Cancer stem cell

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Figure 1: Stem cell specific and conventional cancer therapies

Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells.[1] CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals do not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is difficult to study.

The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill). As CSCs form a small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but do not generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause relapse.

Cancer stem cells were first identified by John Dick in acute myeloid leukemia in the late 1990s. Since the early 2000s they have been an intense cancer research focus.[2]

Tumor propagation models[edit]

In different tumor subtypes, cells within the tumor population exhibit functional heterogeneity and tumors are formed from cells with various proliferative and differentiation capacities.[3] This functional heterogeneity among cancer cells has led to the creation of multiple propagation models to account for heterogeneity and differences in tumor-regenerative capacity: the cancer stem cell (CSC) and stochastic model. However, certain perspectives maintain that this demarcation is artificial, since both processes act in complementary manners as far as actual tumor populations are concerned.[1]

Figure 2: A normal cellular hierarchy comprising stem cells at the apex, which generate common and more restricted progenitor cells and ultimately the mature cell types that constitute particular tissues.
Figure 3. In the cancer stem cell (CSC) model, only the CSCs have the ability to generate a tumor, based on their self-renewal properties and proliferative potential.

The cancer stem cell model[edit]

The cancer stem cell model, also known as the Hierarchical Model proposes that tumors are hierarchically organized (CSCs lying at the apex[4] (Fig. 3).) Within the cancer population of the tumors there are cancer stem cells (CSC) that are tumorigenic cells and are biologically distinct from other subpopulations[5] They have two defining features: their long-term ability to self-renew and their capacity to differentiate into progeny that is non-tumorigenic but still contributes to the growth of the tumor. This model suggests that only certain subpopulations of cancer stem cells have the ability to drive the progression of cancer, meaning that there are specific (intrinsic) characteristics that can be identified and then targeted to destroy a tumor long-term without the need to battle the whole tumor.[6]

Stochastic model[edit]

In order for a cell to become cancerous it must undergo a significant number of alterations to its DNA sequence. This cell model suggests these mutations could occur to any cell in the body resulting in a cancer. Essentially this theory proposes that all cells have the ability to be tumorigenic making all tumor cells equipotent with the ability to self-renew or differentiate, leading to tumor heterogeneity while others can differentiate into non-CSCs [5][7] The cell's potential can be influenced by unpredicted genetic or epigenetic factors, resulting in phenotypically diverse cells in both the tumorigenic and non-tumorigenic cells that compose the tumor.[8]

These mutations could progressively accumulate and enhance the resistance and fitness of cells that allow them to outcompete other tumor cells, better known as the somatic evolution model.[5] The clonal evolution model, which occurs in both the CSC model and stochastic model, postulates that mutant tumor cells with a growth advantage outproliferate others. Cells in the dominant population have a similar potential for initiating tumor growth[9] (Fig. 4).

Figure 4: In the clonal evolution model, all undifferentiated cells have similar possibility to change into a tumorigenic cell.

[10] These two models are not mutually exclusive, as CSCs themselves undergo clonal evolution. Thus, the secondary more dominant CSCs may emerge, if a mutation confers more aggressive properties[11] (Fig. 5).

Tying CSC and stochastic models together[edit]

A study in 2014 argues the gap between these two controversial models can be bridged by providing an alternative explanation of tumor heterogeneity. They demonstrate a model that includes aspects of both the Stochastic and CSC models.[7] They examined cancer stem cell plasticity in which cancer stem cells can transition between non-cancer stem cells (Non-CSC) and CSC via in situ supporting a more Stochastic model.[7][12] But the existence of both biologically distinct non-CSC and CSC populations supports a more CSC model, proposing that both models may play a vital role in tumor heterogeneity.[7]

Figure 5: Both tumor models may play a role in the maintenance of a tumor. Initially, tumor growth is assured with a specific CSC (CSC1). With tumor progression, another CSC (CSC 2) may arise due the clonal selection. The development of a new more aggressive CSC may result from the acquisition of an additional mutation or epigenetic modification.

The cancer stem cell immunology model[edit]

This model suggests that immunological properties may be important for understanding tumorigenesis and heterogeneity. Such, CSCs can be very rare in some tumors,[13] but some researchers found that a large proportion of tumor cells can initiate tumors if transplanted into severely immunocompromised mice,[14] and thus questioned the relevanve of rare CSCs. However, both stem cells[15] and CSCs[16] possess unique immunological properties which render them highly resistant towards immunosurveillance. Thus, only CSCs may be able to seed tumors in patients with functional immunosurveillance, and immune privilege may be a key criterion for CSCs.[17] Furthermore, the model suggests that CSCs may initially be dependent on stem cell niches, and CSCs may there function as a reservoir in which mutations can accumulate over decades unrestricted by the immune system. Clinically overt tumors may grow if: A) CSCs lose their dependence on niche factors (less differentiated tumors), B) their offspring of highly proliferative, yet initially immunogenic normal tumor cells evolve means to escape immunosurveillance or C) the immune system may lose its tumorsuppressive capacity, e.g. due to ageing.[17][citation needed]

Debate[edit]

The existence of CSCs is under debate, because many studies found no cells with their specific characteristics.[13] Cancer cells must be capable of continuous proliferation and self-renewal to retain the many mutations required for carcinogenesis and to sustain the growth of a tumor, since differentiated cells (constrained by the Hayflick Limit[18]) cannot divide indefinitely. For therapeutic consideration, if most tumor cells are endowed with stem cell properties, targeting tumor size directly is a valid strategy. If CSCs are a small minority, targeting them may be more effective. Another debate is over the origin of CSCs - whether from disregulation of normal stem cells or from a more specialized population that acquired the ability to self-renew (which is related to the issue of stem cell plasticity). Confounding this debate is the discovery that many cancer cells demonstrate a Phenotypic plasticity under therapeutic challenge, altering their transcriptomes to a more stem-like state to escape destruction.[19]

Evidence[edit]

The first conclusive evidence for CSCs came in 1997. Bonnet and Dick isolated a subpopulation of leukemia cells that expressed surface marker CD34, but not CD38.[20] The authors established that the CD34+/CD38 subpopulation is capable of initiating tumors in NOD/SCID mice that were histologically similar to the donor. The first evidence of a solid tumor cancer stem-like cell followed in 2002 with the discovery of a clonogenic, sphere-forming cell isolated and characterized from adult human brain gliomas. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro.[21] Cancer stem cells isolated from adult human gliomas were shown to induce tumours that resembled the parent tumour when grafted into intracranial nude mouse models.[22]

In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their efficacy. Tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this was explained by poor methodology (i.e., the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the CSC paradigm argue that only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.[20]

Further evidence comes from histology. Many tumors are heterogeneous and contain multiple cell types native to the host organ. Tumour heterogeneity is commonly retained by tumor metastases. This suggests that the cell that produced them had the capacity to generate multiple cell types, a classical hallmark of stem cells.[20]

The existence of leukemia stem cells prompted research into other cancers. CSCs have recently been identified in several solid tumors, including:

Mechanistic and mathematical models[edit]

Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical models,[39] e.g., based on the cell compartment method. For instance, the growths of abnormal cells can be denoted with specific mutation probabilities. Such a model predicted that repeated insult to mature cells increases the formation of abnormal progeny and the risk of cancer.[40] The clinical efficacy of such models[41] remains unestablished.

