Cancer Stem Cells A Riddle Biology Essay

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Stem cells have two defining properties, self-renewal - the ability to produce more stem cells, and differentiation - the ability to mature into specialized cells (Lobo et al., 2007). Stemness is characterized by self-renewing mitotic divisions in which one or both of the daughter cells are faithful reproductions of the parent stem cell. Conversely, loss of stemness is characterized by differentiation divisions that involve the production of daughter cells which are tissue-specific differentiated cells (Cai et al., 2004). Normal adult stem cells maintain tissues during homeostasis and facilitate their regeneration. Regeneration requires conditions that favour self-renewal divisions, whereas homeostasis requires the balance in the outcome of self-renewal and differentiation divisions (Nguyen et al., 2012). Understanding the molecular mechanisms that regulate self-renewal and differentiation of stem cells not only has great implications in regenerative medicine, but may also shed light on the development of cancer.

The cancer stem cell (CSC) concept proposes that, in a tumor mass, there exists a subpopulation of cells with indefinite self-renewal potential that drives tumorigenesis (Reya et al., 2001). Normal stem cells could be the targets of transformation, which lead to the formation of CSCs, as they already possess active self-renewal pathways (Fialkow, 1990). It is also possible for progenitors and other differentiated cells to give rise to CSCs by acquiring more genetic mutations especially in self-renewal genes (Cozzio et al., 2003; Huntly et al., 2004, and Krivtsov et al., 2006). The CSC concept represents a new paradigm of oncogenesis, which could better model the complex and highly dynamic process of tumorigenesis, tumor relapse, and metastasis (Reya et al., 2001; Trumpp and Wiestler, 2008). This review discusses the concept of CSCs, the origin and characteristics of CSCs, and the implications in cancer treatment.


Cancers originally develop from normal cells that acquire indefinite proliferative potential thus ultimately turn into malignant. These cancerous cells then propagate clonally into tumors and eventually gain the ability for metastasis (Lobo et al., 2007). On this basis, the traditional stochastic model of cancer development, also known as the clonal evolution model, was proposed (Fig. 1A) (Nowell, 1976). This is a non-hierarchical model where a dominant clone is produced by the serial acquisition of genetic or epigenetic alterations. This clone confers selective growth advantage to derive tumor cells with similar tumorigenic capacity. The other derivatives may lack tumorigenicity due to stochastic events (Visvader et al., 2012). Thus, according to the clonal evolution theory every cancer cell has the potential to form a new tumor, but entry into the cell cycle is a stochastic event that occurs with low probability (Nowell, 1976). Given that all cancer cells have similar potential to grow tumors which are clonal in origin, it is rational to expect that even a few cancer cells would be adequate for tumorigenesis.

However, studies on human tumorigenesis showed the requirement of large number of cancer cells for tumor growth (Bruce & Van Der Gaag, 1963). Despite the origin of tumors from a single transformed cell, the cancer cells within tumors displayed different phenotypes with varying potential for proliferation that endows tumor heterogeneity (Fidler & Hart, 1982; Heppner, 1984). These important observations led to the CSC model of tumor heterogeneity (Fig. 1B). This model postulates a hierarchical organization of cells such that only a small subset is responsible for sustaining tumorigenesis and establishing the cellular heterogeneity inherent of primary tumor (Clevers, 2011). Akin to this, a single or set of mutations may bestow stem cell-like properties to a progenitor cell. This mutated progeny could self-renew and be solely accountable for the production of tumor maintenance cells called CSCs. At the same time, the mutated progeny could differentiate into a range of tumor cells each differs in their proliferation potential, thus forming a tumor bulk with a heterogenous population (Lobo et al, 2007). Recently, lineage tracing studies in mouse models have provided compelling evidence for the existence of CSCs (Chen et al., 2012; Driessens et al., 2012; Schepers et al., 2012).

