
Cancer stem cells (CSCs) are
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
cells (found within
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s or
hematological cancers) that possess characteristics associated with normal
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
s, specifically the ability to give rise to all
cell type
A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...
s 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
In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or r ...
and
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
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 model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
s, 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
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cura ...
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
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
in the late 1990s. Since the early 2000s they have been an intense
cancer research
Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure.
Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate ...
focus. The term itself was coined in a highly cited paper in 2001 by biologists
Tannishtha Reya
Tannishtha Reya is an Indian-born American cell and developmental biologist working in cancer research at Columbia University in New York. She has received numerous awards, including an National Institutes of Health, NIH Director's Pioneer Award ...
,
Sean J. Morrison, Michael F. Clarke and
Irving Weissman.
Tumor propagation models
In different
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
subtypes, cells within the tumor population exhibit functional
heterogeneity
Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
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 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.
Importantly it is observed that whereas in the healthy human esophageal epithelium the proliferative burden is met by a stochastically dividing basal epithelium. Upon its transition to the precancerous Barrett's esophagus epithelium, however, a small dedicated stem cell compartment appears that supports proliferation of the epithelium while concomitantly evidence for a stochastically dividing compartment contributing to the maintenance of the tissue disappears. Hence, at least for certain neoplastic tissues, dedicated stem cell compartments maintain and enlarge the size of the transformed compartment
The cancer stem cell model
The cancer stem cell model, also known as the Hierarchical Model proposes that tumors are hierarchically organized (CSCs lying at the apex
(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
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.
Stochastic model
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
The cell's potential can be influenced by unpredicted genetic or
epigenetic
In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
factors, resulting in phenotypically diverse cells in both the tumorigenic and non-tumorigenic cells that compose the tumor. According to the "stochastic model" (or "clonal evolution model") every cancer cell in a tumor could gain the ability to self-renew and differentiate to the numerous and heterogeneous lineages of cancer cells that compromise a tumor
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.
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.
(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).
Tying CSC and stochastic models together
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 "Dreamy" and BULL CSC models.
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
is a Latin phrase meaning 'in place' or 'on site', derived from ' ('in') and ' ( ablative of ''situs'', ). The term typically refers to the examination or occurrence of a process within its original context, without relocation. The term is use ...
supporting a more Stochastic model.
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.
The cancer stem cell immunology model
This model suggests that immunological properties may be important for understanding tumorigenesis and heterogeneity. As such, CSCs can be very rare in some tumors,
[ >] but some researchers found that a large proportion of tumor cells can initiate tumors if transplanted into severely immunocompromised mice, and thus questioned the relevance of rare CSCs. However, both stem cells and CSCs 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 identifying CSCs.
Furthermore, the model suggests that CSCs may initially be dependent on stem cell niches, and CSCs may function there 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.
Debate
The existence of CSCs is under debate, because many studies found no cells with their specific characteristics.
Cancer cells must be capable of continuous proliferation and self-renewal to retain the many mutations required for
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cell (biology), cells are malignant transformation, transformed into cancer cells. The process is characterized by changes at the cellular, G ...
and to sustain the growth of a tumor, since differentiated cells (constrained by the
Hayflick Limit) 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 dysregulation 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
Phenotypic plasticity refers to some of the changes in an organism's behavior, morphology and physiology in response to a unique environment. Fundamental to the way in which organisms cope with environmental variation, phenotypic plasticity encompa ...
under therapeutic challenge, altering their transcriptomes to a more stem-like state to escape destruction. According to one theory, cancer recurrence is caused by the phenotype change of malignant cell populations, when they are exposed to chemotherapy that allows those cells that have a slower pace of proliferation to survive (rather dormant, quiescent cells), while killing those that proliferate faster. The dormant cells may give rise to clones that remain slow-cycling for long periods of time, until they are exposed to conditions (for example inflammation) that trigger the appearance of fast cycling, aggressive tumors. The phenotype plasticity is then at least in part explained by the fact that the "stem-like" cancer cell clones have chromatin that is exposed in a manner that allows those cells to express key genes with different dynamics (kinetics and magnitude) than the rest of the tumor, and also with different dynamics when compared to non-tumor cells.
Evidence
The first conclusive evidence for CSCs came in 1997. Bonnet and Dick isolated a subpopulation of leukemia cells that expressed surface marker
CD34
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.
CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first desc ...
, but not
CD38
CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase, is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in ...
.
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
A glioma is a type of primary tumor, primary Neoplasm, tumor that starts in the glial cells of the Human brain, brain or spinal cord. They are Malignancy, malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain ...
. Human cortical
glial
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cell (biology), cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce Action potential, electrical ...
tumors contain neural stem-like cells expressing astroglial and neuronal markers ''in vitro''. 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.