Origin[edit]

Figure 6: Hierarchical organisation of a tumour according to the CSC model

The origin of CSCs is an active research area. The answer may depend on the tumor type and phenotype. So far the hypothesis that tumors originate from a single "cell of origin" has not been demonstrated using the cancer stem cell model. This is because cancer stem cells are not present in end-stage tumors.

Origin hypotheses include mutants in developing stem or progenitor cells, mutants in adult stem cells or adult progenitor cells and mutant, differentiated cells that acquire stem-like attributes. These theories often focus on a tumor's "cell of origin".

Hypotheses[edit]

Stem cell mutation[edit]

The "mutation in stem cell niche populations during development" hypothesis claims that these developing stem populations are mutated and then reproduce so that the mutation is shared by many descendants. These daughter cells are much closer to becoming tumors and their numbers increase the chance of a cancerous mutation.[42]

Adult stem cells[edit]

Another theory associates adult stem cells (ASC) with tumor formation. This is most often associated with tissues with a high rate of cell turnover (such as the skin or gut). In these tissues, ASCs are candidates because of their frequent cell divisions (compared to most ASCs) in conjunction with the long lifespan of ASCs. This combination creates the ideal set of circumstances for mutations to accumulate: mutation accumulation is the primary factor that drives cancer initiation. Evidence shows that the association represents an actual phenomenon, although specific cancers have been linked to a specific cause.[43][44]

De-differentiation[edit]

De-differentiation of mutated cells may create stem cell-like characteristics, suggesting that any cell might become a cancer stem cell. In other words, a fully differentiated cell undergoes mutations or extracellular signals that drive it back to a stem-like state. This concept has been demonstrated most recently in Prostate cancer models, whereby cells undergoing androgen deprivation therapy appear to transiently alter their transcriptome to that of a neural crest stem-like cell, with the invasive and multipotent properties of this class of stem-like cells.[19]

Hierarchy[edit]

The concept of tumor hierarchy claims that a tumor is a heterogeneous population of mutant cells, all of which share some mutations, but vary in specific phenotype. A tumor hosts several types of stem cells, one optimal to the specific environment and other less successful lines. These secondary lines may be more successful in other environments, allowing the tumor to adapt, including adaptation to therapeutic intervention. If correct, this concept impacts cancer stem cell-specific treatment regimes.[45] Such a hierarchy would complicate attempts to pinpoint the origin.

Identification[edit]

CSCs, now reported in most human tumors, are commonly identified and enriched using strategies for identifying normal stem cells that are similar across studies.[46] These procedures include fluorescence-activated cell sorting (FACS), with antibodies directed at cell-surface markers and functional approaches including side population assay or Aldefluor assay.[47] The CSC-enriched result is then implanted, at various doses, in immune-deficient mice to assess its tumor development capacity. This in vivo assay is called a limiting dilution assay. The tumor cell subsets that can initiate tumor development at low cell numbers are further tested for self-renewal capacity in serial tumor studies.[48]

CSCs can also be identified by efflux of incorporated Hoechst dyes via multidrug resistance (MDR) and ATP-binding cassette (ABC) Transporters.[47]

Another approach is sphere-forming assays. Many normal stem cells such as hematopoietic or stem cells from tissues, under special culture conditions, form three-dimensional spheres that can differentiate. As with normal stem cells, the CSCs isolated from brain or prostate tumors also have the ability to form anchor-independent spheres.[49]

Heterogeneity (markers)[edit]

CSCs have been identified in various solid tumors. Commonly, markers specific for normal stem cells are used for isolating CSCs from solid and hematological tumors. Markers most frequently used for CSC isolation include: CD133 (also known as PROM1), CD44, ALDH1A1, CD34, CD24 and EpCAM (epithelial cell adhesion molecule, also known as epithelial specific antigen, ESA).[50]

CD133 (prominin 1) is a five-transmembrane domain glycoprotein expressed on CD34+ stem and progenitor cells, in endothelial precursors and fetal neural stem cells. It has been detected using its glycosylated epitope known as AC133.

EpCAM (epithelial cell adhesion molecule, ESA, TROP1) is hemophilic Ca2+-independent cell adhesion molecule expressed on the basolateral surface of most epithelial cells.

CD90 (THY1) is a glycosylphosphatidylinositol glycoprotein anchored in the plasma membrane and involved in signal transduction. It may also mediate adhesion between thymocytes and thymic stroma.

CD44 (PGP1) is an adhesion molecule that has pleiotropic roles in cell signaling, migration and homing. It has multiple isoforms, including CD44H, which exhibits high affinity for hyaluronate and CD44V which has metastatic properties.

CD24 (HSA) is a glycosylated glycosylphosphatidylinositol-anchored adhesion molecule, which has co-stimulatory role in B and T cells.

CD200 (OX-2) is a type 1 membrane glycoprotein, which delivers an inhibitory signal to immune cells including T cells, natural killer cells and macrophages.

ALDH is a ubiquitous aldehyde dehydrogenase family of enzymes, which catalyzes the oxidation of aromatic aldehydes to carboxyl acids. For instance, it has a role in conversion of retinol to retinoic acid, which is essential for survival.[51][52]

The first solid malignancy from which CSCs were isolated and identified was breast cancer and they are the most intensely studied. Breast CSCs have been enriched in CD44+CD24−/low,[53] SP[54] and ALDH+ subpopulations.[55][56] Breast CSCs are apparently phenotypically diverse. CSC marker expression in breast cancer cells is apparently heterogeneous and breast CSC populations vary across tumors.[57] Both CD44+CD24 and CD44+CD24+ cell populations are tumor initiating cells; however, CSC are most highly enriched using the marker profile CD44+CD49fhiCD133/2hi.[58]