According to the CSC concept, tumor growth is fed by CSCs, a subpopulation of highly malignant cancerous cells, that comprise the top of the tumor cell hierarchy. They acquire the ability to self-renew and to produce genetically heterogeneous lineages of cancer cells which are various related, but distinct subclones that compete within the tumor mass (Visvader et al., 2012). CSCs have been identified in many leukemias and also in solid tumors such as breast, brain, colon, melanoma, pancreatic, prostate, ovarian and lung cancers (Baccelli and Trumpp, 2012). Thus, eradicating CSCs, the root of cancer origin and recurrence, is a promising approach for curative cancer therapy. Unfortunately, the current therapeutic targeting is directed primarily to the fast propagating tumor mass rather than the slow dividing CSCs (Kvinlaug and Huntly, 2007).


The CSC theory posits that some elements of cellular hierarchy maintained in the stem cells of normal tissues also exist in the hierarchy of CSCs in a tumor mass (Reya et al., 2001; Clevers, 2011; Nguyen et al., 2012). In normal tissues, the niche cells, which constitute the microenvironment of normal stem cells, provide specific signals to maintain the self-renewing ability of the stem cells. Since transiently amplifying progenitors and differentiated cells do not receive these signals, their proliferation is restricted by cellular mechanisms. While these cells undergo cell division, in contrast to their descending proliferation capacity, the degree of differentiation increases with respect to each division (Morrison and Kimble, 2006).

CSCs could originate from mutations of normal stem cells or, alternatively, from progenitors or differentiated cells that mutated to acquire the capability of self-renewal (Clarke & Fuller, 2006; Reya et al., 2001; Huntly et al., 2004). The following are some probable mechanisms that underpin the origin of CSCs (Fig. 2).

Expansion of normal stem cell niche - that permits the expansion of CSCs arose from normal stem cells. This self-renewing pool of CSCs then differentiates abnormally into nontumorigenic cancer cells that comprise the tumor bulk.

Adaptation of CSC niche - CSCs that arose from mutations of normal stem cells endow them to sequester alternative niche called CSC niche for their expansion.

(iii) Niche-independent - CSCs that arose from mutations of normal stem cells license them to become niche-independent. Thus, they acquire cell-autonomous self-renewal for generating tumors of self-renewing CSCs and their nontumorigenic progeny.

(iv) Mutations of progenitors or differentiated cells - CSCs may be originated from progenitors or differentiated cells that acquire multiple oncogenic mutations, resulting in the gain of self-renewal ability.


Recent studies have unveiled some of the chacteristics of CSCs, which provide insights into the complex and dynamic nature of these special cells.

4.1. Hierarchy of CSC clone

Intratumor heterogeneity has been recently reported in several subregions of the primary tumor and metastases from pancreatic and kidney cancers (Campbell et al., 2010; Gerlinger et al., 2012). This may often be a result of genetically unstable CSCs, as evidenced from a couple of milestone discoveries in human acute lymphoblastic leukemia (ALL). These studies showed the coexistence of several genetically distinct leukemic stem cell (LSC) clones within a single patient during the disease progression, after therapy, and after serial xenotransplantation (Anderson et al., 2011; Notta et al., 2011). This might explain at least partially the "acquired resistance" to targeted therapy observed in some patients. For instance, therapeutic-sensitive CSC clones may be taken over by resistant clones that acquire resistance to the applied treatment. Thus, the hierarchy of CSCs may fall in the following two categories. Intra-CSC clone hierarchy represents the existence of dynamic hierarchies within a single CSC clone and its progeny. Conversely, inter-CSC clone hierarchy refers to the competition between two genetically distinct CSC clones (Visvader et al., 2012).