In
cancer research
Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure.
Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate ...
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
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
the frequency of these cells is less than 1 in 10,000.
Further evidence comes from
histology
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
. Many tumors are
heterogeneous
Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
and contain multiple
cell type
A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...
s native to the host organ. Tumour heterogeneity is commonly retained by tumor
metastases
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
. This suggests that the cell that produced them had the capacity to generate multiple cell types, a classical hallmark of
stem cells
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
.
The existence of leukemia stem cells prompted research into other cancers. CSCs have recently been identified in several solid tumors, including:
* Brain
* Breast
* Colon
* Ovary
* Pancreas
* Prostate
*Melanoma
*Multiple Myeloma
*Non-melanoma skin cancer (basal cell carcinoma
and squamous cell carcinoma
)
Mechanistic and mathematical models
Once the pathways to cancer are hypothesized, it is possible to develop predictive
mathematical
Mathematics is a field of study that discovers and organizes methods, Mathematical theory, theories and theorems that are developed and Mathematical proof, proved for the needs of empirical sciences and mathematics itself. There are many ar ...
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.
Origin

The origin of CSCs is an active research area. The answer may depend on the tumor type and
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
. 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
Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek σωματικóς, ...
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
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 (ASC) with tumor formation. This is most often associated with tissues with a high rate of cell turnover (such as the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
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.
De-differentiation
De-differentiation of mutated cells may create stem cell-like characteristics, suggesting that any cell might become a cancer stem cell. In other words, 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
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
models, whereby cells undergoing
androgen deprivation therapy
Androgen deprivation therapy (ADT), also called androgen ablation therapy or androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen, androgen hormones, ...
appear to transiently alter their transcriptome to that of a
neural crest
The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...
stem-like cell, with the invasive and multipotent properties of this class of stem-like cells.
Hierarchy
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
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
. 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 origin.
Identification
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 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 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.
CSCs can also be identified by efflux of incorporated
Hoechst dyes via
multidrug resistance
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are ...
(MDR) and
ATP-binding cassette (ABC)
Transporters.
Another approach is sphere-forming assays. Many normal
stem cells
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
such as
hematopoietic
Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
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
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
or
prostate tumors also have the ability to form anchor-independent spheres.
Recent years have seen an advent of genetic approaches to identify cancer stem cells in experimental rodents. In such studies, following the induction of cancer (usually through the application of mutagens), a genetic cassette is activated resulting in the expression of an easily identifiable marker, for instance green fluorescent protein (GFP). This overcomes the limitations of traditional approaches (e.g. the classic Bromodeoxyuridine (BrdU) labeling technique has been used to identify slow-cycling cells in animals) as genetic approaches are cell cycle independent and can be used for in vivo pulse-chase labeling to identify quiescent/slow-cycling cells. This strategy, for instance, was instrumental for identifying the so-called Lgr5+ compartment as a cancer stem cell compartment in liver cancer and showing its potential as a viable therapeutic target.
Heterogeneity (markers)
CSCs heterogeneity is a pool of differentiated and undifferentiated tumour cells that are replenished by cells possessing both tumour and stem cell like properties and having phenotypic and metabolic heterogeneity inside the single tumour mass. There are two theories to explain the phenotypic and metabolic heterogeneity of CSCs; clonal variation and cancer stem cell theory. While former theory dictates the role of genetic, epigenetic and micro environment where tumour cell resides to acquire undifferentiated tumorigenic traits. The latter theory focus more on the malignancy traits acquired by stem cells where these undifferentiated and highly tumorigenic stem cells repopulate the differentiated tumour mass.
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
CD133 antigen, also known as prominin-1, is a glycoprotein that in humans is encoded by the ''PROM1'' gene. It is a member of pentaspan transmembrane glycoproteins, which specifically localize to cellular protrusions. When embedded in the cell me ...
(also known as
PROM1),
CD44,
ALDH1A1
Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ''ALDH1A1'' gene.
Function
This protein belongs to the aldehyde dehydrogenases family of proteins ...
,
CD34
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.
CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first desc ...
,
CD24 and
EpCAM (
epithelial cell adhesion molecule
Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, pro ...
, also known as epithelial specific antigen,
ESA).
CD133 (prominin 1) is a five-
transmembrane domain
A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
expressed on
CD34
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.
CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first desc ...
+ stem and
progenitor cells
A progenitor cell is a Cell (biology), biological cell that can Cellular differentiation, differentiate into a specific cell type. Stem cell, Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than ...
, in endothelial precursors and
fetal neural stem cells. It has been detected using its
glycosylated
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although e ...
known as AC133.
