Cancer stem cells are cancer

Cancer

Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 cells (found within tumor

Tumor

A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s or hematological cancers) that possess characteristics associated with normal stem cell

Stem cell

This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

s, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause relapse

Relapse

Relapse, in relation to drug misuse, is resuming the use of a drug or a dependent substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate...

 and metastasis

Metastasis

Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

 by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease

Metastasis

Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

.

Existing cancer treatments have mostly been developed based on animal model

Animal model

An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...

s, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study.

The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill

Fractional kill

In oncology, the fact that one round of chemotherapy does not kill all the cells in a tumor is a poorly understood phenomenon called fractional kill, or fractional cell kill....

). As CSCs would form a very small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause a relapse of the disease.

Evidence

The existence of CSCs is a subject of debate within medical research, because many studies have not been successful in discovering the similarities and differences between normal tissue stem cells and cancer stem cells. Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required for carcinogenesis

Carcinogenesis

Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...

, and to sustain the growth of a tumor since differentiated cells (constrained by the Hayflick Limit

Hayflick limit

The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length....

) cannot divide indefinitely . However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties, there is no incentive to focus on a specific sub population. There is also debate on the cell of origin of CSCs - whether they originate from stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity).

The first conclusive evidence for CSCs was published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation of leukaemic cells that express a specific surface marker CD34, but lacks the CD38 marker. The authors established that the CD34⁺/CD38^- subpopulation is capable of initiating tumors in NOD/SCID

Severe combined immunodeficiency

Severe combined immunodeficiency , is a genetic disorder in which both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency...

 mice that is histologically similar to the donor.

In cancer research

Cancer research

Cancer research is basic research into cancer in order to identify causes and develop strategies for prevention, diagnosis, treatments and cure....

 experiments, tumor cells are sometimes injected into an experimental animal

Animal testing

Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...

 to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been explained by poor methodology (i.e. the tumor cells lose their viability

Viability

Viable or viability is the ability of a thing to maintain itself or recover its potentialities.Viable or viability may also refer to:...

 during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the cancer stem cell paradigm argue that only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia

Acute myeloid leukemia

Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...

 the frequency of these cells is less than 1 in 10,000.

Further evidence comes from histology

Histology

Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

, the study of the tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell type

Cell type

A cell type is a distinct morphological or functional form of cell. When a cell switches state from one cell type to another, it undergoes cellular differentiation. A list of distinct cell types in the adult human body may include several hundred distinct types.-References:...

s native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells.

The existence of leukaemic stem cells prompted further research into other types of cancer. CSCs have recently been identified in several solid tumors, including cancers of the:

• Brain
• Breast
• Colon
• Ovary
• Pancreas
• Prostate
• Melanoma

• Multiple Myeloma

Importance

Not only is finding the source of cancer cells necessary for successful treatments, but if current treatments of cancer do not properly destroy enough CSCs, the tumor will reappear. Including the possibility that the treatment of for instance, chemotherapy

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

, will leave only chemotherapy-resistant CSCs, then the ensuing tumor will most likely also be resistant to chemotherapy. If the cancer tumor is detected early enough, enough of the tumor can be killed off and marginalized with traditional treatment. But as the tumor size increases, it becomes more and more difficult to remove the tumor without conferring resistance and leaving enough behind for the tumor to reappear.

Some treatments with chemotherapy, such as paclitaxel

Paclitaxel

Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...

 in ovarian cancer

Ovarian cancer

Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....

 (a cancer usually discovered in late stages), may actually induce chemoresistance (55-75% relapse <2 years). It potentially does this by destroying only the cancer cells susceptible to the drug (targeting those that are CD44

CD44

The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...

-positive, a trait which has been associated with increased survival time in some ovarian cancers), and allowing the cells which are unaffected by paclitaxel (CD44-negative) to regrow, even after a reduction in over a third of the total tumor size. There are studies, though, which show how paclitaxel can be used in combination with other ligands to affect the CD44-positive cells. While paclitaxel alone, as of late, does not cure the cancer, it is effective at extending the survival time of the patients.

Mechanistic and mathematical models

Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology

Mathematical biology

Mathematical and theoretical biology is an interdisciplinary scientific research field with a range of applications in biology, medicine and biotechnology...

 models, e.g., based on the cell compartment method

Compartmental models in epidemiology

In order to model the progress of an epidemic in a large population, comprising many different individuals in various fields, the population diversity must be reduced to a few key characteristics which are relevant to the infection under consideration...

