|Year : 2014 | Volume
| Issue : 4 | Page : 846-852
Cancer stem cells: An insight and future perspective
Sandeep Kaur1, Gurdeep Singh2, Kirandeep Kaur3
1 Department of Oral Medicine and Radiology, Adesh Institute of Dental Sciences and Research, Bathinda, Punjab, India
2 Department of Community Medicine, Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, India
3 Department of Periodontology, Institute of Dental Studies and Technologies, Kadrabad, Modi Nagar, Uttar Pradesh, India
|Date of Web Publication||9-Jan-2015|
Department of Oral Medicine and Radiology, Adesh Institute of Dental Studies and Research, Barnala Road, Bathinda, Punjab - 151 109
Source of Support: None, Conflict of Interest: None
The cancer stem cell (CSC) concept derives from the fact that cancers are dysregulated tissue clones whose continued propagation is vested in a biologically distinct subset of cells that are typically rare. Rare CSCs have been isolated from a number of human tumors, including hematopoietic, brain, colon, and breast cancer. With the growing evidence that CSCs exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. Understanding the biology of CSCs will contribute to the identification of molecular targets important for future therapies.
Keywords: Cancer stem cells, dysregulation, proliferate, self-renewal, signaling, tumorigenic
|How to cite this article:|
Kaur S, Singh G, Kaur K. Cancer stem cells: An insight and future perspective. J Can Res Ther 2014;10:846-52
| > Introduction|| |
Cancer Stem Cells has now been shown definitively in certain cancers that a small subset of cells exist in a tumor with similar regenerative and self-renewal mechanisms that enable tumor formation and progression.  This tiny subset of cells, referred to as cancer stem cells (CSCs), is also considered to be more chemoresistant than the bulk of tumor cells and is thus more difficult to target and eradicate.  CSCs, first identified in acute leukemias, have now been isolated from several human malignancies, such as breast, brain, prostate, and ovarian and also in retinoblastomas (RBs) and melanomas. ,, Stem cells may be preferential targets of initial oncogenic mutations because in most tissues in which cancer originates they are the only long-lived populations and are therefore exposed to more genotoxic stresses than their shorter-lived, differentiated progeny. The cancer stem cell theory proposes that tumors have a cellular hierarchy that is a caricature of their normal tissue counterpart because they reflect the pluripotency of the originally transformed cell.
Self-renewal and cancer
Stem cells in adult tissues produce large numbers of differentiated progeny. These transit amplifying progenitor cells may undergo a limited series of mitotic cycles, sometimes referred to as transit-amplifying cell divisions, before entering a postmitotic fully differentiated state. In this way, the activity of a relatively small number of stem cells can be amplified to produce large numbers of differentiated progeny. 
Self-renewal is a cell division in which one or both of the resulting daughter cells remain undifferentiated and retain the ability to give rise to another stem cell with the same capacity to proliferate as the parental cell. Proliferation, unlike self-renewal, does not require either daughter cell to be a stem cell nor to retain the ability to give rise to a differentiated progeny. The committed progenitor cell (nonself-renewing) is destined to stop the proliferation as with each cell division it's potential to proliferate decreases. In normal tissues, such as the blood, both stem cells and committed progenitor cells have an extensive capacity to proliferate. Although committed progenitor populations can maintain hematopoiesis for up to 6-8 weeks, a single hematopoietic stem cell (HSC) can restore the blood system for the life of the animal. This tremendous potential is a direct result of its capacity to self-renew. In the stem-cell model for cancer, another key event in tumorigenesis is the disruption of genes involved in the regulation of stem-cell self-renewal. Thus, some of the cancer cells within a tumor share with normal stem cells the ability to replicate without losing the capacity to proliferate. Recent evidence has demonstrated that in leukemia and solid tumors, only a minority of cancer cells have the capacity to proliferate extensively and form new tumors. These tumorigenic, or tumor-initiating cells (TICs), have been identified and enriched on the basis of their expression of cell-surface markers. Upon transplantation, TICs give rise to tumors comprising both new TICs as well as heterogeneous populations of nontumorigenic cells reminiscent of the developmental hierarchy in the tissues from which the tumors arise. The genetic constraints on self-renewal restrict the expansion of stem cells in normal tissues. Breakdowns in the regulation of self-renewal is likely a key event in the development of cancer as demonstrated by the fact that several pathways implicated in carcinogenesis also play a key role in normal stem cell self-renewal decisions. 
| > The cancer stem cell hypothesis|| |
All tissues in the body are derived from organ-specific stem cells that are defined by their capacity to undergo self-renewal as well as to differentiate into the cell types that comprise each organ. These tissue-specific stem cells are distinguished from embryonic stem (ES) cells in that their differentiation is largely restricted to cell types within a particular organ. The CSC hypothesis has two separate but related components. 
