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 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.
- 1 Tumor propagation models
- 2 Debate
- 3 Evidence
- 4 Origin
- 5 Cancer stem cell isolation
- 6 Heterogeneity (CSC markers)
- 7 Metastatic cancer stem cells
- 8 Implications for cancer treatment
- 9 Pathways
- 10 Cancer stem cells spheroids (3D module)
- 11 References
- 12 Further reading
- 13 External links
Tumor propagation models
In different tumor subtypes, cells within the tumor population exhibit functional heterogeneity, and tumors are formed from cells with various proliferative and differentiation capacities. 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 clonal evolution models
The cancer stem cell model refers to a subset of tumor cells that have the ability to self-renew and are able to 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 the existence of CSCs is that the tumor population is hierarchically arranged with CSCs lying at the apex (Fig. 3).
The clonal evolution 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 (Fig. 4).
 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 (Fig. 5).
The existence of CSCs is under debate, because many studies have failed to discover their specific characteristics. 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. If most tumor cells are endowed with stem cell properties, targeting tumor size directly remains a valid strategy. If they are a small minority, targeting 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).
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. 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 human brain gliomas. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro.
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.
Further evidence comes from histology. Many tumors are heterogeneous and contain multiple cell types native to the host organ. 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.
The existence of leukemia stem cells prompted research into other cancers. CSCs have recently been identified in several solid tumors, including:
- Multiple Myeloma
- Non-melanoma skin cancer
Mechanistic and mathematical models
Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical models, 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. The clinical efficacy of such models remains unestablished.
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" cannot be demonstrated using the cancer stem cell model. This is because cancer stem cells are not present in 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 tumor formation.[clarification needed]
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.
Stem cell mutation
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.
Adult stem cells
Another theory associates adult stem cells 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, adult stem cells are candidates because of their frequent cell divisions (compared to most adult stem cells) in conjunction with the long lifespan of adult stem cells. 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 it is impossible to link a specific cancer to a specific cause.
De-differentiation of mutated cells may create stem cell-like characteristics, suggesting that any cell might become a cancer stem cell.
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. Such a hierarchy would complicate attempts to pinpoint the cancer stem cell's origin.
Cancer stem cell isolation
CSCs, now reported in most human tumors, are commonly identified and enriched using strategies for identifying normal stem cells that are similar across studies. These procedures include fluorescence-activated cell sorting (FACS), with antibodies directed at cell-surface markers and functional approaches including SP analysis (side population assay) or Aldefluor assay. 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 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.
Another approach is sphere-forming assays. Many normal stem cells such as hematopoietics 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.
Heterogeneity (CSC markers)
CSCs have been identified in various solid tumors. Markers specific for normal stem cells are commonly used for isolating CSCs from solid and hematological tumors. Cell surface markers have proved useful for isolation of CSC-enriched populations including CD133 (also known as PROM1), CD44, CD24, EpCAM (epithelial cell adhesion molecule, also known as epithelial specific antigen, ESA), THY1, ATP-binding cassette B5 (ABCB5)., and CD200.
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.
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.
CD200 (OX-2) is a type 1 membrane glycoprotein, which delivers an inhibitory signal to immune cells including T cells, NK 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 role in conversion of retinol to retinoic acid, which is essential for survival.
The first solid malignancy from which CSCs were isolated and identified was breast cancer. Therefore, these CSCs are the most intensely studied. Breast CSCs have been enriched in CD44+CD24−/low, SP, ALDH+ subpopulations. Breast CSCs are apparently phenotypically diverse. CSC marker expression in breast cancer cells is apparently heterogeneous and breast CSC populations vary across tumors. 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. Stem-like tumor cells have been identified using cell surface markers including CD133, SSEA-1 (stage-specific embryonic antigen-1), EGFR and CD44. 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.
CSCs were reported in human colon cancer. For their identification, cell surface markers such as CD133, CD44 and ABCB5, functional analysis including clonal analysis  and Aldefluor assay were used. 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. In addition, 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, including liver, pancreas, kidney or ovary. In prostate cancer, the tumor-initiating cells have been identified in CD44+ cell subset as CD44+α2β1+, TRA-1-60+CD151+CD166+  or ALDH+  cell populations. Putative 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 tumor cell can metastasize. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes. In epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered as a crucial event in metastasis. 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. EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor β. 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).
Tumor cells undergoing an EMT may be precursors for metastatic cancer cells, or even metastatic CSCs. 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 cell subsets showed similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor led to the reduced metastatic potential without altering tumorigenic capacity.
In breast cancer CD44+CD24−/low cells are detectable in metastatic pleural effusions. By contrast, an increased number of CD24+ cells have been identified in distant metastases in breast cancer patients. It is possible that CD44+CD24−/low cells initially metastasize and in the new site they change their phenotype and undergo limited differentiation. 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 are apparently derived from SCS through the acquisition of transient EMT (Fig. 7).
Implications for cancer treatment
CSCs have implications for cancer therapy, including disease identification, selective drug targets, prevention of metastasis and new intervention strategies.
Normal somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps (such as MDR) that pump out drugs and DNA repair proteins. They have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). 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. Selectively targeting CSCs may allow treatment of aggressive, non-resectable tumors, as well as prevent metastasis and relapse. The hypothesis suggests that upon CSC elimination, cancer could regress due to differentiation and/or cell death. What fraction of tumor cells are CSCs and therefore need to be eliminated is unclear.
Studies looked for specific markers and for proteomic and genomic tumor signatures that distinguish CSCs from others. 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. Some types of cancer cells can survive treatment with salinomycin through autophagy, 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.
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. 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.
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.
The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma and later shown to regulate HSCs. The role of Bmi-1 has been illustrated in neural stem cells. The pathway appears to be active in CSCs of pediatric brain tumors.
The Notch pathway plays a role in controlling stem cell proliferation for several cell types including hematopoietic, neural and mammary stem cells. Components of this 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 regulates a number of cultured cells with cancer stem cell characteristics obtained from glioblastoma patients.
Sonic hedgehog and Wnt
These developmental pathways are stem cell regulators. 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 their activation commonly goes together. This is common rather than universal. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt.
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, inhibits NF-κB signaling) for AML (leukemia) and possibly myeloma and prostate cancer. Telomerase is a study subject in CSC physiology. 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.
Cancer stem cells spheroids (3D module)
The monolayer of CSCs grown as spheroids showed better growth rate than MDA-MB 231 cells, which shows the efficacy of 3D spheroid format of CSCs. CD44 show increased expression in spheroids compared to 2D culture of MDA-MB 231. ALDH1 a key marker of breast stem cells was highly expressed in BCSCs and MDA-MB 231 grown in 3D, while they are absent in CSCs and MDA-MB 231 cells grown in 2D.
CSCs grown as spheroids showed better growth rates, which showed the efficacy of 3D spheroid format for CSCs culture. BCSC prevalence and clinical outcomes are associated and support key roles of CSCs in breast cancer metastasis and drug resistance.
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