the concept of cancer stem cells ( csc ) arose from the discovery that a majority of cells from some human leukemia ( acute myeloid leukemia ) , at different stages of differentiation , originated from transformed undifferentiated pluripotent stem cell .
this led to the hypothesis , then the theory , that as in the normal somatic stem cells ( ssc ) and their derived tissues , a small population of cells , the cancer stem cells ( csc ) would reproduce ad infinitum and generate the very diverse , limited lifespan , multi - lineage differentiated majority of cells in a cancer , called the derived population cells ( dc ) ( fig .  1 ) .
this was the concept of an aberrant stem cell system , a system gone awry . in agreement with such a scheme , csc were assumed to originate from somatic stem cells ( ssc ) and to represent a minor , qualitatively distinct , eternal population , transforming deterministically and irreversibly in a limited lifespan , more or less differentiated hierarchy of derived cells that would constitute the bulk of phenotypically diverse cancer cell populations .
of course clinicians , frustrated by the only partial and transient success of their therapies , liked the idea .
if the concept was valid , they would have to deal with one well - defined , but difficult to identify and study , population of cells responsible for a cancer .
this would allow them to solve the problem of a cancer with one therapy well aimed at these cells .
for industry the definition of different causal populations of cells in different patients would also allow proposing combinations of diagnoses and treatments for each patient .
the experimental support of the concept was essentially that in xenotransplant experiments in immunologically deficient mice , only a minor fraction of the injected cells would generate tumors : the cancer stem cells .
the origin of the csc in the transformation of ssc seemed logical . in cell - shedding tissues , like the skin and mucosae
, it makes sense , as only the ssc would have the time to accumulate the range of mutations necessary for cell transformation .
however , if the first oncogenic event is to confer an increase in loco of the lifespan to the cells , this would not be necessary .
in fact , in experiments in various models in which an oncogene was expressed all during the cells reproducing and differentiating sequence , the transformation took place at the stage of pluripotency as well as of unipotency and even later ( for review , see ref .
, although , to our knowledge , it was not formally expressed , the concept of a minor population of cells , responsible for the progression and evolution of a cancer cast a doubt about the validity and interest of the work on epigenetics and transcription expression performed in bulk tumors , in which most of the cells would be degenerate or terminally differentiated .
the fundamental results of such studies in our knowledge of the biology of cancer and on prognostic diagnosis disagree with this concept : for instance gene expression allows to clarify and treat specifically breast and other cancers .
the notion of csc as a qualitatively distinct population of cells has been implicit and sometimes expressed .
it is not supported by the various experimental tests applied to the cells ( transplants , sphere formation in vitro , cell sorting with biomarkers , etc . ) which always show overlaps with other cells ( dc ) .
on the other hand , if properly transplanted in fully immune - compromised mice , more than one - third of human melanoma cells generate tumors , i.e. , would be csc . even in acute lymphoid leukemia ,
intratumor heterogeneity also bears against the concept of one population of cells generating all the cells in a cancer .
for example , the intratumor heterogeneity of human glioblastomas and other tumors suggests a multiclonal evolution compatible with the stochastic but not the csc model .
another implied property of csc is , as for ssc , the irreversibility of the transformation in more differentiated cells , dc .
this property , in fact , is now questioned for ssc and embryonic stem cells ( esc ) , since the expression of just 4 transcription factors has now been shown to be sufficient to convert fully differentiated cells to an esc state , and progenitor cells spontaneously revert to ssc upon crypt cloning . as for csc  dc cell interconvertibility , the constant conversion of a few csc cells in many multiplying dc is certainly easier to demonstrate than a rare reversion of these numerous dc into a tiny minority of csc .
the irreversibility is not valid in the case of human melanoma and is disproved by the regeneration over time in culture of a diversified cell population from purified dc and by the generation of cancer cells with stemness properties spontaneously following oncogene expression in primary p53-null mouse cells or metastasis or following emt induction in cell lines .
conversely , csc , emt , chemoresistance characteristics are acquired by lung cancer cell lines after treatment with anti egfr drugs . linked to the concepts of irreversibility and qualitative nature of csc to dc transformation
the deterministic character of the conversion was even related to the semiconservative character of dna replication , an asymmetric cell division , of one csc to one conserved csc and one derived cell .
this deterministic character opposes all the evidence in favor of stochastic mechanisms of cancer cell diversity .
of course , again , if these properties applied only to csc , the therapeutic problem would also converge on this cell population .
