Cancer stem cells ( CSC ) are cancer cells (found in tumors or haematological cancers) that have characteristics associated with normal stem cells, in particular the ability to induce all types of cells found in specific cancer samples. CSC is therefore tumorigenic (tumor forming), may be different from other non-tumorigenic cancer cells. CSC can produce tumors through the process of stem cell renewal and differentiation into several types of cells. The cells are hypothesized to survive tumors as different populations and cause recurrence and metastasis by causing new tumors. Therefore, the development of specific therapies targeted at CSC has hope for improved survival and quality of life for cancer patients, especially for patients with metastatic disease.
The existing cancer treatments have largely been developed based on animal models, where therapies capable of promoting tumor shrinkage are considered effective. However, animals do not provide a complete model of human disease. Specifically, in mice, whose lifespan does not exceed two years, recurrent tumors are difficult to study.
The efficacy of cancer treatment, at an early stage of testing, is often measured by a tumor mass ablation fraction (killing fractions). Because CSC forms a small portion of the tumor, it may not always opt for drugs that act specifically on stem cells. This theory suggests that conventional chemotherapies kill different or different cells, which make up most of the tumors but do not produce new cells. The CSC population, which gives rise to it, can 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 the focus of intense cancer research.
Video Cancer stem cell
Model propagasi tumor
In different tumor subtypes, cells in the tumor population exhibit functional heterogeneity and tumors are formed from cells with varying proliferative and differentiation capacities. Functional heterogeneity among cancer cells has led to the creation of multiple propagation models to account for the heterogeneity and differential regenerative capacity of tumors: cancer stem cells (CSC) and stochastic models. However, certain perspectives maintain that this demarcation is artificial, since both processes act complementarily as far as the actual population of the tumor is concerned.
Cancer stem cell model
The cancer stem cell model, also known as the Hierarchical Model suggests that the tumor is hierarchically organized (CSC lying on the peak (Figure 3).) In tumor cancer populations there are cancer stem cells (CSC) that are tumorigenic cells and are biologically different from other sub-populations. They have two main features: their long-term ability to renew themselves and their ability to differentiate into non-tumorigenic progeny but still contribute to tumor growth. This model shows that only certain sub-populations of cancer stem cells have the ability to promote cancer progression, meaning that there are identifiable (intrinsically) specific characteristics and then targeted to destroy long-term tumors without the need to combat the entire tumor.
Stochastic model
In order for the cell to become cancerous, it must undergo a number of significant changes in its DNA sequence. This cell model shows this mutation can occur in cells in the body that produce cancer. Basically this theory proposes that all cells have the ability to become tumorigenic which makes all tumor cells equipped with the ability to self-renew or differentiate, leading to tumor heterogeneity while others can differentiate into non-CSC. Cell potency can be influenced by unpredictable genetics. epigenetic factors, producing diverse phenotypic cells in tumorigenic and non-tumorigenic cells that make up the tumor.
These mutations can further accumulate and increase the resilience and suitability of cells that enable them to defeat other tumor cells, better known as somatic evolution models. The clonal evolution model, which occurs both in the CSC model and the stochastic model, postulates that mutant tumor cells with growth advantages outperform others. Cells in the dominant population have the same potential to initiate tumor growth (Figure 4).
Both of these models are not mutually exclusive, since CSC itself undergoes a clonal evolution. Thus, a more dominant secondary CSC may emerge, if the mutation confer a more aggressive nature (Figure 5).
Tying CSC and stochastic models together
A study in 2014 argues that the gap between these two controversial models can be bridged by providing an alternative explanation of tumor heterogeneity. They show models that cover aspects of both Stochastic and CSC models. They examined the plasticity of cancer stem cells in which cancer stem cells can transition between non-cancer stem cells (Non-CSC) and CSC through in situ supporting more Stochastic models. However, the presence of two distinct non-CSC and CSC populations biologically supports the larger CSC model, suggesting that both models can play an important role in tumor heterogeneity.