EpCAM (epithelial cell adhesion molecule, ESA, TROP1) is hemophilic Ca
2+-independent cell adhesion molecule expressed on the basolateral surface of most
epithelial cells
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
.
CD90 (THY1) is a
glycosylphosphatidylinositol
Glycosylphosphatidylinositol () or glycophosphatidylinositol (GPI) is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles in a wide vari ...
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
anchored in the plasma membrane and involved in
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
. It may also mediate adhesion between
thymocytes
A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.
Thymopoiesis describes the process which turns thym ...
and thymic stroma.
CD44 (PGP1) is an adhesion molecule that has
pleiotropic
Pleiotropy () is a condition in which a single gene or genetic variant influences multiple phenotypic traits. A gene that has such multiple effects is referred to as a ''pleiotropic gene''. Mutations in pleiotropic genes can impact several trait ...
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
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
glycosylphosphatidylinositol-anchored adhesion molecule, which has co-stimulatory role in
B and
T cell
T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s.
CD200 (OX-2) is a type 1 membrane
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
, which delivers an inhibitory signal to immune cells including T cells,
natural killer cell
Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells ...
s and
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s.
Leptin receptor
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD2 ...
(
LEPR) is a type I cytokine receptor for the fat associate hormone
leptin
Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...
, which plays an important role in promoting malignant progression.
ALDH is a ubiquitous
aldehyde dehydrogenase
Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...
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
Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
, which is essential for survival.
The first solid malignancy from which CSCs were isolated and identified was
breast cancer
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
and they are the most intensely studied. Breast CSCs have been enriched in CD44
+CD24
−/low,
SP
and
ALDH
Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...
+ 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
+CD49f
hiCD133/2
hi.
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
A glioma is a type of primary tumor, primary Neoplasm, tumor that starts in the glial cells of the Human brain, brain or spinal cord. They are Malignancy, malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain ...
and some CD133
+ brain tumor cells may not possess tumor-initiating capacity.
CSCs were reported in human
colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...
.
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
The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
,
lung
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
and many other organs, including
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
pancreas
The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
,
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
or
ovary
The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...
.
In
prostate cancer
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
, 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
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
CSCs have been reported, including CD133
+,
ALDH
+,
CD44
+ and oncofetal protein 5T4
+.
Metastasis
Metastasis is the major cause of tumor lethality. However, not every tumor cell can metastasize.
This potential depends on factors that determine
growth,
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
, invasion and other basic processes.
Epithelial-mesenchymal transition
In epithelial tumors, the
epithelial-mesenchymal transition (EMT) is considered to be a crucial event.
EMT and the reverse transition from
mesenchymal
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood, or bone. The interactions between mesenchyme and epithelium help to form nearly ever ...
to an epithelial phenotype (
MET) are involved in
embryonic development
In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...
, which involves disruption of epithelial cell
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
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
Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...
in
adherens junction
In cell biology, adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissues, usually more basa ...
s, where
β-catenin
Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcr ...
may play a significant role. Translocation of β-catenin from adherens junctions to the
nucleus
Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucleu ...
may lead to a loss of E-cadherin and subsequently to EMT. Nuclear β-catenin apparently can directly, transcriptionally activate EMT-associated target
genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
, such as the E-cadherin gene
repressor
In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
SLUG
Slug, or land slug, is a common name for any apparently shell-less Terrestrial mollusc, terrestrial gastropod mollusc. The word ''slug'' is also often used as part of the common name of any gastropod mollusc that has no shell, a very reduced ...
(also known as
SNAI2).
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
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
).
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
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...
also known as a
SDF1 ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
) cells was defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133
+CXCR4
− cells, but both showed similar tumor development capacity.
Moreover, inhibition of the
CXCR4 receptor reduced metastatic potential without altering tumorigenic capacity.
Epithelial-mesenchymal transition requires iron, which is taken up in cells via CD44. These resulting mesenchymal cells have properties of cancer stem cells.
Two-phase expression pattern
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 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 apparently derived from SCS through the acquisition of transient EMT (Figure 7).
Implications
CSCs have implications for cancer therapy, including for disease identification, selective drug targets, prevention of metastasis and intervention strategies.
Treatment
CSCs are inherently more resistant to
chemotherapeutic agents. There are 5 main factors that contribute to this:
:1. Their
niche protects them from coming into contact with large concentrations of anti-cancer drugs.
:2. They express various transmembrane proteins, such as
MDR1 and
BCRP, that pump drugs out of the cytoplasm.
:3. They divide slowly, like
adult stem cell
Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek σωματικóς ...
s tend to do, and are thus not killed by chemotherapeutic agents that target rapidly replicating cells via damaging DNA or inhibiting mitosis.
:4. They upregulate DNA damage repair proteins.
:5. They are characterized by an overactivation of anti-apoptotic signaling pathways.