4.2. CSC biomarkers may differ and not overlap within a same tumor type

In contrast to the current clinical trials that focus primarily on massive tumor regression, the CSC concept suggests the therapeutic targeting of CSC pools within the residual disease (Blagosklonny, 2006). This can be achieved by the identification of reliable and specific CSC biomarkers for each tumor type. However, several studies indicate the existence of different, at times non-overlapping sets of CSC biomarkers within a same tumor type (Table 1). The choice of method, partial detection of CSC clones that coexist in primary tumors, the nature of CSC clone to occupy several immunophenotypically defined cellular compartments, and their genetic heterogeneity may account for this CSC phenotype variation within the same tumor type (Baccelli and Trumpp, 2012).

4.3. Frequency of CSCs varies between tumors

It is generally believed that CSCs are relatively rare and constitute only a minor component of the tumor (Visvader et al., 2012). However, the frequency of CSCs seems to vary substantially between different tumor types (Table 2). Studies of leukemia and lymphoma genetic mouse models also suggest that CSCs are not always rare (Kelly et al., 2007). In addition, the types of immunocompromised mice and xenotransplanation assays used to measure CSC frequency appear to influence the outcome (Quintana et al., 2008).

4.4. Unstable CSC phenotype from primary through tumor-propagating and metastatic stages

The immunophenotype of primary cancers could substantially differ from tumor- propagating cells of xenografts. For instance, CD133+ cells constitute primary serous ovarian cancers, in contrast to the xenografted tumors that possess CD133- tumor-initiating cells (Stewart et al., 2011). This observation suggests the existence of heterogenenous CSC populations within tumor-propagating compartments and indicates the instability of CSC phenotype upon xenograft passaging. Studies on epithelial CSCs also showed that they strongly modulate their phenotype during tumor progression (Thiery et al, 2009). Under such conditions, CSCs detected in an early stage primary tumor might have a completely different phenotype of CSCs that circulate in the blood. Due to this plasticity, panels of CSC biomarkers, rather than individual ones, may be more useful in representing tumor population of different stages (Visvader et al., 2012).

In primary and metastatic tumors, the subset of CSCs may be common or unique depending on tumor types. In breast cancer, primary tumor CSCs represented by CD44 expression also have a functional role in metastasis (Liu et al., 2010). Complementing to this study, the presence of CD26+ cells in primary tumors prognosticates metastasis in patients with colorectal cancer (Pang et al., 2010). Conversely, metastasis is driven by a unique subset of metastatic CSCs in pancreatic cancer. In this case, metastatic activity is exhibited only by CD133+CXCR4+ cells, in contrast to tumor-propagating cells dictated by both CD133+CXCR4+ and CD133+CXCR4- subsets (Hermann et al., 2007). This metastatic CSCs may either be derived from primary tumor CSCs or instead from non-CSCs within the tumor.

4.5. CSCs switch between dormant and active states

CSCs are generally believed to exist as dormant pools. For instance, quiescent LSCs have been reported in a mouse model of acute myeloid leukemia (AML) (Saito et al., 2010). Similarly, delayed contributing CSC clones have been identified in both AML and colon carcinoma by clonal tracking techniques that suggest the existence of long-term quiescent /dormant pools of human CSCs (Hope et al., 2004; Dieter et al., 2011). Recently, in breast cancer, slow cycling cells were correlated with the frequency of CSCs (Pece et al., 2010). As conventional therapies mainly target cycling cells, these dormant or slow cycling CSCs usually escape from clinical treatment. However, the dormancy could be broken under some circumstances. For example, CSCs may be reactivated to render tumor relapse even after many years of remission (Aguirre-Ghiso, 2007).


Quantification of malignant cells with transplantable tumorigenic ability was first attempted by Hewitt and Wilson by limiting-dilution transplants (Hewitt and Wilson, 1959). Following this, in vivo colony assay for a mouse lymphoma-initiating cell was reported (Bruce and Van Der Gaag, 1963). This was based on the colony-forming unit-spleen assay that had been used to quantify transplantable bone marrow cells (Becker et al., 1963). Subsequently, genetically modified mice with increasing severities of immunodeficiencies were generated (reviewed in Baiocchi et al., 2010). These xenograft models enabled the detection and quantification of cells that have tumour-initiating activity in many primary human tumours. These Xenografts are considered the 'gold standard' in human CSC assay.