however if csc multiply fast ( vide infra ) , it should be related to another attribute .
indeed abcg drug transporters and enhanced dna repair have been observed in some cancer cells .
however , again , the congruence of these properties with the other proposed csc properties has not been demonstrated .
the analogy between ssc and csc has even been extended to the concept of the niche .
in fact , rapidly dividing supposed csc are often found in preferential sites of the tumor , e.g. , near capillaries .
however , it is a farfetched extrapolation to interpret these favorable spaces as preordained sites , the niche .
it seems simpler , even if less spectacular , to assume that an oxygen - rich environment is more favorable for proliferation .
the use of biomarkers , allowing purifying , to some extent , csc by cell sorting , has greatly contributed to the expansion of the field ( e.g. , cd44 , cd133 , ald4 ) .
however , the validity of these biomarkers is cast in doubt by one disturbing fact .
although the question was asked several times in reviews , sequential cell sorting purifying csc having all the properties and biomarkers of csc has , to our knowledge , never been reported .
in fact , the fraction of cells expressing one biomarker in breast csc was not expressing another biomarker . with this and other methodologies ,
the separation of a proportion of cells by any criterion ( whether seeding capacity , sphere formation , biomarker - based cell sorting , etc . ) assumes that the property used is stable in tissue , i.e. , cells in a negative phase of any fluctuating property ( e.g. , epigenetic , transcriptional , feedback linked control ) will be missed .
of course this would not apply to a qualitatively irreversibly well - defined csc population ! in fact , any criterion used to define a cell population applies to those cells that answer it at the moment it is used .
in fact some of them are good markers for normal tissue adjacent to a tumor . in the csc literature
, there has always been an ambiguity with regard to the proliferative or quiescent state of the csc cells .
in fact , the normal stem cell models have opposite characteristics : while esc are strongly proliferative , ssc were , until recently , considered as rarely dividing cells .
this was even used , for some ssc , as a criterion to identify them by the remnants of their dna labeling . however , even for some ssc , it is now accepted that there may be 2 interconverting populations of ssc , one quiescent , one proliferating . the concept of quiescent csc , while useful to explain the continued presence of cancer cells after therapy , does not fit in with other proposed properties of the supposed csc : e.g. , the spheroid formation assay , which allows purification to some extent csc by selective growth , the sp cells which extrude drugs and which would soon disappear if they reproduced less than other cancer cells . moreover ,
this concept is even more incompatible with the existence of csc in cell lines : they would soon disappear .
with the progressive abandonment of claimed ssc and esc properties , the csc concept has evolved toward the existence of very competitive cancer cells continuously generating a majority of cells , less active , degenerating , and with limited reproduction capacity and even survival potential .
it explained the important discrepancy between cell proliferation rates , evaluated by tritiated thymidine labeling of biopsies , and the measured in vivo tumor growth rate in breast cancers . this has been confirmed and visualized more directly by the more sophisticated method of linear tracing in experimental models in which the expression of an oncogene is induced at a chosen time and the consequences examined in the cell of origin of the tumor and in its successive descendants .
the hierarchy of progressively more diversified tumor phenotypes , in fact , reproduces the well - known behavior of cells in developing metastases .
it is easily explained by the fact that most genetic ( and probably epigenetic and others ) events , when not neutral , lead to loss of competitiveness and much more rarely to an increase of competitiveness . in the case of cancer cells , as in esc ,
the default state of the cell is differentiation , which may be due to loss of the stem cell program . in this framework ,
the different characteristics of so - called csc do not necessarily coexist in the same cells .
in fact , in several cases , cells that exhibit the biochemical markers of csc are precisely not those that have the functional characteristics of sphere formation and tumorigenicity .
the progressive simplification and evolution of the definition of csc has been called euphemistically  a paradigm shift  and described as  the plasticity of csc  ,  plasticity and clonal diversity of csc  ,  stemness as a flexible quality of cancer cell  ,
this constantly evolving definition has of course made the concept an elusive target for critical analysis .
reprogramming stemness with nanog and lin28 may even reverse back the cancer character of sarcoma cells and , as shown more than 30 y ago , the oncogenic potential of teratocarcinoma cells after grafting in blastocysts was reversed .
is stemness not rather a property or phenotype that cancer cells may have , lose , and even acquire , like the other hallmarks of cancer , rather than the definition of a distinct population of cells ?
