defining cancer stem cells and their origins is of much controversy , and constitutes a challenged knockout for cell targeting- anticancer drugs .
herein , we put forward a hypothetic model for cancer stem cells initiation from bone marrow stem cells .
these later , will differentiate into an ancestral progenitor that activates a memorial program - the black box cassette- that is responsible of abnormal neo - organogenesis in the form of tumors and metastases . to approve this model
, we assume that characterizing and investigating the most primitive forms of the bone marrow progenitors is required ; both inside their niche and in circulation of cancer patients .
even as tremendous inventions had have ameliorated anticancer therapeutic practices , these pathologies ' developmental and progressive mechanisms are still disputed ; and inclined a chiefly limiting factor in front of drugs ' efficiency .
consequently , several opinions and hypotheses have been formulated to define tumorigenesis and metastasis origins .
johannes muller ( 1838 ) and her student rudolph virchow ( 1821 - 1902 ) were the first pathologists describing the cellular origin of cancer .
huge plethora of studies has depicted , one by one , cascades of cancer development , to finally draw the cancer stemness theory which is reinforced by several molecular and genomic scrutinies .
because of the important heterogeneity of the characterized cancer stem cells ( cscs ) , which are harbored within different kinds of tumors ; it was stubborn to accurately demarcate their origins . in regard of the copious common patterns shared with cscs
, we hope to highlight relevant opinions dealing with the possibility that bone marrow progenitors did initiate the cancerous transformation .
the cell transformation and progression , from normalcy to malignancy , could be simulated to a honey - bees ' colonial development and reproduction .
this insect 's queen gives naissance to numerous and various individuals , amongst which only rare genetically defined mature females ( future queens ) will generate new outposts , when and where conditions are favorable .
thus , in certain circumstances , normal cell will transform to a csc through several mechanisms , and acquire a genomic program enabling it to get patterns of " honey- bees ' queen " .
several works impressively assembled and described the cellular , molecular and genetic circuitry that is ensued by the transformed cell to result into metastases [ 4 , 5 ] .
they commonly stippled for a repeated cascade of events that permit various capabilities for tumoral cells : self- sufficiency in growth signals , insensitivity to antigrowth signals , escaping to apoptosis , unlimited replicative potential , sustained angiogenesis , tissue invasion , migration and metastasis . nonetheless , these events are physiological alterations , eroding the multi - cellular organism homeostasis , that are guaranteed by both the csc ( intrinsic factors ) and the surrounding microenvironment ( extrinsic factors ) .
the genetic and epigenetic alterations constitute the major intrinsic factors leading to the disease 's development and progression ; while extrinsic factors assemble various elements such as immune surveillance depletion ; aging   and inflammation .
these two factors constitute the basic trait for paget ' hypothesis : the seed and soil .
seemingly , the reliability between intrinsic and extrinsic elements outlines a rate of knot for csc evolutionary scenario .
thus , it is conceivable that each genomic modification might , reciprocally , match with an adequate environmental variation point .
whether these two sequential events fit one to other , is still an important inquiry to enlighten .
it was assumed that , at least , two or more mutational events ( genomic modifications ) should occur to initiate the primary cancerous transformation ; but to raise into metastasis in distant organs several passive and/ or active modifications are required , in both cscs ' daughters and their surrounding microenvironment .
garraway and sellers ( 2006 ) have developed a model of aberrant lineage ontogeny and somatic genetics , in order to explain the chronological evolving of the disease .
they proposed that tumorigenesis and metastasis arose from the activation of an inborn " backward " developmental program of lineage progenitors and their survival genetic programs .
such system might generate an ancestral form of stem cells that aberrantly grow and invade into the body , like as it occurred during organogenesis .
hold inactive in normal cells ' memory , this black box cassette is unexpectedly reactivated under some defined conditions , and will turn on a fastidious machinery of organogenesis leading to tumor development and metastases . in conjunction to the cancer stemness theory , this conception could bring simple explanations in oncology .
bone marrow constitute the primarily reservoir of stem cells ( bmscs ) in the body .
when bmscs are in contact with other tissues , they give raise to tissues ' neo- genesis . also , it has been revealed that bmscs acquire tissue morphology and landmarks , by spontaneous fusion with normal cells [ 15 , 16 ] .
thus , it is plausible to seek for bmscs as the origin of various cancer diseases
. some experimental models of bmscs transplantations into nude or immune- compromised animals prompted relative improving for their transformation into solid tumors [ 17 - 19 ] .
this pathologic deviation of bmscs could be mediated by the accumulated chromosomal instability , as observed in murine model . using similar experimental model , zheng and liang ( 2008 ) ,
showed that the donating - males ' bmscs did not contribute to the induced hepatocellular carcinoma into receptive females .
