbidity, and, mortality, worldwide, with, >1.2, million, new, cancer, cases, and, 600,000,deaths,esEmated,in,2008, " CRC, results, from, a, series, of, geneec/epigeneec, alteraeons, and, interaceons, with, micronenvironmental, and,germnline,factors,,that,transform,normal,colonic,mucosa,into,an,aberrant,phenotype, " The, intesene, is, subject, to, a, complex, crosstalk, of, conserved, pathways, such, as, Wnt,, Notch,, and, Hedgehog,,which,control,the,balance,between,proliferaEon,,differenEaEon,,migraEon,,and,renewal, " The, Wnt, pathway,is, responsible, for, endoderm, formaeon, and, exerts, a, fundamental, role, in, crypt, development,,maintenance,and,proliferaeon cnmyc,,cyclin,d1,and,lgrn5,are,its,various,targets, " MutaEons,in,the,APC,gene,(80%,in,sporadic,cancers),,βNcatenin,,or,the,regulatory,proteins,in,the,Wnt, pathway, result, in, consetueve, acevaeon.,, This, may, lead, to, uncontrolled, proliferaeon,, a, shif, from, asymmetrical,to,symmetric,divisions,,and,augmented,cell,survival, " Wnt,signaling,is,also,involved,in,the,process,of,EMT, " Notch,may,drive,tumorigenesis,because,it,potenEates,proliferaEon,,and,inhibits,differenEaEon, " TGFNβ,is,an,inhibitor,of,intesEnal,epithelial,cell,proliferaEon,and,an,inducer,of,apoptosis, " The,Hedgehog,proteins,carry,signals,between,stromal,and,epithelial,cells, " In, colorectal, carcinogenesis,, acevaeon, of, the, phosphoinosiede, 3Nkinase, (PI3K), pathway, results, in, a, rapid,and,excessive,proliferaeon,of,intesenal,stem,cells, " CD133, expression, in, CRC, lines, correlates, with, stem, cell, poteneal,, worse, clinical, prognosis,, and, low, survival, " In, addieon, to, CD133,, other, markers, proposed, as, CSC, markers, include, CD44,, CD24,, CD166,, LgrN5,, and, ALDHN1,

9 Markers,Currently,UElized,to,Characterize,CSCs:, QuanEtaEve,Market,Penetrance, Percent!of!Respondents!Surveyed! 25%! 20%! 15%! 10%! 5%! Respondents!could!choose! 1!marker,!therefore!sum!of!! percentages!=!100%! 0%! " The!Most!Penetrant!Markers!in!the!Research!Community!are!EpCAM!and!CD133! " CD44!is!also!Penetrant!in!the!Research!Community!

10 SegmentaEon,of,the,CSC,Marketplace,visNàNvis, the,intracellular/signaling,pathway,studied! Percent!of!Respondents!Surveyed! 45%! 40%! 35%! 30%! 25%! 20%! 15%! 10%! 5%! 0%! Respondents!could!choose!1!pathway! which!they!study!primarily,!therefore!sum!of!! percentages!=!100%! EMT:,The,Most,Penetrant,Pathway,which,is,Being,Studied,in,CSCs,Space,

11 The,Cancer,Stem,Cells,(CSCs),is,currently,an,amorphous, field,wherein,the,cscs,are,not,well,characterized,and, indeed,there,is,much,controversy,in,the,field,as,to,their, surface,phenotype,,intracellular,pathways,,and,role,in, metastaec,progression, We,have,sought,to,understand,the,marketplace,by, performing,market,surveys,of,researchers,studying, CSCs,,thereby,illuminaEng,the,current,research,trends, Much,remains,to,be,studied,in,this,field,as,the, interrelaeonship,between,cscs,and,ctcs,needs,to,be, clarified, CSCs,may,be,therapeuEc,targets,as,well,as,potenEally, biomarkers,for,cancer,progression,monitoring, In Summary