After chemotherapy treatment, surviving CSCs are able to repopulate the tumor and cause a relapse. Additional treatment targeted at removing CSCs in addition to cancerous somatic cells must be used to prevent this.
Targeting
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. The fraction of tumor cells that are CSCs and therefore need to be eliminated is unclear.
Studies looked for specific markers
and for
proteomic and
genomic
Genomics is an interdisciplinary field of molecular biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, ...
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
Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...
, a commonly used chemotherapeutic agent. It was later shown in 2017 that salinomycin kills cancer stem cells by sequestering iron in lysosomes and killing the cells by exploiting their vulnerability to ferroptosis.
Some types of cancer cells can survive treatment with salinomycin through
autophagy
Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
, whereby cells use acidic
organelle
In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...
s such as
lysosome
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
s 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
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...
(AML) but not on normal CD34+CD38-
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
cells. Treating AML-engrafted NOD/SCID mice with a CD123-specific
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodie ...
impaired LSCs homing to the bone marrow and reduced overall AML cell repopulation including the proportion of LSCs in secondary mouse recipients.
A 2015 study packaged nanoparticles with
miR-34a and
ammonium bicarbonate
Ammonium bicarbonate is an inorganic compound with formula (NH4)HCO3. The compound has many names, reflecting its long history. Chemically speaking, it is the bicarbonate salt of the ammonium ion. It is a colourless solid that degrades readily to ...
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.
In 2017 it was demonstrated that cancer stem cells have more iron and that this is an Achille's heel of these cells. Targeting iron, particularly by sequestering it in lysosomes, can selectively kill this cell population.
A 2018 study identified inhibitors of the ALDH1A family of enzymes and showed that they could selectively deplete putative cancer stem cells in several ovarian cancer cell lines.
A novel small molecule inhibitor, called compound 974 specifically targets cancer stem cells and inhibits cancer stem cell pathways and genes. This inhibitor also reduced the cancer stem cell frequency in mice. This 2022 study also identified a novel relation between ALDH1A1 and senescence. Blocking senescence by compound 974, inhibited cancer stemness in ovarian cancer cells.
It has also been found that CSCs have the ability to exacerbate drug resistance through overexpression of ABC transporter proteins that can pump hydrophobic compounds.
Pathways
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
Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
, 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
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
may be transformed into a CSC through dysregulation of the proliferation and differentiation
pathways controlling it or by inducing
oncoprotein activity.
BMI-1
The
Polycomb group transcriptional repressor
In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
Bmi-1 was discovered as a common
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. activated in
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
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
Pediatrics (American English) also spelled paediatrics (British English), is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, pediatrics covers many of their youth ...
brain tumor
A brain tumor (sometimes referred to as brain cancer) occurs when a group of cells within the Human brain, brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign ...
s.
Notch
The
Notch pathway
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animal, animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTC ...
plays a role in controlling stem cell proliferation for several cell types including hematopoietic, neural and mammary
SCs. Components of this pathway have been proposed to act as oncogenes in mammary
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.
Sonic hedgehog and Wnt
These developmental pathways are SC regulators.
Both
Sonic hedgehog
Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene.
This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...
(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
glioma
A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of ...
s, where they are highly expressed. A degree of
crosstalk
In electronics, crosstalk (XT) is a phenomenon by which a signal transmitted on one circuit or channel of a transmission system creates an undesired effect in another circuit or channel. Crosstalk is usually caused by undesired capacitive, ...
exists between the two pathways and they are commonly activated together.
By contrast, in colon cancer hedgehog signalling appears to antagonise Wnt.
Sonic hedgehog blockers are available, such as
cyclopamine
Cyclopamine (11-deoxojervine) is a naturally occurring steroidal alkaloid. It is a teratogenic component of corn lily ('' Veratrum californicum''), which when consumed during gestation has been demonstrated to induce birth defects, including the ...
. A water-soluble cyclopamine may be more effective in cancer treatment. DMAPT, a water-soluble derivative of
parthenolide
Parthenolide is a sesquiterpene lactone of the germacranolide class which occurs naturally in the plant feverfew ('' Tanacetum parthenium''), after which it is named, and in the closely related tansy (''Tanacetum vulgare''). It is found in highes ...
, induces oxidative stress and inhibits
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
signaling for AML (leukemia) and possibly myeloma and prostate cancer.
Telomerase
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
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
Drug design, often referred to as rational drug design or simply rational design, is the invention, inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic compound, organi ...
", involving AlphaScreens and
ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay is a solid-phase type of enzyme immunoassay (EIA) to detect the presence of ...
technologies.
References
Further reading
*
*
{{DEFAULTSORT:Cancer Stem Cell
Stem cells
Carcinogenesis