CSCs have been reported in many brain tumors. Stem-like tumor cells have been identified using cell surface markers including CD133,[59] SSEA-1 (stage-specific embryonic antigen-1),[60] EGFR[61] and CD44.[62] The use of CD133 for identification of brain tumor stem-like cells may be problematic because tumorigenic cells are found in both CD133+ and CD133 cells in some gliomas and some CD133+ brain tumor cells may not possess tumor-initiating capacity.[61]

CSCs were reported in human colon cancer.[25] For their identification, cell surface markers such as CD133,[25] CD44[63] and ABCB5,[64] functional analysis including clonal analysis [65] and Aldefluor assay were used.[66] Using CD133 as a positive marker for colon CSCs generated conflicting results. The AC133 epitope, but not the CD133 protein, is specifically expressed in colon CSCs and its expression is lost upon differentiation.[67] In addition, CD44+ colon cancer cells and additional sub-fractionation of CD44+EpCAM+ cell population with CD166 enhance the success of tumor engraftments.[63]

Multiple CSCs have been reported in prostate,[68] lung and many other organs, including liver, pancreas, kidney or ovary.[51][69] In prostate cancer, the tumor-initiating cells have been identified in CD44+[70] cell subset as CD44+α2β1+,[71] TRA-1-60+CD151+CD166+ [72] or ALDH+ [73] cell populations. Putative markers for lung CSCs have been reported, including CD133+,[74] ALDH+,[75] CD44+ [76] and oncofetal protein 5T4+.[77]

Metastasis[edit]

Metastasis is the major cause of tumor lethality. However, not every tumor cell can metastasize. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes.

Epithelial-mesenchymal transition[edit]

In epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered to be a crucial event.[78] EMT and the reverse transition from mesenchymal to an epithelial phenotype (MET) are involved in embryonic development, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype.[79] EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor β.[80]

EMT's important feature is the loss of membrane E-cadherin in adherens junctions, where β-catenin may play a significant role. Translocation of β-catenin from adherens junctions to the nucleus may lead to a loss of E-cadherin and subsequently to EMT. Nuclear β-catenin apparently can directly, transcriptionally activate EMT-associated target genes, such as the E-cadherin gene repressor SLUG (also known as SNAI2).[81] Mechanical properties of the tumor microenvironment, such as hypoxia, can contribute to CSC survival and metastatic potential through stabilization of hypoxia inducible factors through interactions with ROS (reactive oxygen species).[82][83]

Tumor cells undergoing an EMT may be precursors for metastatic cancer cells, or even metastatic CSCs.[84] In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells was defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4 cells, but both showed similar tumor development capacity.[85] Moreover, inhibition of the CXCR4 receptor reduced metastatic potential without altering tumorigenic capacity.[86]

Two-phase expression pattern[edit]

In breast cancer CD44+CD24−/low cells are detectable in metastatic pleural effusions.[24] By contrast, an increased number of CD24+ cells have been identified in distant metastases in breast cancer patients.[87] It is possible that CD44+CD24−/low cells initially metastasize and in the new site change their phenotype and undergo limited differentiation.[88] The two-phase expression pattern hypothesis proposes two forms of cancer stem cells - stationary (SCS) and mobile (MCS). SCS are embedded in tissue and persist in differentiated areas throughout tumor progression. MCS are located at the tumor-host interface. These cells are apparently derived from SCS through the acquisition of transient EMT (Figure 7).[89]

Figure 7: The concept of migrating cancer stem cells (MSC). Stationary cancer stem cells are embedded in early carcinomas and these cells are detectable in the differentiated central area of a tumor. The important step toward malignancy is the induction of epithelial mesenchymal transition (EMT) in the stationary cancer stem cells (SCS), which become mobile or migrating cancer stem cells. Stem cells divide asymmetrically. One daughter cell will begin proliferation and differentiation. The remaining MCS migrates a short distance before undergoing a new asymmetric division, or disseminates through blood vessels or lymphatic vessels and produces a metastasis.

Implications[edit]

CSCs have implications for cancer therapy, including for disease identification, selective drug targets, prevention of metastasis and intervention strategies.

Treatment[edit]

Somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps (such as MDR[citation needed]) that pump out drugs and DNA repair proteins. They have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells).[citation needed] CSCs that develop from normal stem cells may also produce these proteins, which could increase their resistance towards chemotherapy. The surviving CSCs then repopulate the tumor, causing a relapse.[90]

Targeting[edit]

Selectively targeting CSCs may allow treatment of aggressive, non-resectable tumors, as well as prevent metastasis and relapse.[90] The hypothesis suggests that upon CSC elimination, cancer could regress due to differentiation and/or cell death.[citation needed] The fraction of tumor cells that are CSCs and therefore need to be eliminated is unclear.[91]

Studies looked for specific markers[24] and for proteomic and genomic tumor signatures that distinguish CSCs from others.[92] In 2009, scientists identified the compound salinomycin, which selectively reduces the proportion of breast CSCs in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent.[93] Some types of cancer cells can survive treatment with salinomycin through autophagy,[94] whereby cells use acidic organelles such as lysosomes to degrade and recycle certain types of proteins. The use of autophagy inhibitors can kill cancer stem cells that survive by autophagy.[95]

The cell surface receptor interleukin-3 receptor-alpha (CD123) is overexpressed on CD34+CD38- leukemic stem cells (LSCs) in acute myelogenous leukemia (AML) but not on normal CD34+CD38- bone marrow cells.[96] Treating AML-engrafted NOD/SCID mice with a CD123-specific monoclonal antibody impaired LSCs homing to the bone marrow and reduced overall AML cell repopulation including the proportion of LSCs in secondary mouse recipients.[97]

A 2015 study packaged nanoparticles with miR-34a and ammonium bicarbonate and delivered them to prostate CSCs in a mouse model. Then they irradiated the area with near-infrared laser light. This caused the nanoparticles to swell three times or more in size bursting the endosomes and dispersing the RNA in the cell. miR-34a can lower the levels of CD44.[98][99]

Pathways[edit]

The design of new drugs for targeting CSCs requires understanding the cellular mechanisms that regulate cell proliferation. The first advances in this area were made with hematopoietic stem cells (HSCs) and their transformed counterparts in leukemia, the disease for which the origin of CSCs is best understood. Stem cells of many organs share the same cellular pathways as leukemia-derived HSCs.

A normal stem cell may be transformed into a CSC through disregulation of the proliferation and differentiation pathways controlling it or by inducing oncoprotein activity.

BMI-1[edit]

The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma[100] and later shown to regulate HSCs.[101] The role of Bmi-1 has been illustrated in neural stem cells.[102] The pathway appears to be active in CSCs of pediatric brain tumors.[103]

Notch[edit]

The Notch pathway plays a role in controlling stem cell proliferation for several cell types including hematopoietic, neural and mammary[104] SCs. Components of this pathway have been proposed to act as oncogenes in mammary[105] and other tumors.