Immunology model of cancer stem cells
While CSCs can be very rare in some tumors, some researchers have found that most tumor cells can initiate tumors if transplanted into immunocompromised mice, and thus question the rare CSC relevance. However, both stem cells and CSC have unique immunological properties that make them highly resistant to immunosurveilans. Thus, only CSCs are able to breed tumors in patients with functional immunosurveillance, and immune rights may be the main criterion for CSC. Furthermore, this model suggests that CSC may initially depend on the niche of the stem cell, and CSC can serve as a reservoir where mutations can accumulate for decades without resistance by the immune system. Clinical bright tumors can grow if: A) CSC cells lose their dependence on niche factors, B) their offspring from normal, highly proliferative normal tumor cells, but initially immunogenically evolved to escape immunosurveillance or C) the immune system may lose tumor capacity suppressing, eg. because of aging.
Maps Cancer stem cell
Debate
The existence of CSC is being debated, as many studies do not find cells with their specific characteristics. Cancer cells must be capable of sustained proliferation and self-renewal to retain many of the mutations necessary for carcinogenesis and to maintain tumor growth, because different cells (limited by the Hayflick Limit) can not divide indefinitely. For therapeutic considerations, if most of the tumor cells have stem cell properties, targeting tumor size directly is a valid strategy. If CSC is a small minority, targeting them may be more effective. Another debate is about the origin of CSC - whether from dysregulated normal stem cells or from more specialized populations that gain self-renewal (which is linked to the problem of stem cell plasticity). Confusing this debate is the discovery that many cancer cells demonstrate phenotypic plasticity under therapeutic challenges, transforming their transcripts into more rod-like states to avoid destruction.
Evidence
The first conclusive evidence for CSC came in 1997. Bonnet and Dick isolated subpopulations of leukemia cells that showed a CD34 surface marker, but not CD38. The authors determined that CD34 /CD38 - subpopulations were able to initiate tumors in NOD/SCID mice that were histologically similar to donors. The first evidence of a dense cancer such as tumor stem cell followed in 2002 with the discovery of a clonogenic, isolated and characterized clonogenic ball former from human brain glioma. Human glial tumors contain cells such as nerve stems expressing astroglial and neuronal markers in vitro .
In cancer research experiments, tumor cells are sometimes injected into experimental animals to form tumors. The progression of the disease is then followed in time and new drugs can be tested for its efficacy. The formation of tumors requires thousands or tens of thousands of cells to be introduced. Classically, this is explained by a poor methodology (ie, tumor cells losing viability during transfer) or the importance of the microenvironment, the particular biochemical environment of the injected cell. Proponents of the CSC paradigm argue that only a small proportion of injected cells, CSC, have the potential to produce tumors. 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 many original cell types from the host organ. The heterogeneity of the tumor is generally maintained by tumor metastasis. This suggests that the cells that produce them have the capacity to produce several cell types, a classic feature of stem cells.
The presence of leukemia stem cells prompted research into other cancers. CSC has recently been identified in several solid tumors, including:
- Brain
- Breast
- Colon
- Ovary
- Pancreas
- Prostate
- Melanoma
- Multiple Myeloma
- Non-melanoma skin cancer
Mechanical and mathematical models
Once the path to cancer is hypothesized, it is possible to develop a predictive mathematical model, for example, based on the cell compartment method. For example, the growth of abnormal cells can be represented by the probability of specific mutations. Such models predict that repeated insults in mature cells increase the formation of abnormal progeny and cancer risk. The clinical efficacy of such models remains undetermined.
Origin
The origin of CSC is an active research area. The answer may depend on the type of tumor and phenotype. So far the hypothesis that a tumor originating from a single "cell of origin" has not been proven using a cancer stem cell model. This is because cancer stem cells are absent in end-stage tumors.
Original hypotheses include mutants in developing stem cells or progenitors, mutants in adult stem cells or adult and mutant progenitor cells, differentiated cells that acquire rod-like attributes. These theories often focus on "cell origin" of the tumor.