Nevertheless, these models do have some caveats. First, most primary tumour cells do not grow autonomously due to their addiction to species-specific factors (Miyauchi et al., 1987; Wunderlich et al., 2010). Second, in many of the mouse models, the DNA repair genes are mutated to induce severe combined immunodeficiency, thus making the mice hypersensitive to DNA-damaging agents (Fulop and Phillips, 1990). Thus, utility of these strains is greatly limited in assessing the responses of engrafted human CSCs to DNA-damaging drugs. A third constraint is that these mice are immunodeficient. This facilitates their engraftment with human cells but also provides a system that lacks many elements that are recently believed to compel the tumour growth (Finak et al., 2008; Steidl and Gascoyne, 2011). Moreover, the ~2 year lifespan of mice may restrict the detection of slow-growing human tumours and thus could enforce age-related differences in host factors that control tumor behaviour.


The tumor microenvironment is composed of inflammatory cells, hematopoietic cells, stromal cells and vascular endothelial cells (Hanahan and Coussens, 2012). Maintenance of CSC functional traits may require specific set of extrinsic interactions with their micoenvironment called "niche" (Cabarcas et al., 2011). Tumor cells may either be induced or selected depending on their niche effect which varies for every tumor subtype.

6.1. Perivascular niche

Vascular endothelial cells secrete nitric oxide that induces Notch signaling in glioma cells (Charles et al., 2010) and their CSCs are shown to be dependent on nitric oxide synthase-2 (Eyler et al., 2011). Reversibly, CSCs in glioblastoma also directly supported the development of local vasculature by secreting vascular endothelial growth factor (VEGF) (Gilbertson and Rich, 2007). Interestingly, recent studies reported tumor vascularization through endothelial differentiation of glioblastoma CSCs (Ricci-Vitiani et al., 2010; Wang et al., 2010a). Complementing roles of perivascular niche in cutaneous squamous cell carcinomas suggest the establishment of an autocrine loop that promotes CSC activity by VEGF which controls both the microenvironment and intrinsic self-renewal pathways of CSCs (Beck et al., 2011).

6.2. Stromal niche

Cells within the tumor-associated stroma, such as myofibroblasts, enhance the self-renewal of colorectal CSCs via hepatocyte growth factor (HGF) that activates Wnt signalling. Moreover, this pathway could also induce the in vivo tumorigenicity of non-CSCs, suggesting the role of micrenvironment in governing tumor cell "stemness" (Vermeulen et al., 2010). Another stromal factor periostin regulates interactions between CSCs and their metastatic niche and is essential for metastatic colonization in mammary tumorigenesis (Malanchi et al., 2011). Osteoprogenitors are also stromal mesenchymal cells. Upon perturbation, they cause deregulation of homeostasis, leading to the commencement of myelodysplasia and secondary leukemia (Raaijmakers et al., 2010).

6.3. Inflammatory niche

In human models of leukemia, the lineage fate of LSCs is decided by microenvironmental cues such as cytokines, growth factors or even the immune-deficient state (Wei et al., 2008). Similar roles of inflammatory niche have also been reported in solid tumors. For instance, infiltration of immune cells in the tumor that secretes inflammatory molecules such as interleukin 6 promotes the proliferation of colitis-associated CSCs (Grivennikov et al., 2009).


The salient features of CSCs that have been exploited in the current therapeutic targeting strategies are CSC-specific biomarkers, molecular signaling pathways, self-renewal pathways, chemoresistance, quiescence and radioresistance (Visvader et al., 2012).