1. The first component concerns the cellular origin of tumors,
2. A second related component of this hypothesis is that tumors are driven by cellular components that display "stem cell properties."
The concept that cancer might arise from a rare population of cells with stem cell properties was proposed about 150 years ago.  Over 40 years ago, it was postulated that tissue-specific stem cells may be the cell of origin of cancer. 
Over 30 years ago, Pierce,  proposed that cancers represented a maturation arrest of stem cells. The concept that tumors contain cell populations with stem cell properties was also suggested by in vitro "clonogenic assays" that showed subpopulations of tumor cells with increased proliferative capacity as shown by colony formation in in vitro assays using cells isolated from tumor specimens [Figure 1].  A major limitation of these studies, however, was that they measured in vitro proliferation rather than true self-renewal. In addition, it has been observed that the production of human tumor xenografts in animal models required a relatively large number of cells. However, it was unclear whether this was due to the inefficiency of these cells in promoting tumor growth or to the existence of rare subpopulations within a tumor that were uniquely tumorgenic in these systems. 
The concept that cancers arise from the transformation of stem cells is appealing for several reasons. Stem cells by their long-lived nature are subject to the accumulation of multiple mutations that are required for carcinogenesis. One of the key early events in transformation may be the dysregulation of the normally highly regulated process of self-renewal. Stem cells are the only cells capable of undergoing self-renewal divisions. In the steady state, these divisions are asymmetric in which a stem cell is able to produce an exact copy of itself as well as a daughter cell that undergoes differentiation into the lineages found in differentiated tissues. During stem cell expansion and tumorgenesis, stem cells may undergo symmetric divisions in which stem cells produce two identical stem cell progeny, thus allowing for stem cell expansion.
During normal development, stem cell self-renewal is regulated by signals from the surrounding stem cell "niche." As has been elegantly shown in bone marrow transplantation models, a single HSC introduced into a lethally irradiated mouse is able to repopulate the stem cell compartment resulting in reconstitution of the entire hematopoietic system. Extensive expansion in the stem cell population stops when this pool is replenished, illustrating the tight control of this process. Deregulation of this self-renewal process leading to stem cell expansion may be a key early event in carcinogenesis.
Recently, the pathways that regulate the self-renewal of normal stem cells, including signaling molecules such as Wnt, Notch, and Hedgehog have begun to be elucidated. These signaling pathways have been implicated in regulating the self-renewal of hematopoietic, neuronal, and mammary stem cells. The dysregulation of each of these pathways in rodent models leads to tumorigenesis. Furthermore, there is substantial evidence that dysregulation of these pathways also plays an important role in human carcinogenesis. Defects in the Wnt signaling pathway are seen early in colon cancer carcinogenesis. Alterations in Hedgehog signaling were first shown in human basal carcinomas of the skin [Figure 2]. More recently, evidence for dysregulation of this pathway has been reported in human pancreatic, gastric, prostate, and breast carcinomas. Alterations in Notch signaling have been observed in human T-cell acute lymphoblastic leukemia, cervical cancer, and breast cancer. Recent studies have suggested that tumors may arise from progenitor cells and tissue stem cells. Transformation of these cells may require that they acquire the stem cell property of self-renewal. In support of this hypothesis, Jamieson et al.  showed that chronic myelogenous leukemia blast crisis may originate in hematopoietic progenitor cells as a consequence of dysregulated Wnt signaling, allowing these cells to self-renew, a property normally restricted to HSCs. 
|Figure 2: Signaling pathways that regulate self-renewal mechanisms during normal stem cell development and during transformation|
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| > Prospective isolation of cancer stem cells|| |
In 1994, John Dick's group (Bonnet and Dick 1997,  Lapidot et al.  1994) reported the prospective isolation of primitive HSCs in acute myeloid leukemia (AML).
Severe combined immunodeficiency disease (SCID) immunodeficient mouse was used as a model to study the proliferation and self-renewal potential of transplanted human AML cells.