Hypothesis
Stem cell mutation
The "mutations in the stem cell niche population during development" hypothesized that the stem growing population mutates and then reproduce so that mutations are shared by many offspring. These child cells are much closer to becoming tumors and their number increases the likelihood of cancerous mutations.
Adult stem
Another theory links adult stem cells (ASC) with tumor formation. This is most often associated with tissues with high cell turnover rates (such as skin or gut). In this network, ASCs are candidates because of their frequent cell division (compared with most ASCs) along with long ASC lifetimes. This combination creates the ideal set of circumstances for accumulated mutations: the accumulation of mutations is a major factor driving cancer initiation. Evidence suggests that the association is a true phenomenon, although certain cancers have been linked to specific causes.
De-differentiation
De-differentiation of mutated cells can create characteristics such as stem cells, suggesting that each cell may become a cancer stem cell. In other words, a fully differentiable cell undergoes a mutation or extracellular signal that pushes it back into a rod-like state. This concept has been shown recently in the model of prostate cancer, in which cells undergoing androgen deprivation therapy seem to transform their transcripts temporarily into stem cells such as neural dentures, with the invasive and multipotent nature of the class of cells such as stems.
Hierarchy
The concept of tumor hierarchy claims that the tumor is a heterogeneous population of mutant cells, all of which have several mutations, but vary in specific phenotypes. Tumors have several types of stem cells, one is optimal for certain environments and other less successful lines. These secondary lines may be more successful in other environments, allowing tumors to adapt, including adaptation to therapeutic interventions. If true, this concept affects the cancer stem cell treatment regimen. Such a hierarchy will make it difficult to determine its origin.
Identify
CSC, now reported in most human tumors, is generally identified and enriched using a strategy to identify normal stem cells that are similar throughout the study. These procedures include fluorescence-activated cell sorting (FACS), with antibodies directed at cell-surface markers and functional approaches including side population tests or Aldefluor tests. CSC enriched results were then implanted, at various doses, in mice with an immune-deficiency to assess tumor progression capacity. This in vivo assay is called a limited dilution test. A subset of tumor cells that can initiate tumor development at low cell counts is further tested for self-renewal capacity in serial tumor studies.
The CSC can also be identified by the end of Hoechst dye inserted through multidrug resistance (MDR) and ATP-binding cassette (ABC) Transporters.
Another approach is ball-forming test. Many normal stem cells such as hematopoietic or stem cells from tissue, under special cultural conditions, form a three-dimensional sphere that can differentiate. Like normal stem cells, CSCs isolated from brain tumors or prostates also have the ability to form independent balls.
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Heterogeneity (marker)
CSC has been identified in a variety of solid tumors. Generally, special markers for normal stem cells are used to isolate CSCs from solid tumors and hematologists. The most commonly used markers for CSC isolation include: CD133 (also known as PROM1), CD44, ALDH1A1, CD34, CD24 and EpCAM (epithelial cell adhesion molecules, also known as specific antigen epithelium, ESA).
CD133 (prominin 1) is a five-transmembrane domain glycoprotein expressed in stem cell and progenitor CD34 , on endothelial precursors and fetal neural stem cells. It has been detected using a glycosylated epitope known as AC133.
Epicam (epithelial cell adhesion molecule, ESA, TROP1) is a molecule of Ca cell adhesion found on the basolateral surface of most epithelial cells.
CD90 (THY1) is a glycosylphosphatidylinositol glycoprotein anchored in the plasma membrane and is involved in signal transduction. It may also mediate adhesion between thymocytes and thymic stroma.
CD44 (PGP1) is an adhesion molecule that has a pleiotropic role in cell signaling, migration and homing. It has several isoforms, including CD44H, which shows a high affinity for hyaluronate and CD44V that have metastatic properties.
CD24 (HSA) is a glycosylated glycosylphosphatidylinositol-adhesion molecule, which has a co-stimulating role in B and T cells.