A branch of the Notch signaling pathway that involves the transcription factor Hes3 regulates a number of cultured cells with CSC characteristics obtained from glioblastoma patients.[106]

Sonic hedgehog and Wnt[edit]

These developmental pathways are SC regulators.[107] Both Sonic hedgehog (SHH) and Wnt pathways are commonly hyperactivated in tumors and are necessary to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are highly expressed. A degree of crosstalk exists between the two pathways and they are commonly activated together.[108] By contrast, in colon cancer hedgehog signalling appears to antagonise Wnt.[109]

Sonic hedgehog blockers are available, such as cyclopamine. A water-soluble cyclopamine may be more effective in cancer treatment. DMAPT, a water-soluble derivative of parthenolide, induces oxidative stress and inhibits NF-κB signaling[110] for AML (leukemia) and possibly myeloma and prostate cancer. Telomerase is a study subject in CSC physiology.[111] GRN163L (Imetelstat) was recently started in trials to target myeloma stem cells.

Wnt signaling can become independent of regular stimuli, through mutations in downstream oncogenes and tumor suppressor genes that become permanently activated even though the normal receptor has not received a signal. β-catenin binds to transcription factors such as the protein TCF4 and in combination the molecules activate the necessary genes. LF3 strongly inhibits this binding in vitro, in cell lines and reduced tumor growth in mouse models. It prevented replication and reduced their ability to migrate, all without affecting healthy cells. No cancer stem cells remained after treatment. The discovery was the product of "rational drug design", involving AlphaScreens and ELISA technologies.[112]

References[edit]