such debate might be caused by the important conditioning , like the immune system depletion that permits not only tumorigenesis but also any introduced pathogen 's growth .
so , clinical investigations are likely much relevant to improve our knowledge on the pragmatic release of tumorigenic cells from bmscs .
beyond , the great assays examining the genetic and cluster designating landmarks of cells , bmscs have been identified in the core of tumor , in cancer patients .
reciprocally , cancerous cells were found to circulate and to home into the bone marrow niche .
this mutual relocation of both tumorigenic cells and bmscs derived ones rappels the circulatory loops of immune cells . interestingly , osteosarcomas that could directly originate inside the bone marrow niche , is the most frequent metastasis in childhood .
furthermore , in myeloma patients , there are several chromosomal translocations that occur into osteoclasts ' nuclei . according to the authors , these genetic aberrations are hybrids of osteoclasts with myeloma cells .
tumoral cells have been characterized into bone marrow aspirates from non- metastatic , and disease- free breast cancer patients , after systemic recovery ; and in earlier stages ( i and ii ) of the disease [ 23 , 26 ] .
( 2011 ) , who summarized that the tumor progression is firmly dependent on bone marrow stromal cells ' lineages .
the most primitive form of bmscs , the innate bmsc , will replicate and self - renew to generate various normal progenitor lineages ( hscs : hematopoietic stem cells , and bmdscs : somatic bone marrow derived stem cells ) , in order to ensure homeostasis and damaged tissues ' repair . under the influence of various extrinsic and eventually intrinsic factors
, these progenitors will systematically lead to different kinds of the known myeloma ; diffuse and follicular lymphomas ; and distant sarcomas ( yellow panels ) .
( 2012 ) showed that a pluripotent stem cell derived from bmscs could re - differentiate into hematopoietic cells .
this prompted the possibility that bmscs produces an ancestral form of progenitors that exhibit an active engine dotted for organogenesis : the black box cassette ( green panels ) .
these ancestral cells exhibit embryonic - like stem cells properties and could be found both into bone marrow niche and the blood circulation . ultimately , they will easily enter sequential and spontaneous differentiations to any kind of stromal cells progenitors and migrate to a definite organ where they clone and contribute to tumorigenesis . perhaps , there will be swaying and switching between the yellow and green pathways , dependently on lineages ' nature and the surrounding microenvironment ( dotted lines ) .
perhaps , this might explain the possible reversibility of the metastatic neuro - blastoma observed in childhood .
furthermore , this theoretical scenario of tumor development and metastasis could reveal the mystery of cancers without defined origins .
several investigations evidenced the existence of such memorial program , in various stromal cells , which was expected to be under epigenetic factors ' control [ 33 , 34 ] .
so , the consecutive spatio- temporal variation in derived progenitor cells   would be subsequent to dna methylation dynamic that is supposed to guide memory in stem cells .
since that , the epigenetic alterations in bmscs will prompt the black box cassette program to viaduct an erroneous organogenesis ( figure 1 ) .
our opinion outlines that cancer initiating- cells could derive from bone marrow progenitors . to do so ,
bmscs are firstly pushed to generate an ancestral form of progenitors that have an activated memorial program - the black box cassette- leading to fastidious tissular neo - genesis .
this scenario , did involve few genomic modifications that are needed for the ancestral cell release ; whereas tumorigenesis and metastases progression are spontaneously mediated without requirement of further genetic interventions . in this way of thinking ,
the intra and inter- tumoral cells ' heterogeneity and diversity are quietly acquired during both the colonization or at the first transformations leading to various ancestral progenies of stem cells .
however , it could be envisaged that they are temporarily expressed by the progenitors as they have instable genomes . to get better comprehension concerning this hypothesis
, we suggest that fine - tuning of cells ' depicting techniques toward the characterization and isolation of the most primitive forms of cancer patients ' bmscs , into both bone marrow niche ( aspirates ) and the circulation ( blood and lymph ) , is necessary .
thereafter , accurate experimental models will be helpful to find the relationships between these cells and tumorigenesis and metastasis .
 backgrounddefining cancer stem cells and their origins is of much controversy , and constitutes a challenged knockout for cell targeting- anticancer drugs . 
 herein , we put forward a hypothetic model for cancer stem cells initiation from bone marrow stem cells . 
 these later , will differentiate into an ancestral progenitor that activates a memorial program - the black box cassette- that is responsible of abnormal neo - organogenesis in the form of tumors and metastases . to approve this model 
 , we assume that characterizing and investigating the most primitive forms of the bone marrow progenitors is required ; both inside their niche and in circulation of cancer patients . 