Cancer stem cell
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. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed 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 sufferers of 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 could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally 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 would form a very 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 are unable to generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause a relapse of the disease.
Models for tumor propagation 
In different tumor subtype, cells within the tumor population exhibit functional heterogeneity, cells with various proliferative and differentiative capacities. This functional heterogeneity among cancer cells lead to create at least two models, which have put forward to account for heterogeneity and differences in tumor-regenerative capacity, the cancer stem cells (CSC) and clonal evolution models
The cancer stem cells model refer to a subset of tumor cells that has the ability to self-renew and their capable generate the diverse tumor cells. These cells have been termed cancer stem cells to reflect their stem-like properties. One implication of the CSC model and existence of CSCs is that the cancer is hierarchically arranged with CSCs lying at the apex of the hierarchy (Fig. 2).
On the other, the clonal evolution model postulates that mutant tumor cells with a growth advantage are selected and expanded. Cells in the dominant population have a similar potential for initiating or regenerative tumor growth (Fig. 3).
 These two models are not mutually exclusive, as CSCs themselves undergo clonal evolution. Thus, the second more dominant CSCs may emerge, if a mutation confers more aggressive properties (Fig. 4).
The existence of CSCs is a subject of debate within medical research, because many studies have not been successful in discovering the similarities and differences between normal tissue stem cells and cancer stem cells. Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required for carcinogenesis, and to sustain the growth of a tumor since differentiated cells (constrained by the Hayflick Limit) cannot divide indefinitely. However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties, there is no incentive to focus on a specific sub population. There is also debate on the cell of origin of CSCs - whether they originate from stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity).
The first conclusive evidence for CSCs was published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation of leukaemic cells that express a specific surface marker CD34, but lacks the CD38 marker. The authors established that the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that is histologically similar to the donor.
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 ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been 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 cancer stem cell 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.
Further evidence comes from histology, the study of the tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells.
The existence of leukaemic stem cells prompted further research into other types of cancer. CSCs have recently been identified in several solid tumors, including cancers of the:
- Multiple Myeloma
Mechanistic and mathematical models 
Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology models, e.g., based on the cell compartment method. For instance, the growths of the abnormal cells from their normal counterparts can be denoted with specific mutation probabilities. Such a model has been employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer. Considerable work needs to be done, however, before the clinical efficacy of such models is established.
The origin of cancer stem cells is still an area of ongoing research. Several camps have formed within the scientific community regarding the issue, and it is possible that several answers are correct, depending on the tumor type and the phenotype the tumor presents. One important distinction that will often be raised is that the cell of origin for a tumor can not be demonstrated using the cancer stem cell as a model. This is because cancer stem cells are isolated from end-stage tumors. Therefore, describing a cancer stem cell as a cell of origin is often an inaccurate claim, even though a cancer stem cell is capable of initiating new tumor formation.
With that caveat mentioned, various theories define the origin of cancer stem cells. In brief, they may be: mutants in developing stem or progenitor cells, mutants in adult stem cells or adult progenitor cells, or mutant cells that acquire stem like attributes. These theories often do focus on a tumor's cell of origin and as such must be approached with skepticism.
Some researchers favor the theory that the cancer stem cell is caused by a mutation in stem cell niche populations during development. The logical progression claims that these developing stem populations are mutated and then expand such that the mutation is shared by many of the descendants of the mutated stem cell. These daughter stem cells are then much closer to becoming tumors, and since there are many of them there is more chance of a mutation that can cause cancer.
Another theory associates adult stem cells with the formation of tumors. This is most often associated with tissues with a high rate of cell turnover (such as the skin or gut). In these tissues, it has long been expected that stem cells are responsible for tumor formation. This is a consequence of the frequent cell divisions of these stem cells (compared to most adult stem cells) in conjunction with the extremely long lifespan of adult stem cells. This combination creates the ideal set of circumstances for mutations to accumulate; accumulation of mutations is the primary factor that drives cancer initiation. In spite of the logical backing of the theory, only recently has evidence appeared that this association represents an actual phenomenon. It is important to bear in mind that, due to the heterogeneous nature of evidence it is possible that any individual cancer could come from an alternative origin.
A third possibility often raised is the potential de-differentiation of mutated cells such that these cells acquire stem cell like characteristics. This is often used as a potential alternative to any specific cell of origin, as it suggests that any cell might become a cancer stem cell.
Another related concept is the concept of tumor hierarchy. This concept claims that a tumor is a heterogeneous population of mutant cells, all of which share some mutations but will vary in specific phenotype. In this model, the tumor is made up of several types of stem cells, one optimal to the specific environment and several less successful lines. These secondary lines can become more successful in some environments, allowing the tumor to adapt to its environment, including the methods by which tumors can be treated. If this situation is accurate, it has severe repercussions on the realism of a cancer stem cell specific treatment regime. Within a tumor hierarchy model, it would be extremely difficult to pinpoint the cancer stem cell's origin.