Authors reported that only subset of cells were able to transplant AML into recipient mice. This is another example for which the multiple mature cells found in cancer are an indication of a common transformed progenitor cell. Although the authors (Bonnet and Dick 1997,  Lapidot et al. 1994.  ) transplanted human AML cells into immune-deficient mice, the leukemias closely resembled the disease of the original patients. Therefore, the transplanted leukemias reflected the effects of the original oncogenic mutations. The authors also reported a 30-100-fold expansion of the CD34 + CD38 − cells within the AML when the cells were transplanted into recipient mice.
| > Cancer stem cells|| |
Most cancer cells divide rapidly and can be grown indefinitely in culture as immortal cells and express a plasticity of differentiation, similar to ES cells and adult stem cells. In fact, before the advances that led to an understanding of the developmental plasticity of ES cells, embryonal carcinoma and teratocarcinoma cells (derived from germ cell tumors and known to differentiate to give rise to cells of many lineages) were used as in vitro models for studies relating to development and differentiation. 
In 1976, Beatrice Mintz and Ralph Brinster showed independently that teratocarcinomas could also give rise to normal chimeric mice. ,
The realization of an involvement of stem cells in cancer has been built up over the last several decades - almost a century ago, John Beard is indeed considered "father of CSC biology." However, the first direct evidence for the existence of CSCs came from the work of John Dick et al.(Lapidot et al.), who identified the presence of CSCs in acute lymphocytic leukemia through extensive cell cloning and demonstration of their self-renewing capacity - a critical property of all stem cells. 
Further studies from John Dick et al. (Hope et al.  2004) used lineage tracing to prove that a single leukemia stem cell could give rise to the various populations of leukemia cells.
Cancer stem cell identification in leukemia has, in fact, changed the way that many scientists view cancer, , and has led to their isolation from some solid tumors. CSCs represent only about 1% of the tumor, but appear to be the only cells capable of generating a new tumor in immune compromised mouse models.
Activation of stem cells and cancer
The modern era has seen the cloning of many genes mutated in the germline of patients in families segregating cancer as a genetic trait. These tumor suppressor genes are thought to be critical in preventing the formation of cancer. However, it is unclear why mutations in a gene such as RB or TP53, expressed in all the cells of a human being, should give rise to tissue-specific cancers such as RB or breast cancer. The oncogenic potential of different resident stem cells may be distinct since the genetic or epigenetic factors vary from person to person and even between organs in the same person. A question thus arises: How do CSCs arise in tissues and progress to give rise to a new organ that is, the tumor [Box 1]. 
To address this issue among related issues, research over the last decade has attempted to associate cellular mechanisms with mutagenic effects within tissues leading to the emergence of CSCs. The possibilities that emerge include the following:
Stem cells as targets of transforming mutations
For most cancers, the target cell of transforming mutations is unknown; however, there is considerable evidence that certain types of leukemia arise from mutations that accumulate in HSCs. The cells capable of initiating human AML in nonobese diabetic/SCID mice have a CD34 + CD38 − phenotype in most AML subtypes and thus have a phenotype similar to normal HSCs. Conversely, CD34 + CD38 + leukemia cells cannot transfer disease to mice in the vast majority of cases, despite the fact that they exhibit a leukemic blast phenotype. This suggests that normal HSCs rather than committed progenitors are the target for leukemic transformation.
A disruption of the stem cell niche with a shift toward growth-promoting signals rather than growth-inhibiting signals results in dominant stem cell activation rather than the transient activation that is required for normal tissue homeostasis. This could occur by hormonal stimulation, recurrent post tissue damage, inflammation, radiation, chemicals, infections, inactivation of tumor suppressor gene (s), and/or activation of oncogene (s). The change in the tissue microenvironment leads to a chronic activation of stem cells and results in their long-term proliferation. Such chronically dividing stem cells could become vulnerable to additional genetic events. The recognized effects of these events include autonomous growth, loss of cell cycle regulation, and resistance to apoptosis, which are all well-understood properties of cancer cells. 
Cancer can thus be thought of as a disease resulting from the abnormal growth of stem cells resulting from their chronic activation followed by genetic insults, culminating in transformation.