CD200 (OX-2) is a type 1 membrane glycoprotein, which provides signaling inhibition to immune cells including T cells, natural killer cells and macrophages.
ALDH is a family of omega-dehydrogenase aldehyde enzymes, which catalyzes the oxidation of aromatic aldehydes to carboxyl acids. For example, it has a role in the conversion of retinol to retinoic acid, which is essential for survival.
The first solid malignancy from which CSC was isolated and identified was breast cancer and those who were studied most intensively. Breast CSC has been enriched in CD44 CD24 -/low , SP and ALDH subpopulations. CSC's breasts are apparently diverse phenotypes. The CSC markers in breast cancer cells appear to be heterogeneous and the breast CSC population varies across tumors. CD44 populations CD24 - and CD44 CD24 were tumor initiation cells; however, CSC is most enriched using the CD44 marker profile CD49f hi CD133/2 hi .
CSC has been reported in many brain tumors. Tumor cells such as stem have been identified using surface cell markers including CD133, SSEA-1 (stage-specific embryonic antigen-1), EGFR and CD44. The use of CD133 for the identification of cells such as brain tumors may be problematic because tumorigenic cells are found in CD133 and CD133 - cells in some glioma and some CD133 brain tumor cells may not have tumor initiation capacity.
CSC is 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 CSC colon produces conflicting results. The AC133 epitope, but not the CD133 protein, is specifically expressed in the CSC of the large intestine and its expression is lost in differentiation. In addition, CD44 colon cancer cells and additional sub-fractionation of the CD44 cell population EpCAM with CD166 increased the success of tumor engraftment.
Some CSCs have been reported in the prostate, lungs and many other organs, including liver, pancreas, kidney or ovary. In prostate cancer, tumor initiation cells have been identified in CD44 cell subset as CD44 ? 2? 1 , TRE-1 -60 CD151 CD166 or ALDH cell population. Putative markers for pulmonary CSC have been reported, including CD133 , ALDH , CD44 and 5T4 oncofetal protein.
Metastasis
Metastasis is a major cause of lethality of tumors. However, not every tumor cell can metastasize. This potential depends on the factors that determine growth, angiogenesis, invasion and other basic processes.
Epithelial-mesenchymal transition
In epithelial tumors, the epithelial-mesencalal (EMT) transition is considered an important event. EMT and mesenchymal transition back to the epithelial phenotype (MET) are involved in embryonic development, involving epithelial cell homeostatic disorders and acquisition of migrating mesenchymal phenotypes. EMT seems to be controlled by a canonical path like WNT and change growth factor ?.
The important feature of EMT is the loss of E-cadherin membrane at the adherent junction, where? -the blade can play an important role. Translocation? -katin from crossing junction to nucleus can cause loss of E-cadherin and then to EMT. Nuclear? -catenin appears to be directly, transcriptionally activating EMT-related target genes, such as the EU cadherin SLUG gene repressor (also known as SNAI2). The mechanical properties of the tumor microenvironment, such as hypoxia, can contribute to CSC survival and metastatic potential through the stabilization of inducible hypoxia factors through interaction with ROS (reactive oxygen species).
The tumor cells undergoing EMT can be precursors to metastatic cancer cells, or even metastatic CSCs. On the invasive edge of pancreatic carcinoma, a subset of CD133 CXCR4 (receptor for CXCL12 chemokine also known as SDF1 ligand) is defined. These cells exhibit much more robust migration activity than their CD133 CXCR4 - cells, but both show similar tumor progression capacity. In addition, inhibition of the CXCR4 receptor reduces the metastatic potential without altering tumorigenic capacity.
Two-phase expression pattern
In breast cancer cells CD44 CD24 -/low can be detected on the pleural effusion of metastasis. In contrast, an increase in cell CD24 numbers has been identified in distant metastases in breast cancer patients. It is possible that CD44 CD24 -/low cells initially metastasize and on new sites alter their phenotype and undergo limited differentiation. The hypothesis of a two-phase expression pattern proposes two forms of cancer stem cells - stationary (SCS) and mobile (MCS). SCS is embedded in the tissues and persists in different areas along the tumor's development. MCS is located in the tumor-host interface. These cells appear to originate from SCS through interim acquisition of EMT (Figure 7).
