Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, 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 hypothesized to persist in tumors as a distinct population and cause relapse and metastasis 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 models, 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 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 in the late 1990s. Since the early 2000s they have been an intense cancer research focus. The term itself was coined in a highly cited paper in 2001 by biologists Tannishtha Reya, Sean J. Morrison, Michael F. Clarke and Irving Weissman.
Tumor propagation models In different tumor subtypes, cells within the tumor population exhibit functional heterogeneity 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 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 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 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 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, but not CD38. 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. Human cortical glial 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 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 the frequency of these cells is less than 1 in 10,000.
Further evidence comes from histology. Many tumors are heterogeneous and contain multiple cell types native to the host organ. Tumour heterogeneity is commonly retained by tumor metastases. This suggests that the cell that produced them had the capacity to generate multiple cell types, a classical hallmark of stem cells.
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 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.
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