7.1. CSC biomarkers in therapeutic targeting

CD44 is a transmembrane glycoprotein expressed in tumor CSCs of breast, pancreas, gastric, head and neck, ovarian and colon tissues (Zöller, 2011). It plays a critical role in the cellular functions of cell-cell adhesion and cell-matrix adhesion. In xenograft studies, CD44 antibody diminishes human AML LSC proliferation probably by preventing their interaction with the niche (Jin et al., 2006; Krause et al., 2006). Specific targeting of different CD44 isoforms that specifically expressed in tumor cells may be helpful, as universal targeting of CD44 could be deleterious due to its ubiquitous expression in many normal adult stem cells (Heider et al., 2004). Antibody that blocks CD123 (interleukin-3 [IL-3] receptor α chain) was also successfully used to eliminate AML LSCs in xenografted mice (Jin et al., 2009). However, the universal expression of CD123 imposes a risk of severe adverse effects (Taussig et al., 2005). Recently, antibody-mediated blocking of CD47, which serves as a ''don't eat me'' signal to tumor macrophages, has been shown to efficiently eradicate LSCs in ALL (Chao et al., 2011).

CD133 is a glycosylated, 120-kDa protein found in the CSC populations of lung, pancreatic, liver, prostate, gastric, colorectal, and head and neck cancers (Hu and Fu, 2012). Genotoxic treatments like ionizing radiation exclude CD133+ CSCs in glioblastoma due to their increased DNA damage check point response and DNA repair capacities. Treatment of glioblastoma with CHK kinase inhibitor increased the radiosensitivity of CSCs (Bao et al., 2006). Aldehyde dehydrogenase (ALDH) is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids. It is crucial for CSC longevity and it tends to produce toxic aldehyde intermediates by which CSCs acquire resistance to chemotherapy. CSCs specified by ALDH are found in breast, lung, head and neck, colon and liver tumors as well as in leukemia (Hu and Fu, 2012). Compelling evidence suggests that ALDH+ CSCs are sensitized to cyclophosphamide (CPA) and 4-hydroperoxycyclophosphamide treatment by both shRNA and siRNA-mediated knockdown of ALDH1 in colorectal xenografts and lung cells, respectively (Dylla et al., 2008; Moreb et al., 2007). ABCG2 is a member of the ATP-binding cassette transporters that promotes stem cell proliferation and plays a critical role in the maintenance of the stem cell phenotype (Hu and Fu, 2012). Both siRNA-mediated and chemical inhibition of ABCG2 show significant abolition of CSC proliferation (Chen et al., 2010). But clinical trials were halted due to its pivotal functions in the maintenance of blood-brain barrier and adult stem cells (Hermann et al., 2006).

7.2. CSC self-renewal pathways in therapeutic targeting

Stem cell maintenance pathways could be targeted for eradication of CSCs. However, this is feasible only if the self-renewal genetic programs are differentially regulated between normal stem cells and CSCs (Visvader et al., 2012). Bone morphogenetic proteins (BMPs) might be a paradigm of "differentiation therapy", as they were reported to drive differentiation of brain CSCs by inhibiting the TGFβ pathway that led to the successful cure of the disease in a xenograft model (Piccirillo et al., 2006). CSCs may be induced to switch from a symmetric to an asymmetric mitotic program by differentiation-inducing agents, including Wnt, Hedgehog (Hh), the transforming growth factor (TGF), and epidermal growth factor (EGF). Telomere shortening, which has been implicated in replicative senescence, chromosome instability, and arrest of the cell cycle (Counter et al., 1992), may also be employed for targeting CSCs. The critical role of telomerase in CSC function is evident from telomeric repeat assays that revealed upregulation of telomerase activity in glioblastoma multiforme-derived cultured neural cells and in original tumor cells but not in human fetal neural stem cells (Galli et al., 2004). Thus, targeting the molecular mechanism of aberrant telomerase activity in CSCs may provide a novel therapeutic strategy.