. For instance, the growths of the abnormal cells from their normal counterparts can be denoted with specific mutation probabilities. Such a model has been employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer. Considerable work needs to be done, however, before the clinical efficacy of such models is established.

Origins

The origin of cancer stem cells is still an area of ongoing research. Several camps have formed within the scientific community regarding the issue, and it is possible that several answers are correct, depending on the tumor type and the phenotype

Phenotype

A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

 the tumor presents. One important distinction that will often be raised is that the cell of origin for a tumor can not be demonstrated using the cancer stem cell as a model. This is because cancer stem cells are isolated from end-stage tumors. Therefore, describing a cancer stem cell as a cell of origin is often an inaccurate claim, even though a cancer stem cell is capable of initiating new tumor formation.

With that caveat mentioned, various theories define the origin of cancer stem cells. In brief, they may be: mutants in developing stem or progenitor cells, mutants in adult stem cells or adult progenitor cells, or mutant cells that acquire stem like attributes. These theories often do focus on a tumor's cell of origin and as such must be approached with skepticism.

Some researchers favor the theory that the cancer stem cell is caused by a mutation in stem cell niche

Stem cell niche

Stem cell niche is a phrase loosely used in the scientific community to describe the microenvironment in which stem cells are found, which interacts with stem cells to regulate stem cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem cell microenvironment...

 populations during development. The logical progression claims that these developing stem populations are mutated and then expand such that the mutation is shared by many of the descendants of the mutated stem cell. These daughter stem cells are then much closer to becoming tumors, and since there are many of them there is more chance of a mutation that can cause cancer.

Another theory associates adult stem cells with the formation of tumors. This is most often associated with tissues with a high rate of cell turnover (such as the skin

Skin

-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

 or gut

Gut (zoology)

In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...

). In these tissues, it has long been expected that stem cells are responsible for tumor formation. This is a consequence of the frequent cell divisions of these stem cells (compared to most adult stem cells) in conjunction with the extremely long lifespan of adult stem cells. This combination creates the ideal set of circumstances for mutations to accumulate; accumulation of mutations is the primary factor that drives cancer initiation. In spite of the logical backing of the theory, only recently has evidence appeared that this association represents an actual phenomenon. It is important to bear in mind that, due to the heterogeneous nature of evidence it is possible that any individual cancer could come from an alternative origin.

A third possibility often raised is the potential de-differentiation of mutated cells such that these cells acquire stem cell like characteristics. This is often used as a potential alternative to any specific cell of origin, as it suggests that any cell might become a cancer stem cell.

Another related concept is the concept of tumor hierarchy. This concept claims that a tumor is a heterogeneous population of mutant cells, all of which share some mutations but will vary in specific phenotype. In this model, the tumor is made up of several types of stem cells, one optimal to the specific environment and several less successful lines. These secondary lines can become more successful in some environments, allowing the tumor to adapt to its environment, including the methods by which tumors can be treated. If this situation is accurate, it has severe repercussions on the realism of a cancer stem cell specific treatment regime. Within a tumor hierarchy model, it would be extremely difficult to pinpoint the cancer stem cell's origin.

Implications for cancer treatment

The existence of CSCs has several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new intervention strategies.

Normal somatic stem cells are naturally resistant to chemotherapeutic agents- they have various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). CSCs that have mutated from normal stem cells may also express proteins that would increase their resistance towards chemotherapeutic agents. These surviving CSCs then repopulate the tumor, causing relapse. By selectively targeting CSCs, it would be possible to treat patients with aggressive, non-resectable tumors, as well as preventing the tumor from metastasizing. The hypothesis suggests that upon CSC elimination, cancer would regress due to differentiation and/or cell death. What fraction of tumor cells are CSCs and therefore need to be eliminated is not clear yet.

A number of studies have investigated the possibility of identifying specific markers that may distinguish CSCs from the bulk of the tumor (as well as from normal stem cells). Proteomic and genomic signatures of tumors are also being investigated . In 2009, scientists identified one compound, Salinomycin

Salinomycin

Salinomycin is an antibacterial and coccidiostat ionophore therapeutic drug.- Use in cancer :Salinomycin has been shown by Piyush Gupta et al. of the Massachusetts Institute of Technology and the Broad Institute to kill breast cancer stem cells at least 100 times more effectively than another...