  1. ^ a b M, Sreepadmanabh (2018). "Investigations into the cancer stem cell niche using in-vitro 3-D tumor models and microfluidics". Biotechnology Advances. 36 (4): 1094–1110. doi:10.1016/j.biotechadv.2018.03.009 – via Elsevier Science Direct. 
  2. ^ Mukherjee, Siddhartha. "The Cancer Sleeper Cell". New York Times. New York Times. Retrieved 15 July 2014. 
  3. ^ Heppner GH, Miller BE (1983). "Tumor heterogeneity: biological implications and therapeutic consequences". Cancer Metastasis Reviews. 2 (1): 5–23. doi:10.1007/BF00046903. PMID 6616442. 
  4. ^ Bonnet D, Dick JE (July 1997). "Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell". Nature Medicine. 3 (7): 730–7. doi:10.1038/nm0797-730. PMID 9212098. 
  5. ^ a b c Beck B, Blanpain C (2013), "Unravelling cancer stem cell potential", Nat Rev Cancer, 13 (10): 727–38, doi:10.1038/nrc3597, PMID 24060864 
  6. ^ Shackleton M, Quintana E, Fearon ER, Morrison SJ (September 2009). "Heterogeneity in cancer: cancer stem cells versus clonal evolution". Cell. 138 (5): 822–9. doi:10.1016/j.cell.2009.08.017. PMID 19737509. 
  7. ^ a b c d Wang W, Quan Y, Fu Q, Liu Y, Liang Y, Wu J, Yang G, Luo C, Ouyang Q, Wang Y (2014), "Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts", PLOS One, 9 (1): e84654, Bibcode:2014PLoSO...984654W, doi:10.1371/journal.pone.0084654, PMC 3886990Freely accessible, PMID 24416258 
  8. ^ Kreso A, Dick JE (2014), "Evolution of the cancer stem cell model", Cell Stem Cell, 14 (3): 275–91, doi:10.1016/j.stem.2014.02.006, PMID 24607403 
  9. ^ Barabé F, Kennedy JA, Hope KJ, Dick JE (April 2007). "Modeling the initiation and progression of human acute leukemia in mice". Science. 316 (5824): 600–4. Bibcode:2007Sci...316..600B. doi:10.1126/science.1139851. PMID 17463288. 
  10. ^ Nowell PC (October 1976). "The clonal evolution of tumor cell populations". Science. 194 (4260): 23–8. Bibcode:1976Sci...194...23N. doi:10.1126/science.959840. PMID 959840. 
  11. ^ Clark EA, Golub TR, Lander ES, Hynes RO (August 2000). "Genomic analysis of metastasis reveals an essential role for RhoC". Nature. 406 (6795): 532–5. doi:10.1038/35020106. PMID 10952316. 
  12. ^ Cabrera MC, Hollingsworth RE, Hurt EM (2015), "Cancer stem cell plasticity and tumor hierarchy", World J Stem Cells, 7 (1): 27–36, doi:10.4252/wjsc.v7.i1.27, PMC 4300934Freely accessible, PMID 25621103 
  13. ^ a b Gupta PB, Chaffer CL, Weinberg RA (September 2009). "Cancer stem cells: mirage or reality?". Nature Medicine. 15 (9): 1010–2. doi:10.1038/nm0909-1010. PMID 19734877. [permanent dead link]>
  14. ^ Quintana, E; Shackleton, M; Sabel, M. S; Fullen, D. R; Johnson, T. M; Morrison, S. J (2008). "Efficient tumour formation by single human melanoma cells". Nature. 456 (7222): 593–8. Bibcode:2008Natur.456..593Q. doi:10.1038/nature07567. PMC 2597380Freely accessible. PMID 19052619. 
  15. ^ Ichiryu N, Fairchild PJ (2013). "Immune Privilege of Stem Cells". In Zavazava N. Embryonic Stem Cell Immunobiology. Methods in Molecular Biology. 1029. pp. 1–16. doi:10.1007/978-1-62703-478-4_1. ISBN 978-1-62703-477-7. PMID 23756938. 
  16. ^ MacCalli, C; Volontè, A; Cimminiello, C; Parmiani, G (2014). "Immunology of cancer stem cells in solid tumours. A review". European Journal of Cancer. 50 (3): 649–55. doi:10.1016/j.ejca.2013.11.014. PMID 24333096. 
  17. ^ a b Bruttel, V. S; Wischhusen, J (2014). "Cancer stem cell immunology: Key to understanding tumorigenesis and tumor immune escape?". Frontiers in Immunology. 5: 360. doi:10.3389/fimmu.2014.00360. PMC 4114188Freely accessible. PMID 25120546. 
  18. ^ Hayflick L (March 1965). "THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS". Experimental Cell Research. 37 (3): 614–36. doi:10.1016/0014-4827(65)90211-9. PMID 14315085. 
  19. ^ a b Nouri M, Caradec J, Lubik AA, Li N, Hollier BG, Takhar M, Altimirano-Dimas M, Chen M, Roshan-Moniri M, Butler M, Lehman M, Bishop J, Truong S, Huang SC, Cochrane D, Cox M, Collins C, Gleave M, Erho N, Alshalafa M, Davicioni E, Nelson C, Gregory-Evans S, Karnes RJ, Jenkins RB, Klein EA, Buttyan R (March 2017). "Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance". Oncotarget. 8 (12): 18949–18967. doi:10.18632/oncotarget.14850. PMC 5386661Freely accessible. PMID 28145883. 
  20. ^ a b c Bonnet D, Dick JE (July 1997). "Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell". Nature Medicine. 3 (7): 730–7. doi:10.1038/nm0797-730. PMID 9212098. 
  21. ^ Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (September 2002). "Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro". Glia. 39 (3): 193–206. doi:10.1002/glia.10094. PMID 12203386. 
  22. ^ Sundar SJ, Hsieh JK, Manjila S, Lathia JD, Sloan A (December 2014). "The role of cancer stem cells in glioblastoma". Neurosurgical Focus. 37 (6): E6. doi:10.3171/2014.9.FOCUS14494. PMID 25434391. 
  23. ^ Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (September 2003). "Identification of a cancer stem cell in human brain tumors". Cancer Research. 63 (18): 5821–8. PMID 14522905. 
  24. ^ a b c Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (April 2003). "Prospective identification of tumorigenic breast cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3983–8. Bibcode:2003PNAS..100.3983A. doi:10.1073/pnas.0530291100. PMC 153034Freely accessible. PMID 12629218. 
  25. ^ a b c O'Brien CA, Pollett A, Gallinger S, Dick JE (January 2007). "A human colon cancer cell capable of initiating tumour growth in immunodeficient mice". Nature. 445 (7123): 106–10. Bibcode:2007Natur.445..106O. doi:10.1038/nature05372. PMID 17122772. 
  26. ^ Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP (June 2008). "Identification and characterization of ovarian cancer-initiating cells from primary human tumors". Cancer Research. 68 (11): 4311–20. doi:10.1158/0008-5472.CAN-08-0364. PMC 2553722Freely accessible. PMID 18519691. 
  27. ^ a b Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, Rutherford T, Silasi DA, Steffensen KD, Waldstrom M, Visintin I, Mor G (January 2009). "Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance". Cell Cycle. 8 (1): 158–66. doi:10.4161/cc.8.1.7533. PMC 3041590Freely accessible. PMID 19158483. 
  28. ^ Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (February 2007). "Identification of pancreatic cancer stem cells". Cancer Research. 67 (3): 1030–7. doi:10.1158/0008-5472.CAN-06-2030. PMID 17283135. 
  29. ^ Maitland NJ, Collins AT (June 2008). "Prostate cancer stem cells: a new target for therapy". Journal of Clinical Oncology. 26 (17): 2862–70. doi:10.1200/JCO.2007.15.1472. PMID 18539965. 
  30. ^ Lang SH, Frame FM, Collins AT (January 2009). "Prostate cancer stem cells". The Journal of Pathology. 217 (2): 299–306. doi:10.1002/path.2478. PMC 2673349Freely accessible. PMID 19040209. 
  31. ^ Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH (January 2008). "Identification of cells initiating human melanomas". Nature. 451 (7176): 345–9. Bibcode:2008Natur.451..345S. doi:10.1038/nature06489. PMC 3660705Freely accessible. PMID 18202660. 