Fusion of tissue-specific stem cells with circulating bone marrow stem cells
The finding that fusion of circulating bone marrow-derived stem cells with differentiated tissue cells can create cells with self-renewal capacity leads to yet another speculation on the origin of CSCs.  This is believed to involve the mobilization of bone marrow-derived cells either at the wrong time and/or their incorporation at the wrong place within other tissues, as a first step toward transformation. The adult stem cells giving rise to cancer is an attractive hypothesis, given that the classic multistep model of carcinogenesis requires a long-lived cell in which multiple genetic hits can occur. However, regardless of whether the cell of origin is a normal adult stem cell or progenitor or a differentiated tissue cell, and regardless of the mechanism of its emergence, CSCs are defined by their stem cell-like properties [Box 2]. 
| > Cancer stem cell plasticity as regulated by intrinsic and extrinsic stem cell factors|| |
In contrast to normal stem cells, it has been theorized that CSCs undergo genomic alterations that allow them to escape cell cycle regulation and achieve growth factor, anchorage independence, and resistance to apoptosis, besides contributing to dysregulation of self-renewal and expansion.  This understanding implies that the plasticity gained by CSCs is regulated by a cooperative effect of cell intrinsic (autocrine) factors, which may either involve changes in DNA sequences/copy number of genes or gene silencing through methylation or altered chromatin architecture (genetic and epigenetic effects), together with cell extrinsic (paracrine/derived from the tumor microenvironment) factors.
Stem cell intrinsic factors
Genetic and epigenetic effects
A disturbed balance in gene regulation of tissue stem cells promoting self-renewal and/or aberrant differentiation is characteristic of cancer. However, uncontrolled expansion of stem cells by itself may not produce fully invasive tumors. 
Thereby, proliferating proto-oncogenic stem cells appear to require at least one additional permanent genetic mutation to drive them along a trajectory toward transformation.  This could be achieved either through oncogene activation or by silencing of tumor suppressor genes, which effectively supplements the perturbed shift toward self-renewal; continuing mutagenesis would further ensure clone amplification and disease progression. 
Stem cell extrinsic effects
Niche effects and microenvironmental signaling
The stem cell niche is loosely defined as stem cells surrounded by other differentiated cells within a tissue at defined locations. The niche consists of heterologous cell types that harbor stem cells and influence their fate through direct contact, thereby functioning to balance the quiescence and activation of stem cells,  the key to homeostatic regulation of stem cells, yet supporting ongoing tissue regeneration. The niche is thus a physical anchoring site for stem cells and generates factors including certain extracellular matrix (ECM) components and signaling molecules that control stem cell number, proliferation, and fate determination. Examples of stem cell niches include the hair follicle bulge compartment, ,,, and the crypts of Lieberkuhn, located at the base of villi within the intestinal epithelium. 
Another function of the tumor niche is the active recruitment of new endothelial and stromal cells into tumors that is essential for developing a pro-angiogenic environment that enhances tumor survival under adverse conditions. A normal niche may evolve to become proto-oncogenic, or in fact may be the prime feature in tumorigenesis and therefore represent an oncogenic state. 
The concept of proto-oncogenic stem cell niches is best exemplified in lung cancer, wherein different histological types of neoplasias have been correlated with stem/progenitor populations at specific tissues in the lung. 
Oncogenic stem cell niches have just recently been described. The RB gene, identified as a tumor suppressor, has been shown to regulate HSCs extrinsically by maintaining the competence of the adult bone marrow to support their growth and normal homeostatic hematopoiesis. Loss of RB expression in the niche and myeloid cells leads to degradation of the osteoblastic niche and consequent displacement of HSCs. The latter then undergo rapid expansion and mobilization to the spleen, promoting myeloid development that ultimately culminates in myeloproliferative disease syndrome (MPS).  Along similar lines, mice deficient for another gene (i.e. the retinoic acid receptor γ [RAR]), develop MPS driven by a RARγ-deficient microenvironment.  The MPS phenotype in both cases (i.e. loss of RB and RARγ) continues through the lifespan of the mice and is more pronounced in older mice. Moreover, the disease cannot be propagated through successive transplantation of HSCs from MPS-affected mice to normal mice, identifying the disease to be extrinsic to tumor-derived HSCs. Another common feature of the tumor and tissue stem cells is the utilization of similar signal pathways that normally control cell fate during early embryogenesis. Such regulatory signal molecules, including components of the Notch, Wnt, and Hedgehog pathways, bone morphogenetic proteins, fibroblast growth factor, leukemia inhibitory factor, and transforming growth factor-β,,, have been shown to play roles in controlling stem cell self-renewal and in regulating lineage fate in different systems. In numerous tumors, however, the signaling cascades initiated by these molecules have now been demonstrated to be dysregulated (e.g. in skin, liver, colorectal, and pancreatic cancers, Wnt signaling has been demonstrated to be aberrant. , In ovarian cancer, the Wnt signal transducer β-catenin is overexpressed at an advanced stage of tumor progression.  The Hedgehog cascade, well-known as a regulator of patterning during embryonic development,  has been associated with breast,  ovarian,  and prostate cancers,  whereas Notch overstimulation has been strongly implicated in T-cell malignancies.  It has been demonstrated further that various lineage determination molecules within these signaling pathways exhibit a significant degree of crosstalk.  An important difference in the signals between normal and transformed states is that those in normal tissues are transiently expressed stem cell-activation signals, whereas in cancer, these signals dominate and lead to a state of long-term or permanent activation. 