, that selectively reduces the proportion of breast CSCs in mice by more than 100-fold relative to Paclitaxel

Paclitaxel

Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...

, a commonly used chemotherapeutic agent.

Pathways

The design of new drugs

Drug design

Drug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...

 for the treatment of CSCs will likely require an understanding of the cellular mechanisms that regulate cell proliferation. The first advances in this area were made with hematopoietic stem cells (HSCs) and their transformed counterparts in leukemia

Leukemia

Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

, the disease for which the origin of CSCs is best understood. It is now becoming increasingly clear that stem cells of many organs share the same cellular pathways as leukemia-derived HSCs.

Additionally, a normal stem cell

Adult stem cell

Adult stem cells are undifferentiated cells, found throughout the body after embryonic development, that multiply by cell division to replenish dying cells and regenerate damaged tissues...

 may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways

Cell signaling

Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...

 controlling it or by inducing oncoprotein activity.

Bmi-1

The Polycomb group

Polycomb-group proteins

Polycomb-group proteins are a family of proteins first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place...

 transcriptional

Transcription (genetics)

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 repressor

Repressor

In molecular genetics, a repressor is a DNA-binding protein that regulates the expression of one or more genes by binding to the operator and blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called...

 Bmi-1 was discovered as a common oncogene

Oncogene

An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...

 activated in lymphoma and later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells. The pathway appears to be active in CSCs of pediatric brain tumor

Brain tumor

A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...

s.

Notch

The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including hematopoietic, neural and mammary stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors.

Sonic hedgehog and Wnt

These developmental pathways are also strongly implicated as stem cell regulators. Both Sonic hedgehog

Sonic hedgehog

Sonic hedgehog homolog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog and Indian hedgehog . SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as...

 (SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from glioma

Glioma

A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...

s, where they are commonly expressed at high levels. A degree of crosstalk

Crosstalk (biology)

Biological crosstalk refers to instances in which one or more components of a signal transduction pathway affect a different pathway. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction...

 exists between the two pathways and their activation commonly goes hand-in-hand. This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt.

Sonic hedgehog blockers are available, such as cyclopamine

Cyclopamine

Cyclopamine is a naturally occurring chemical that belongs to the group of steroidal jerveratrum alkaloids. It is a teratogen isolated from the corn lily that causes usually fatal birth defects. It can prevent the fetal brain from dividing into two lobes and cause the development of a single eye...

. There is also a new water soluble cyclopamine that may be more effective in cancer treatment. There is also DMAPT, a water soluble derivative of parthenolide

Parthenolide

Parthenolide is a sesquiterpene lactone of the germacranolide class which occurs naturally in the plant feverfew , after which it is named. It is found in highest concentration in the flowers and fruit....

 (induces oxidative stress, inhibits NF-κB signaling) for AML (leukemia), and possibly myeloma and prostate cancer. A clinical trial of DMAPT is to start in England in late 2007 or 2008. Finally, the enzyme telomerase

Telomerase

Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...

 may qualify as a study subject in CSC physiology.; GRN163L (Imetelstat) was recently started in trials to target myeloma stem cells. If it is possible to eliminate the cancer stem cell, then a potential cure may be achieved if there are no more CSCs to repopulate a cancer.

External links

• Cancer Stem Cell News A blog of news items related to cancer stem cells, with an emphasis on recent research and articles that are openly accessible
• Exploring the role of cancer stem cells in radioresistance Abstract of a review by Michael Baumann, Mechthild Krause, Richard Hill, "Nat Rev Cancer" 2008(Jul); 8(7):545-54
• "A Tumor's Lifeblood", Jessica Gorman, CR magazine, Summer 2006
• "Cancer Stem Cell Scientific Literature Review", UMDNJ Stem Cell Research and Regenerative Medicine, June 17, 2006
• "Stem cells may cause some forms of bone cancer", News-Medical.Net, December 7, 2005
• "The Bad Seed: Rare stem cells appear to drive cancers", Science News Online, March 20, 2004
• "The Real Problem in Breast Tumors: Cancer Stem Cells", Genome News Network, March 7, 2003
• Differentiation Therapy - A Different Approach to Treating Tumors (from Beaker Blog)
• Characteristics of Cancer Cells Cancer Inform Blog