Cancers stem cells isolation 
CSC, now reported in most human tumors, are commonly identified and enriched using for strategies for identifying normal stem cells and are similar across the studies. The procedures include fluorescence-activated cell sorting (FACS) with antibodies directed at cell-surface markers and functional approaches including SP analysis or Aldefluor assay. The CSC-enriched population purified by these approaches is then implanted, at various cell doses, in immune-deficient mice to assess their tumor development capacity. This in vivo assay is called 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 capacity.
Another approach which also been used for identification of cell subset enrich in CSC in vitro is sphere-forming assays. Many normal stem cells such as hematopoietic or stem cells from tissues are capable, under special culture conditioned, form three-dimensional spheres, which can differentiated into multiple cell types. Similarly as normal stem cells, the CSC isolated from brain or prostate tumors has also ability to form anchorage-independent spheres.
Heterogeneity (CSC markers) 
Data over recent years have indicated the existence of CSC in various solid tumors. For isolating CSC from solid and hematological tumors are commonly use markers specific for normal stem cells of the same organ. Nevertheless, a number of cell surface markers have proved useful for isolating of subsets enriched for CSC including CD133 (also now as PROM1), CD44, CD24, EpCAM (epithelial cell adhesion molecule, also now as epithelial specific antigen, ESA), THY1, ATP-binding cassette B5 (ABCB5) and Hoechst33342.
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 by its glycosylated epitope know 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.
Hoechst SP is site population (SP) phenotype due to the Hoechst33342 efflux pump on the plasma membrane.
CD44 (PGP1) is an adhesion molecule that has pleiotropic roles in cell signaling, migration and homing. It has multiple isoforms, including CD44H, exhibit high affinity for hyaluronate, and CD44V which has metastatic properties.
ALDH1 is a ubiquitous aldehyde dehydrogenase family of enzymes, which catalyze the oxidation of aromatic aldehydes to carboxyl acids. In addition, it has role in conversion of retinol to retinoic acid, which is essential for survival.
The first solid malignancy from which CSC were isolated and identified was breast cancer and therefore they are the most intensely studied. Breast CSC have been enriched in CD44+CD24-/low, SP, ALDH+  and [[PKH26 dye|[[PKH26]] dye]] retaining. However, recent evidence indicates that breast CSC are very phenotypically diverse population, and there are evidence that not only CSC marker expression in breast cancer cells is heterogeneous but also there exist many subsets of breast CSC. Last studies provide further support to this point. 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.
CSCs have been reported in many brain tumors. The stem-like tumors cells have been identified using cell surface markers including CD133, SSEA-1 (stage-specific embryonic antigen-1), EGFR[disambiguation needed] and CD44. However, there is uncertainties surrounding the use of CD133 for identification of brain tumor stem-like cells, because tumorigenic cells are found in both CD133+ and CD133- in some gliomas, and some CD133+ brain tumor cells may not possess tumor-initiating capacity.
Similarly, CSCs have been also reported in human colon cancer. For their identification were use cell surface markers as CD133, CD44 and ABCB5, or functional analysis including clonal analysis  or Aldefluor assay. In addition, using CD133 as positive marker for colon CSCs has generated conflicting results. Nevertheless, recent studies indicated that the AC133 epitope, but not CD133 protein, is specifically expressed in colon CSCs and its expression is lost upon differentiation. In addition, using CD44+ colon cancer cells and additional sub-fractionation of CD44+EpCAM+ cell population with CD166 enhance the success of tumor engraftments.
Multiple CSCs have been reported in prostate, lung and many other organs cancer, including liver, pancreas, kidney or ovary. In prostate cancer, the tumor-initiating cells have been identified in CD44+  cell subset as a CD44+α2β1+, or TRA-1-60+CD151+CD166+  and ALDH+  cell populations. Putative surface markers for lung CSCs have been reported, including CD133+, ALDH+, CD44+  and oncofetal protein 5T4+.
Metastatic cancer stem cells 
Metastasis is the major cause of tumor lethality in patients. However, not every cell in the tumor has the ability to metastases. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes of tumor cells. In the many epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered as a crucial events in the metastatic process. 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. The EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor β pathway. The important feature of EMT is the loss of membrane E-cadherin in adherens junctions, where the β-catenin may play significant role. Translocation of β-catenin from adherens junctions to the nucleus, may lead to a loss of E-cadherine, and subsequently, the EMT. There is an evidence that nuclear β-catenin can directly transcriptionally activate EMT-associated target genes, such as the E-cadherine gene repressor SLUG (also known as SNAI2).