The molecules and underlying machinery used by normal stem cells for homing or mobilization and CSCs for invasion and metastasis are also realized to be similar. For example, during HSC activation and mobilization, matrix metalloproteinase-9 (MMP-9) is required for proteolysis of the ECM components and converting stem cell factor from a membrane-bound form into a free form, which then promotes HSC proliferation and mobilization through a c-Kit receptor. Intriguingly, the molecules of the MMP family are considered as key players in the process of cancer cell metastasis. In addition, cell surface receptors and the ligands required for their activation, such as SDF1 and CXCR4 are also expressed during normal stem cell homing and mobilization as well as cancer cell metastasis. 
| > Opportunities for new therapeutics|| |
The CSC model suggests that it may be necessary to alter the current paradigm in drug development. Eradication of cancers may require the targeting and elimination of CSCs. This represents a challenge because many pathways, such as those involved in self-renewal, are shared by CSCs and their normal counterparts. However, a variety of recent studies using animal models that have targeted these pathways indicate the feasibility of this approach. For example, Notch signaling requires processing by the enzyme g-secretase. An inhibitor of this enzyme has been recently shown to have activity against breast cancers that over express Notch 1. , Agents targeting Hedgehog signaling have recently been shown to have antineoplastic activity. The Hedgehog inhibitor cyclopamine that specifically inhibits Hedgehog signaling was used to treat animals bearing a variety of tumor xenografts. Cyclopamine caused dramatic regression of tumors that did not recur following cessation of treatment. Furthermore, at least over brief periods, the administration of these agents seemed to be nontoxic.  A Hedgehog pathway inhibitor, HhAntag, with greater activity than cyclopamine has recently been shown to block medulloblastoma formation in a transgenic mouse model. These studies support the feasibility of selectively targeting the CSC population. The elimination of this key cell population may result in improved therapeutic outcomes for patients with even advanced cancers. 
| > Conclusions and Future Perspectives|| |
It is widely accepted view that malignancy results from a complex network of interactions between altered cellular genes and numerous exogenous and endogenous factors of a tissue-derived cell. The probability of the accumulation and effects of such changes and interactions is almost certainly highest in long-lived tissue stem cells, but is equally effective in progenitors or differentiated cells that acquire an immortal phenotype. Unfortunately, it is not precisely known how CSCs arise in tissues or which of the resident tissue cells would be more susceptible to the transformation process. Thus, at a very fundamental level, we have yet to determine the extent to which stem cell biology is relevant to all types of human cancers. The role of CSCs in migration and metastases would be much different than their role in primary tumors. Such differential regulation of migrating CSCs and those in metastases is also not yet identified. The development of a new generation of treatments to target the rare CSCs is thus critical, but poses formidable challenges. 
- Ideally, a therapy should target unique CSC pathways and "turn back the clock" from a state of disease to one of normal tissue and organ homeostasis
- A concern in achieving the goal stated above is that normal stem and progenitor cells actually prove to be more sensitive than CSCs to the effects of current chemotherapeutic drugs. This provides a competitive advantage to CSCs and makes their positive selection quite likely, leading to the emergence of drug-resistant clones. Thus, one must devise strategies that can selectively kill these CSCs while sparing normal stem cells, such as those in the gut and bone marrow. Delineation of the effects of the new drug regimens on the evolution of CSCs is thereby imperative
- In cases where clinical remission is achieved, the presence of drug-resistant CSCs that have "escaped" chemotherapy would initiate a relapse. This necessitates the development of sensitive methods for detection of residual CSCs for follow-up in patients in remission. The establishment of diagnostic endpoints by which treatment success can be measured is thus required. A culmination of understanding of CSC biology will thus aid the development of more effective and targeted therapies to treat this astoundingly complex and devastating disease. 
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[Figure 1], [Figure 2]