7.3. CSC key developmental pathways in therapeutic targeting

The key developmental pathways that frequently deregulated in CSCs are the Wnt, Hh and Notch pathways (Visvader et al., 2012). β-Catenin, the essential mediator of Wnt signaling is necessary for self-renewal of both hematopoietic stem cells (HSCs) and CSCs (Taipale and Beachy, 2001). A broad spectrum of compounds that specifically interfere with Wnt/β-Catenin signaling could be effective in eradicating drug-resistant CSCs, which are responsible for tumor relapse and metastasis. One group of such drugs is the non-steroidal anti-inflammatory drugs (NSAIDs), which interfere with Wnt signaling by directly inhibiting the Wnt target COX2 (e.g. aspirin and sulindac) or by promoting degradation of TCF (Celecoxib) (Takahashi-Yanaga and Khan, 2010). In addition, monoclonal antibodies and siRNAs against Wnt1/2, WIF1 and SFRPs, PRI-724 and CWP232291 are also being tested in preclinical studies (Hu and Fu, 2012).

Hh ligands exhibit dual role in the maintenance of both CSCs and their niche, since stromal cells show increased expression of these ligands (Visvader et al., 2012). In human and mouse leukemias, pharmacologic inhibition of the Hh pathway prevents the expansion of imatinib-resistant CML (Dierks et al., 2008; Zhao et al., 2009). Thus, targeting the Hh pathway may be helpful in overriding imatinib-resistant recurrence of CML. Importantly, blockade of Hh signaling by pharmacologic drug or siRNA shows profound reduction in the tumorigenic potential of CSCs in glioblastoma, medulloblastoma, breast cancer, pancreatic adenocarcinoma, and multiple myeloma (reviewed in Merchant and Matsui, 2010).

The Notch pathway plays an important role in the maintenance of CSCs in glioblastoma, breast cancer and some other tumors (Hu and Fu, 2012). By blocking this pathway, CSCs in brain cancer tend to be more sensitive to radiation (Wang et al., 2010b). Neutralizing antibodies against DLL4 inhibit the Notch pathway and show reduction of CSCs found in different solid tumor xenografts (Hoey et al., 2009). Similarly, inhibition of Notch-4 expression in CSCs profoundly ablates breast tumor growth (Harrison et al., 2010). In certain tumors such as undifferentiated pleomorphic sarcomas, a combination of Notch and Hh signaling governs the self-renewal of CSCs (Wang et al., 2012). Pharmacologic inhibition of the Nodal/Activin pathway, which is involved in embryonic stem cell (ESC) maintenance, sensitizes CSCs to gemcitabine in a human xenograft model. Combinatorial therapy with Nodal/Activin inhibition and a stroma-targeting Hh inhibitor significantly prolongs survival (Lonardo et al., 2011). The other pathways that have been manipulated in CSCs include Bmi-1 (PCGF4) - a member of the Polycomb-group protein family, Sonic hedgehog (Shh), Pten and HOX protein family (Lobo et al., 2007). Therapeutic targeting of these pathways may unveil novel approaches for eliminating CSCs.

7.4. Priming of CSCs in therapeutic targeting

Sensitization of chemo- and radio-resistant CSCs, also called CSC priming, could be another approach to prevent tumor relapse (Visvader et al., 2012). Inhibition of IL-4 in colon cancer has been shown to effectively prime CSCs to chemotherapy (Francipane et al., 2008). In the case of dormant CSCs, priming allows exit from the quiescent state, and subsequent chemotherapy could eradicate the tumor, including the initially dormant and resistant CSCs. For instance, quiescent LSCs in AML were shown to be induced by cytokines such as the granulocyte-colony stimulating factor (G-CSF) to enter the cell cycle and sensitized to different chemotherapeutic agents (Saito et al., 2010). Indeed, combination of G-CSF with chemotherapy that induces apoptosis appears to be effective in eradicating human LSCs in vivo. An alternative means for eliminating slow cycling LSCs involves the inhibition of DNA repair mechanisms (Viale et al., 2009). In addition, LSCs expressing PML-RARα (pro-myelocytic leukemia-retinoic acid receptor α) in an acute pro-myelocytic leukemia (APL) mouse model were shown to differentiate, leading to LSC clearance, when treated with arsenic, cyclic AMP, and retinoic acid (de Thé and Chen, 2010).