in the present stage of uncertainty , the use of a precise well - defined terminology based on operational definitions would certainly clarify a literature confused by the use of the variously defined , constantly changing , fuzzy concept of csc .
the literature proposes such definitions : the cell of origin of a tumor ( cot ) is the one in which the original oncogenic event(s ) occurred .
the tumor initiating cell ( tic ) is the cell that first showed the signs of transformation and initiated the tumor .
it may not necessarily be the cell of origin : for instance , in linear tracing experiments the expression of the oncogene begins at the time chosen by the experimenter , but the transformation may occur at a later stage of the cell evolution ( e.g. , pluripotent cell ) .
cell of origin and tic identity may bear on the phenotype of the resulting tumor .
the tumor propagating cell ( tpc ) or cancer repopulating cell is the already committed cancer cell that is able to generate a tumor ; for instance , in xenotranplants the cancer cell transplant does not initiate a cancer , it merely propagates it in a new site .
xenotransplants can be orthoptic ( implanted at the site of the naturally occurring tumor ) or ectopic ( other sites ) . in situ and metastatic propagations should be distinguished . 
cancer stemloids  would be the rapidly dividing , evolving cells of the cancer that generate the slower dividing , more differentiated  derived cells  .
this is a phenotype adopted for example by disseminated tumor cells , which at some time may explode in metastatic growth . in some cases ,
( e.g. , cd44++ cd24- cells , cd133 + cells , aldehyde dehydrogenase - expressing cells adh , etc . ) should be called by their operational property , e.g. , cd133 cells etc .
cancer cells expressing an embryonic stem cell program , essential for maintaining dedifferentiation , and thus repressing the expression of the various differentiation programs that constitute the hierarchical descendants of these cells , are just cells expressing the stemness esc program or pluripotency .
such a program may totally or partially overlap with other programs developed at some time by cancer cells , such as the epithelial 
the 3 programs stemcellness , emt , and radioresistance can be induced together by emt inducing transcription factors ( e.g. , zeb ) in some cell lines .
thus , stemness would be a hallmark or a phenotype of cancer , probably linked to dedifferentiation , characterizing in a cancer some cells at some time
. there would not be a separate population of csc , just as there is no population of cancer emt cells !
the stemness could be a functional ( transplant , hierarchy , etc . ) or / and a biochemical ( expression of esc inducing transcription factors ) property or hallmark .
in fact , the state of any given cell in a tumor results from the programs expressed , at the time of the investigation , by this cell . this is more or less reversible depending of the mechanisms involved , genetic , epigenetic , or resulting from a signaling equilibrium .
presumably , a large majority of tumor cells with a differentiated phenotype and a limited lifespan will never revert to active dedifferentiated phenotype .
of course , if to treat a cancer one had to target one population of well - defined csc , the aim of therapeutic research should be to find drugs for this target .
our and other analyses bear against this approach . on the other hand , if , as the evidence suggests , we have to deal with a constantly evolving diversified population of cells , the best therapies should then , as in the case of hiv , be simultaneous multi - target therapies : hit most of the cells at the same time , not allowing cells already resistant to one therapy to survive and permit some of them to acquire later resistance to another therapy .
 the cancer stem cells ( csc ) hypothesis represents a pathological extrapolation of the physiological concept of embryonic and somatic stem cells . in its initial definition , it encompassed the hypothesis of a qualitatively distinct population of immortal cancer cells originating from somatic stem cells , which generate in xenotransplants by a deterministic irreversible process , the hierarchy of more differentiated finite lifespan derived cells , which constitute , themselves , the bulk of the cancer . 
 these csc would express specific biomarkers and gene expressions related to chemo- and radioresistance , stemness , epithelial  
 mesenchymal transition , etc . 

 no convincing congruence of several of these properties in one cell population has been demonstrated . 
 the concept has greatly evolved with time and with different authors (  the plasticity of cancer stem cells  ) , leading to a minimal definition of cells generating a hierarchy of derived cells . in this article 
 these concepts are analyzed . 
 it is proposed that stemness is a property , more or less reversible , a hallmark of some cells at some time in a cancer cell population , as immortality , dormancy , chemo- or radioresistance , epithelial  
 mesenchymal transition etc . 
 these phenotypic properties represent the result of independent , linked , or more or less congruent , genetic , epigenetic , or signaling programs . 
The Cancer Stem Cell Concept
Proposed Attributes of the Cancer Stem Cells
Present State of the Literature
Necessity of the Use of a Well-Defined Terminology
Conclusion