  32. ^ Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, Butler PD, Yang GP, Joshua B, Kaplan MJ, Longaker MT, Weissman IL (July 2010). "Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271". Nature. 466 (7302): 133–7. Bibcode:2010Natur.466..133B. doi:10.1038/nature09161. PMC 2898751Freely accessible. PMID 20596026. 
  33. ^ Schmidt P, Kopecky C, Hombach A, Zigrino P, Mauch C, Abken H (February 2011). "Eradication of melanomas by targeted elimination of a minor subset of tumor cells". Proceedings of the National Academy of Sciences of the United States of America. 108 (6): 2474–9. Bibcode:2011PNAS..108.2474S. doi:10.1073/pnas.1009069108. PMC 3038763Freely accessible. PMID 21282657. 
  34. ^ Civenni G, Walter A, Kobert N, Mihic-Probst D, Zipser M, Belloni B, Seifert B, Moch H, Dummer R, van den Broek M, Sommer L (April 2011). "Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth". Cancer Research. 71 (8): 3098–109. doi:10.1158/0008-5472.CAN-10-3997. PMID 21393506. 
  35. ^ Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI, Jones RJ (March 2004). "Characterization of clonogenic multiple myeloma cells". Blood. 103 (6): 2332–6. doi:10.1182/blood-2003-09-3064. PMC 3311914Freely accessible. PMID 14630803. 
  36. ^ Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I, McNiece I, Lin L, Ambinder RF, Peacock C, Watkins DN, Huff CA, Jones RJ (January 2008). "Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance". Cancer Research. 68 (1): 190–7. doi:10.1158/0008-5472.CAN-07-3096. PMC 2603142Freely accessible. PMID 18172311. 
  37. ^ Colmont CS, Benketah A, Reed SH, Hawk NV, Telford WG, Ohyama M, Udey MC, Yee CL, Vogel JC, Patel GK (January 2013). "CD200-expressing human basal cell carcinoma cells initiate tumor growth". Proceedings of the National Academy of Sciences of the United States of America. 110 (4): 1434–9. Bibcode:2013PNAS..110.1434C. doi:10.1073/pnas.1211655110. PMC 3557049Freely accessible. PMID 23292936. 
  38. ^ Patel GK, Yee CL, Terunuma A, Telford WG, Voong N, Yuspa SH, Vogel JC (February 2012). "Identification and characterization of tumor-initiating cells in human primary cutaneous squamous cell carcinoma". The Journal of Investigative Dermatology. 132 (2): 401–9. doi:10.1038/jid.2011.317. PMC 3258300Freely accessible. PMID 22011906. 
  39. ^ Preziosi, Luigi (2003). Cancer Modelling and Simulation. Boca Raton: CRC Press. ISBN 1-58488-361-8. 
  40. ^ Ganguly R, Puri IK (February 2006). "Mathematical model for the cancer stem cell hypothesis". Cell Proliferation. 39 (1): 3–14. doi:10.1111/j.1365-2184.2006.00369.x. PMID 16426418. 
  41. ^ Ganguly R, Puri IK (June 2007). "Mathematical model for chemotherapeutic drug efficacy in arresting tumour growth based on the cancer stem cell hypothesis". Cell Proliferation. 40 (3): 338–54. doi:10.1111/j.1365-2184.2007.00434.x. PMID 17531079. 
  42. ^ Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, Lee EY, Zhu Y (June 2009). "Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model". Cancer Cell. 15 (6): 514–26. doi:10.1016/j.ccr.2009.04.001. PMC 2721466Freely accessible. PMID 19477430. 
  43. ^ López-Lázaro M (2015-01-01). "The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis". Oncoscience. 2 (5): 467–75. doi:10.18632/oncoscience.159. PMC 4468332Freely accessible. PMID 26097879. 
  44. ^ López-Lázaro M (2015-08-18). "Stem cell division theory of cancer". Cell Cycle. 14 (16): 2547–8. doi:10.1080/15384101.2015.1062330. PMC 5242319Freely accessible. PMID 26090957. 
  45. ^ Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (October 2006). "Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells". Cancer Research. 66 (19): 9339–44. doi:10.1158/0008-5472.CAN-06-3126. PMID 16990346. 
  46. ^ Golebiewska A, Brons NH, Bjerkvig R, Niclou SP (February 2011). "Critical appraisal of the side population assay in stem cell and cancer stem cell research". Cell Stem Cell. 8 (2): 136–47. doi:10.1016/j.stem.2011.01.007. PMID 21295271. 
  47. ^ a b Scharenberg CW, Harkey MA, Torok-Storb B (January 2002). "The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors". Blood. 99 (2): 507–12. doi:10.1182/blood.V99.2.507. PMID 11781231. 
  48. ^ Pastrana E, Silva-Vargas V, Doetsch F (May 2011). "Eyes wide open: a critical review of sphere-formation as an assay for stem cells". Cell Stem Cell. 8 (5): 486–98. doi:10.1016/j.stem.2011.04.007. PMC 3633588Freely accessible. PMID 21549325. 
  49. ^ Nicolis SK (February 2007). "Cancer stem cells and "stemness" genes in neuro-oncology". Neurobiology of Disease. 25 (2): 217–29. doi:10.1016/j.nbd.2006.08.022. PMID 17141509. 
  50. ^ Kim YS, Kaidina AM, Chiang JH, Yarygin KN, Lupatov AY (2017). "Cancer stem cell molecular markers verified in vivo". Biochem. Moscow Suppl. Ser. B. 11 (1): 43–54. doi:10.1134/S1990750817010036. 
  51. ^ a b Meng E, Mitra A, Tripathi K, Finan MA, Scalici J, McClellan S, Madeira da Silva L, Reed E, Shevde LA, Palle K, Rocconi RP (September 12, 2014). "ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling". PLOS One. 9 (9): e107142. doi:10.1371/journal.pone.0107142. PMC 4162571Freely accessible. PMID 25216266. 
  52. ^ Visvader JE, Lindeman GJ (October 2008). "Cancer stem cells in solid tumours: accumulating evidence and unresolved questions". Nature Reviews. Cancer. 8 (10): 755–68. doi:10.1038/nrc2499. PMID 18784658. 
  53. ^ Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (April 2003). "Prospective identification of tumorigenic breast cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3983–8. Bibcode:2003PNAS..100.3983A. doi:10.1073/pnas.0530291100. PMC 153034Freely accessible. PMID 12629218. 
  54. ^ Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK (September 2004). "A distinct "side population" of cells with high drug efflux capacity in human tumor cells". Proceedings of the National Academy of Sciences of the United States of America. 101 (39): 14228–33. Bibcode:2004PNAS..10114228H. doi:10.1073/pnas.0400067101. PMC 521140Freely accessible. PMID 15381773. 
  55. ^ Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (November 2007). "ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome". Cell Stem Cell. 1 (5): 555–67. doi:10.1016/j.stem.2007.08.014. PMC 2423808Freely accessible. PMID 18371393. 
  56. ^ Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG, Di Fiore PP (January 2010). "Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content". Cell. 140 (1): 62–73. doi:10.1016/j.cell.2009.12.007. PMID 20074520. 
  57. ^ Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, Connolly DC, Zhang Y, Montone K, Bützow R, Coukos G, Zhang L (April 2010). Cao Y, ed. "Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers". PLOS One. 5 (4): e10277. Bibcode:2010PLoSO...510277D. doi:10.1371/journal.pone.0010277. PMC 2858084Freely accessible. PMID 20422001. 
  58. ^ Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK (June 2010). "CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer". Cancer Research. 70 (11): 4624–33. doi:10.1158/0008-5472.CAN-09-3619. PMC 4129519Freely accessible. PMID 20484027. 
  59. ^ Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (November 2004). "Identification of human brain tumour initiating cells". Nature. 432 (7015): 396–401. Bibcode:2004Natur.432..396S. doi:10.1038/nature03128. PMID 15549107. 