Implications
CSC has implications for cancer therapy, including for disease identification, selective drug targeting, metastatic prevention and intervention strategies.
Treatment
Somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps (such as MDR) that pump drugs and DNA repair proteins. They have a slow rate of cell turnover (chemotherapy agents naturally target cells that replicate quickly). CSCs that develop from normal stem cells can also produce these proteins, which can increase their resistance to chemotherapy. The surviving CSC then replenishes the tumor, causing relapse.
Targeting
Selectively targeting CSCs may allow aggressive, non-resectable tumor treatment, as well as prevent metastasis and recurrence. The hypothesis shows that after CSC elimination, the cancer may retreat due to differentiation and/or cell death. The fraction of tumor cells that are CSC and therefore need to be removed is not clear.
The study looked for specific markers and for proteomic and genomic tumor markers that differentiate CSCs from others. In 2009, scientists identified a salinomycin compound, which selectively reduces the proportion of breast CSC in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapy agent. Several types of cancer cells can survive with salinomycin treatment through autophagy, in which cells use acid organelles such as lysosomes to decrease and recycle certain types of proteins. The use of autophagy inhibitors can kill cancer stem cells that survive by autophagy.
The interleukin-3 receptor-alpha (CD123) surface receptor is overexpressed on CD34 CD38-leukemic stem cells (LSCs) in acute myelogenous leukemia (AML) but not on normal CD34 - CD38 - bone marrow cells. Treating NOD/SCID mice adopted AML with specific CD123 monoclonal antibodies damaging LSC attached to bone marrow and reducing the overall population of AML cells including the proportion of LSC in the rat secondary recipients.
A 2015 study packed nanoparticles with miR-34a and ammonium bicarbonate and sent it to CSC prostate in a mouse model. Then they illuminate the area with near-infrared laser light. This causes the nanoparticles to swell three times or more in the size of bursting endosomes and spread RNA inside the cell. miR-34a may decrease CD44 levels.
Path
New drug designs for CSC targeting 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, a disease in which CSC's origins are best understood. Stem cells from many organs have the same cellular pathway as HSCs derived from leukemia.
Normal stem cells can be converted to CSC via dysregulated pathways of proliferation and differentiation that control it or by inducing oncoprotein activity.
BMI-1
Polycomb Bmi-1 group transcription controller is found as a common oncogene that is activated in the lymphoma and then shown to regulate HSC. The role of Bmi-1 has been illustrated in neural stem cells. The pathway appears to be active in CSC from a child's brain tumor.
Notch
The notch path plays a role in controlling the proliferation of stem cells for some cell types including hematopoietic, neural and mammary SCs. The component of this pathway has been proposed to act as oncogenes in the breast and other tumors.
Notch signaling branches involving Hes3 transcription factors regulate a number of cultured cells with CSC characteristics obtained from glioblastoma patients.
Sonic Hedgehog and Wnt
This development path is the SC regulator. Sonic Hedgehog (SHH) and Wnt pathways are generally hyperactive in tumors and are necessary to maintain tumor growth. However, the transcription factor Gli regulated by SHH takes their name from glioma, where they are highly expressed. The degree of crosstalk exists between two paths and they are generally activated together. In contrast, in the signs of hedgehog bowel cancer appears to be hostile to Wnt.
Sonic hedge blockade is available, such as cyclopamine. Water-soluble cyclopamine may be more effective in treating cancer. DMAPT, a water-soluble derivative of parthenolide, induces oxidative stress and inhibits NF-B signaling for AML (leukemia) and possibly myeloma and prostate cancer. Telomerase is the subject of study in the physiology of CSC. GRN163L (Imetelstat) has recently started in trials to target myeloma stem cells.
Source of the article : Wikipedia
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