Recent data have supported the concept, where tumor cells undergoing an EMT could be precursor for metastatic cancer cells, or even metastatic CSCs. Recent data have been supported for metastatic CSC concept. In the invasive edge of pancreatic carcinoma has been defined subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4- cells, but both cell subsets shoeing similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor leads to the reduced metastatic potential without altering their tumorigenic capacity.
On the other hand, in the breast cancer CD44+CD24-/low are detectable in metastatic pleural effusions. By contrast, an increased number of CD24+ cells have been identified in distant metastasis in patients with breast cancer. Although, there are only few data on mechanisms mediating metastasis in breast cancer, but it is possible that CD44+CD24-/low initially metastasize and in the new site they change their phenotype and undergo limited differentiation. These finding lead to postulate new dynamic two-phase expression pattern concept based on the existence of two forms of cancer stem cells - stationary cancer stem cells (SCS) and mobile cancer stem cells (MCS). Stationary cancer stem cells are embedded in tissue and persist in differentiated areas throughout all tumor progression. The term mobile cancer stem cell describes cells that are located at the tumor-host interface. There is an evidence that these cells are derived from SCS through the acquisition of transient EMT  (Fig. 5)
Implications for cancer treatment 
The existence of CSCs has several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new intervention strategies.
Normal somatic stem cells are naturally resistant to chemotherapeutic agents- they have various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). CSCs that have mutated from normal stem cells may also express proteins that would increase their resistance towards chemotherapeutic agents. These surviving CSCs then repopulate the tumor, causing relapse. By selectively targeting CSCs, it would be possible to treat patients with aggressive, non-resectable tumors, as well as preventing the tumor from metastasizing. The hypothesis suggests that upon CSC elimination, cancer would regress due to differentiation and/or cell death. What fraction of tumor cells are CSCs and therefore need to be eliminated is not clear yet.
A number of studies have investigated the possibility of identifying specific markers that may distinguish CSCs from the bulk of the tumor (as well as from normal stem cells). Proteomic and genomic signatures of tumors are also being investigated.. In 2009, scientists identified one compound, Salinomycin, that selectively reduces the proportion of breast CSCs in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent.
The cell surface receptor interleukin-3 receptor-alpha (CD123) was shown to be overexpressed on CD34+CD38- leukemic stem cells (LSCs) in acute myelogenous leukemia (AML) but not on normal CD34+CD38- bone marrow cells. Jin et al., then demonstrated that treating AML-engrafted NOD/SCID mice with a CD123-specific monoclonal antibody impaired LSCs homing to the bone marrow and reduced overal AML cell repopulation including the proportion of LSCs in secondary mouse recipients.
The design of new drugs for the treatment of CSCs will likely require an understanding of 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. It is now becoming increasingly clear that stem cells of many organs share the same cellular pathways as leukemia-derived HSCs.
The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma and later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells. The pathway appears to be active in CSCs of pediatric brain tumors.
The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including hematopoietic, neural and mammary stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors.
A particular branch of the Notch signaling pathway that involves the transcription factor Hes3 has been shown to regulate the number of cultured cells with cancer stem cell characteristics obtained from glioblastoma patients.
Sonic hedgehog and Wnt 
These developmental pathways are also strongly implicated as stem cell regulators. Both Sonic hedgehog (SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand. This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt.
Sonic hedgehog blockers are available, such as cyclopamine. There is also a new water soluble cyclopamine that may be more effective in cancer treatment. There is also DMAPT, a water soluble derivative of parthenolide (induces oxidative stress, inhibits NF-κB signaling) for AML (leukemia), and possibly myeloma and prostate cancer. A clinical trial of DMAPT is to start in England in late 2007 or 2008. Finally, the enzyme telomerase may qualify as a study subject in CSC physiology. GRN163L (Imetelstat) was recently started in trials to target myeloma stem cells. If it is possible to eliminate the cancer stem cell, then a potential cure may be achieved if there are no more CSCs to repopulate a cancer.
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Further reading 
- Polyak K, Weinberg RA (April 2009). "Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits". Nature Reviews Cancer 9 (4): 265–73. doi:10.1038/nrc2620. PMID 19262571.
- Sánchez-García I, Vicente-Dueñas C, Cobaleda C (December 2007). "The theoretical basis of cancer-stem-cell-based therapeutics of cancer: can it be put into practice?". BioEssays 29 (12): 1269–80. doi:10.1002/bies.20679. PMID 18022789.
- Gao JX (2008). "Cancer stem cells: the lessons from pre-cancerous stem cells". Journal of Cellular and Molecular Medicine 12 (1): 67–96. doi:10.1111/j.1582-4934.2007.00170.x. PMID 18053092.
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