  60. ^ Son MJ, Woolard K, Nam DH, Lee J, Fine HA (May 2009). "SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma". Cell Stem Cell. 4 (5): 440–52. doi:10.1016/j.stem.2009.03.003. PMID 19427293. 
  61. ^ a b Mazzoleni S, Politi LS, Pala M, Cominelli M, Franzin A, Sergi Sergi L, Falini A, De Palma M, Bulfone A, Poliani PL, Galli R (October 2010). "Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis". Cancer Research. 70 (19): 7500–13. doi:10.1158/0008-5472.CAN-10-2353. PMID 20858720. 
  62. ^ Anido J, Sáez-Borderías A, Gonzàlez-Juncà A, Rodón L, Folch G, Carmona MA, Prieto-Sánchez RM, Barba I, Martínez-Sáez E, Prudkin L, Cuartas I, Raventós C, Martínez-Ricarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J (December 2010). "TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma". Cancer Cell. 18 (6): 655–68. doi:10.1016/j.ccr.2010.10.023. PMID 21156287. 
  63. ^ a b Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF (June 2007). "Phenotypic characterization of human colorectal cancer stem cells". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10158–63. Bibcode:2007PNAS..10410158D. doi:10.1073/pnas.0703478104. PMC 1891215Freely accessible. PMID 17548814. 
  64. ^ Wilson BJ, Schatton T, Zhan Q, Gasser M, Ma J, Saab KR, Schanche R, Waaga-Gasser AM, Gold JS, Huang Q, Murphy GF, Frank MH, Frank NY (August 2011). "ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients". Cancer Research. 71 (15): 5307–16. doi:10.1158/0008-5472.CAN-11-0221. PMC 3395026Freely accessible. PMID 21652540. 
  65. ^ Odoux C, Fohrer H, Hoppo T, Guzik L, Stolz DB, Lewis DW, Gollin SM, Gamblin TC, Geller DA, Lagasse E (September 2008). "A stochastic model for cancer stem cell origin in metastatic colon cancer". Cancer Research. 68 (17): 6932–41. doi:10.1158/0008-5472.CAN-07-5779. PMC 2562348Freely accessible. PMID 18757407. 
  66. ^ Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM (April 2009). "Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis". Cancer Research. 69 (8): 3382–9. doi:10.1158/0008-5472.CAN-08-4418. PMC 2789401Freely accessible. PMID 19336570. 
  67. ^ Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoek M, Zeilstra J, Pals ST, Mehmet H, Stassi G, Medema JP (January 2010). "The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation". Cancer Research. 70 (2): 719–29. doi:10.1158/0008-5472.CAN-09-1820. PMID 20068153. 
  68. ^ Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, Wiggins JF, Bader AG, Fagin R, Brown D, Tang DG (February 2011). "The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44". Nature Medicine. 17 (2): 211–5. doi:10.1038/nm.2284. PMC 3076220Freely accessible. PMID 21240262. 
  69. ^ Ho MM, Ng AV, Lam S, Hung JY (May 2007). "Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells". Cancer Research. 67 (10): 4827–33. doi:10.1158/0008-5472.CAN-06-3557. PMID 17510412. 
  70. ^ Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, Reilly JG, Chandra D, Zhou J, Claypool K, Coghlan L, Tang DG (March 2006). "Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells". Oncogene. 25 (12): 1696–708. doi:10.1038/sj.onc.1209327. PMID 16449977. 
  71. ^ Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, García-Echeverría C, Schultz PG, Reddy VA (January 2009). "The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations". Proceedings of the National Academy of Sciences of the United States of America. 106 (1): 268–73. Bibcode:2009PNAS..106..268D. doi:10.1073/pnas.0810956106. PMC 2629188Freely accessible. PMID 19116269. 
  72. ^ Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI (January 2011). "Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling". Nature Communications. 2 (1): 162. Bibcode:2011NatCo...2E.162R. doi:10.1038/ncomms1159. PMC 3105310Freely accessible. PMID 21245843. 
  73. ^ Li T, Su Y, Mei Y, Leng Q, Leng B, Liu Z, Stass SA, Jiang F (February 2010). "ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients' outcome". Laboratory Investigation; A Journal of Technical Methods and Pathology. 90 (2): 234–44. doi:10.1038/labinvest.2009.127. PMC 3552330Freely accessible. PMID 20010854. 
  74. ^ Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (March 2008). "Identification and expansion of the tumorigenic lung cancer stem cell population". Cell Death and Differentiation. 15 (3): 504–14. doi:10.1038/sj.cdd.4402283. PMID 18049477. 
  75. ^ Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA, Honorio S, Xie Y, Scaglioni PP, DiMaio JM, Gazdar AF, Shay JW, Wistuba II, Minna JD (December 2010). "Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling". Cancer Research. 70 (23): 9937–48. doi:10.1158/0008-5472.CAN-10-0881. PMC 3058307Freely accessible. PMID 21118965. 
  76. ^ Leung EL, Fiscus RR, Tung JW, Tin VP, Cheng LC, Sihoe AD, Fink LM, Ma Y, Wong MP (November 2010). Jin D, ed. "Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties". PLOS One. 5 (11): e14062. Bibcode:2010PLoSO...514062L. doi:10.1371/journal.pone.0014062. PMC 2988826Freely accessible. PMID 21124918. 
  77. ^ Damelin M, Geles KG, Follettie MT, Yuan P, Baxter M, Golas J, DiJoseph JF, Karnoub M, Huang S, Diesl V, Behrens C, Choe SE, Rios C, Gruzas J, Sridharan L, Dougher M, Kunz A, Hamann PR, Evans D, Armellino D, Khandke K, Marquette K, Tchistiakova L, Boghaert ER, Abraham RT, Wistuba II, Zhou BB (June 2011). "Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells". Cancer Research. 71 (12): 4236–46. doi:10.1158/0008-5472.CAN-10-3919. PMID 21540235. 
  78. ^ Thiery JP (June 2002). "Epithelial-mesenchymal transitions in tumour progression". Nature Reviews. Cancer. 2 (6): 442–54. doi:10.1038/nrc822. PMID 12189386. 
  79. ^ Angerer LM, Angerer RC (June 1999). "Regulative development of the sea urchin embryo: signalling cascades and morphogen gradients". Seminars in Cell & Developmental Biology. 10 (3): 327–34. doi:10.1006/scdb.1999.0292. PMID 10441547. 
  80. ^ Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA (June 2007). "Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10069–74. Bibcode:2007PNAS..10410069M. doi:10.1073/pnas.0703900104. PMC 1891217Freely accessible. PMID 17537911. 
  81. ^ Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze'ev A (November 2003). "Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK". The Journal of Cell Biology. 163 (4): 847–57. doi:10.1083/jcb.200308162. PMC 2173691Freely accessible. PMID 14623871. 
  82. ^ Comito G, Calvani M, Giannoni E, Bianchini F, Calorini L, Torre E, Migliore C, Giordano S, Chiarugi P (August 2011). "HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells". Free Radical Biology & Medicine. 51 (4): 893–904. doi:10.1016/j.freeradbiomed.2011.05.042. PMID 21703345. 
  83. ^ Spill F, Reynolds DS, Kamm RD, Zaman MH (August 2016). "Impact of the physical microenvironment on tumor progression and metastasis". Current Opinion in Biotechnology. 40: 41–48. doi:10.1016/j.copbio.2016.02.007. PMC 4975620Freely accessible. PMID 26938687. 