Several lines of evidence suggest the presence of radio-resistant CSCs in solid tumors, especially in brain cancer. In medulloblastoma, sensitization to radiation is promoted by targeting perivascular cells with Akt inhibitors (Hambardzumyan et al., 2008), which represents a classic example of targeting CSC niche for therapy. Similarly, selective targeting of breast CSCs by inhibition of the Akt pathway has been reported. In this case, blocking the Akt pathway impairs canonical Wnt signalling and abolishes repair of DNA damage, thus sensitizing the CSCs to ionizing radiation (Zhang et al., 2010). Most relevantly, CSCs in glioma were reported to be regulated in part by the adhesion molecule L1CAM that activates the ATM kinase pathway and DNA damage checkpoint response, thus conferring radioresistance (Cheng et al., 2011). In some breast tumors, certain subsets of CSCs show lower levels of reactive oxygen species (ROS) in comparison with their nontumorigenic counterparts and, thus, may render radioresistance (Diehn et al., 2009).

7.5. Novel drug discovery platforms in the therapeutic targeting of CSCs

High-throughput screens using small molecules, miRNA and siRNA libraries are some of the modern drug discovery platforms that grab bulk of the attention for therapeutic targeting of CSCs. High throughput screening for targeting breast CSCs identified salinomycin as a novel drug compound that showed efficacy in reducing tumor sizes and lung metastases (Gupta et al., 2009). Similar screening of small molecule inhibitors for LSCs found in AML led to the identification of kinetin riboside (McDermott et al., 2012). Another possible strategy involves systemic delivery of miR-34a to treat prostate cancer. miR-34a has recently been shown to inhibit prostate cancer stem cells and metastasis by directly repressing CD44 (Liu et al., 2011).


Current clinical therapeutic strategies operate under the presumption that all cancer cells are equally malignant within a tumor. Thus, there are in dearth of therapies that specifically target the tumorigenic cells. As a result, the current clinical regimens shrink the bulk of tumors but often fail to eradicate the CSCs, usually resulting in tumor relapse. It is challenging to produce agents against CSCs, as it requires the identification of molecular targets that are unique to CSCs. Better understanding of stem cell programs specific to normal stem cells and CSCs is of paramount importance for developing novel, stem cell-directed therapies. Such targeted therapies could be much less toxic and more efficacious than current treatment modalities.


Fig. 1. Flow chart depicting the clonal evolution theory and Cancer stem cell (CSC) model

(A) The non-hierarchical model of clonal evolution theory where genetic and epigenetic alterations produce a dominant cancer trait that acquires selective growth advantage and undergoes clonal propagation to derive homogenous tumorigenic cells with similar proliferation potential. The other mutated progeny may lack tumorigenicity due to stochastic events. (B) The hierarchical model of cancer stem cells (CSCs) in which a subset of genetic or epigenetic alterations endow self-renewal ability to progenitor cell. This mutated progeny is solely responsible for the production of tumor maintenance cells called CSCs by self-renewal divisions. At the same time, it could differentiate into a range of tumor cells each differs in their proliferation potential, thus forming a tumor bulk with heterogenous population.

Fig. 2. Hypothetical scheme of CSC origin

Depicted here is the two possible origins of CSCs - either from normal stem cells or from progenitors or differentiated cells. The origin of a CSC (green) from a normal stem cell (orange) is differentially regulated by niche effects as follows - Expansion of normal stem cell niche (purple) permits the expansion of CSC, mutations of normal stem cell endow CSC to sequester alternative niche called CSC niche (pink), mutations of normal stem cell endow CSC to be niche-independent. CSCs may also arise from genetic or epigenetic alterations of progenitors or differentiated cells that acquire self-renewal ability.