  84. ^ Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (December 2005). "VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche". Nature. 438 (7069): 820–7. Bibcode:2005Natur.438..820K. doi:10.1038/nature04186. PMC 2945882Freely accessible. PMID 16341007. 
  85. ^ Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (September 2007). "Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer". Cell Stem Cell. 1 (3): 313–23. doi:10.1016/j.stem.2007.06.002. PMID 18371365. 
  86. ^ Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PW, Lam CT, Poon RT, Fan ST (February 2008). "Significance of CD90+ cancer stem cells in human liver cancer". Cancer Cell. 13 (2): 153–66. doi:10.1016/j.ccr.2008.01.013. PMID 18242515. 
  87. ^ Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K (March 2007). "Molecular definition of breast tumor heterogeneity". Cancer Cell. 11 (3): 259–73. doi:10.1016/j.ccr.2007.01.013. PMID 17349583. 
  88. ^ Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D'Angelica M, Kemeny N, Lyden D, Rafii S (June 2008). "CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors". The Journal of Clinical Investigation. 118 (6): 2111–20. doi:10.1172/JCI34401. PMC 2391278Freely accessible. PMID 18497886. 
  89. ^ Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (September 2005). "Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression". Nature Reviews. Cancer. 5 (9): 744–9. doi:10.1038/nrc1694. PMID 16148886. 
  90. ^ a b Mraz M, Zent CS, Church AK, Jelinek DF, Wu X, Pospisilova S, Ansell SM, Novak AJ, Kay NE, Witzig TE, Nowakowski GS (October 2011). "Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance". British Journal of Haematology. 155 (1): 53–64. doi:10.1111/j.1365-2141.2011.08794.x. PMC 4405035Freely accessible. PMID 21749361. 
  91. ^ Dirks P (July 2010). "Cancer stem cells: Invitation to a second round". Nature. 466 (7302): 40–1. Bibcode:2010Natur.466...40D. doi:10.1038/466040a. PMID 20596007. 
  92. ^ Haskins WE, Eedala S, Jadhav YL, Labhan MS, Pericherla VC, Perlman EJ (May 2012). "Insights on neoplastic stem cells from gel-based proteomics of childhood germ cell tumors". Pediatric Blood & Cancer. 58 (5): 722–8. doi:10.1002/pbc.23282. PMC 3204330Freely accessible. PMID 21793190. 
  93. ^ Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES (August 2009). "Identification of selective inhibitors of cancer stem cells by high-throughput screening". Cell. 138 (4): 645–659. doi:10.1016/j.cell.2009.06.034. PMC 4892125Freely accessible. PMID 19682730. 
  94. ^ Jangamreddy JR, Ghavami S, Grabarek J, Kratz G, Wiechec E, Fredriksson BA, Rao Pariti RK, Cieślar-Pobuda A, Panigrahi S, Łos MJ (September 2013). "Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells". Biochimica et Biophysica Acta. 1833 (9): 2057–69. doi:10.1016/j.bbamcr.2013.04.011. PMID 23639289. 
  95. ^ Vlahopoulos S, Critselis E, Voutsas IF, Perez SA, Moschovi M, Baxevanis CN, Chrousos GP (2014). "New use for old drugs? Prospective targets of chloroquines in cancer therapy". Current Drug Targets. 15 (9): 843–51. doi:10.2174/1389450115666140714121514. PMID 25023646. 
  96. ^ Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, Meyerrose T, Rossi R, Grimes B, Rizzieri DA, Luger SM, Phillips GL (October 2000). "The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells". Leukemia. 14 (10): 1777–84. doi:10.1038/sj.leu.2401903. PMID 11021753. 
  97. ^ Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, Guthridge MA, Thomas D, Barry EF, Boyd A, Gearing DP, Vairo G, Lopez AF, Dick JE, Lock RB (July 2009). "Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells". Cell Stem Cell. 5 (1): 31–42. doi:10.1016/j.stem.2009.04.018. PMID 19570512. 
  98. ^ "'Nanobombs' that blow up cancer cells | KurzweilAI". www.kurzweilai.net. 2015-12-07. Retrieved 2016-02-20. 
  99. ^ Wang H, Agarwal P, Zhao S, Yu J, Lu X, He X (January 2016). "A Near-Infrared Laser-Activated "Nanobomb" for Breaking the Barriers to MicroRNA Delivery". Advanced Materials. 28 (2): 347–55. doi:10.1002/adma.201504263. PMID 26567892. 
  100. ^ Haupt Y, Bath ML, Harris AW, Adams JM (November 1993). "bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis". Oncogene. 8 (11): 3161–4. PMID 8414519. 
  101. ^ Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF (May 2003). "Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells". Nature. 423 (6937): 302–5. Bibcode:2003Natur.423..302P. doi:10.1038/nature01587. PMID 12714971. 
  102. ^ Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (October 2003). "Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation". Nature. 425 (6961): 962–7. Bibcode:2003Natur.425..962M. doi:10.1038/nature02060. PMC 2614897Freely accessible. PMID 14574365. 
  103. ^ Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (December 2003). "Cancerous stem cells can arise from pediatric brain tumors". Proceedings of the National Academy of Sciences of the United States of America. 100 (25): 15178–83. Bibcode:2003PNAS..10015178H. doi:10.1073/pnas.2036535100. PMC 299944Freely accessible. PMID 14645703. 
  104. ^ Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS (2004). "Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells". Breast Cancer Research. 6 (6): R605–15. doi:10.1186/bcr920. PMC 1064073Freely accessible. PMID 15535842. 
  105. ^ Diévart A, Beaulieu N, Jolicoeur P (October 1999). "Involvement of Notch1 in the development of mouse mammary tumors". Oncogene. 18 (44): 5973–81. doi:10.1038/sj.onc.1202991. PMID 10557086. 
  106. ^ Park DM, Jung J, Masjkur J, Makrogkikas S, Ebermann D, Saha S, Rogliano R, Paolillo N, Pacioni S, McKay RD, Poser S, Androutsellis-Theotokis A (2013). "Hes3 regulates cell number in cultures from glioblastoma multiforme with stem cell characteristics". Scientific Reports. 3: 1095. Bibcode:2013NatSR...3E1095P. doi:10.1038/srep01095. PMC 3566603Freely accessible. PMID 23393614. 
  107. ^ Beachy PA, Karhadkar SS, Berman DM (November 2004). "Tissue repair and stem cell renewal in carcinogenesis". Nature. 432 (7015): 324–31. Bibcode:2004Natur.432..324B. doi:10.1038/nature03100. PMID 15549094. 
  108. ^ Zhou BP, Hung MC (June 2005). "Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis". Cell Cycle. 4 (6): 772–6. doi:10.4161/cc.4.6.1744. PMID 15917668. 
  109. ^ Akiyoshi T, Nakamura M, Koga K, Nakashima H, Yao T, Tsuneyoshi M, Tanaka M, Katano M (July 2006). "Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation". Gut. 55 (7): 991–9. doi:10.1136/gut.2005.080333. PMC 1856354Freely accessible. PMID 16299030. 
  110. ^ She M, Chen X (January 2009). "Targeting Signal Pathways active in Cancer Stem Cells to Overcome Drug Resistance". Zhongguo Fei Ai Za Zhi = Chinese Journal of Lung Cancer. 12 (1): 3–7. doi:10.3779/j.issn.1009-3419.2009.01.001 (inactive 2018-06-25). PMID 20712949. 
  111. ^ Bollmann FM (August 2008). "The many faces of telomerase: emerging extratelomeric effects". BioEssays. 30 (8): 728–32. doi:10.1002/bies.20793. PMID 18623070. 
  112. ^ Hodge, Russ (2016-01-25). "Hacking the programs of cancer stem cells". medicalxpress.com. Medical Express. Retrieved 2016-02-12. 

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