A thought-provoking article published by a cancer survivor poses the question, ‘‘Are we losing the war on cancer?’’ (Leaf, 2004). Since the ‘war on cancer’ began in 1961, there have been significant advances in the treatments of diseases such as childhood leukaemia and the overall mortality rate of epithelial based cancers, such as breast and lung, have been declining due to early detection and prevention methods. However, as Leaf mentions, for the most common epithelial based cancers, the survival of patients with metastatic disease have not improved significantly over the past few decades. Despite these statistics, there is significant optimism within the cancer research community that novel treatments will improve these rates considerably. So, as our ability to attack specific targets improves, a fundamental question still remains, “Are we targeting the right cells”?
The identification and characterisation of cancer cells that have the most potential to metastasise and hence, contribute to disease progression, could lead to the development of more efficient and effective treatments. Controversial though they are, cancer stem cells (CSCs) are a very promising therapeutic target. If one cell type was responsible for resistance to treatment and the metastatic spread of cancer, it would explain treatment failures and provide a novel idea of how to attack the disease, as there is accumulating evidence that CSCs play a pivotal role in drug resistance, tumour regeneration and metastasis of various cancer entities.To achieve this goal it will be necessary to determine which cancers follow a cancer stem cell model and which do not, to address technical issues related to tumourigenesis assays, and to test the extent to which cancer cell heterogeneity arises from genetic versus epigenetic differences. Here, we will discuss the cancer stem cell hypothesis, including evidence for its validity, their implications in cancer therapy and concluding with some unanswered questions and future directions for research.
The Cancer Stem Cell Hypothesis
Despite extensive cancer research, the exact origin and method of tumour growth is not exactly clear. Solid tumours are often made up of a heterogeneous population of cells where some cells can divide repeatedly, whereas some appear to differentiate and no longer divide, so no longer contribute towards tumour growth. There are two models proposed to explain this tumour heterogeneity and growth: the cancer stem cell model and the stochastic model. The stochastic model suggests that all cancer cells have the same potential to grow and divide, although only a fraction of them will contribute towards growth, due to genetic or epigenetic changes. It builds upon this by suggesting that cells within a tumour are not in an organised system, where any cell has the same potential to contribute to tumour growth but they either are self-renewing or differentiated. The CSC model offers a different explanation for tumour growth; where tumours grow in a similar hierarchical, organised manner to normal tissue, with CSCs at the top and giving rise to all the other cancer cells. Currently, there is no definitive proof proving either of these models over the other, however both models could be true dependent on cancer type and the stage of the cancer. Personally, I would hypothesise that the CSC model is more likely to be true as the stochastic model is made up of differentiated cancer cells, which no longer contribute to growth, and another mature cell type called transit amplifying cells. These cell types do not possess the ability to self-renew, so cannot be solely responsible for the long-term survival and growth of solid tumours. This emphasises that the CSC model may be the true model as the tumours stem from self-renewing cells, with similar properties to normal stem cells, and would be responsible for the maintenance of the tumour.
CSCs in Cancer Therapeutics
So, what relevance does this knowledge of CSCs have? CSC activity could explain clinical observations from cancer patients, for example, the high degree of local recurrence after initially successful therapy against solid tumours. This could be due to CSCs being able to survive the therapies and repopulating the area. Conventional cancer therapies tend to eliminate the non-CSCs within the tumour and leave behind the chemotherapy/radiotherapy resistant CSCs, which potentially could generate clinical relapses. This emphasises the need to specifically target the CSC population within in tumours, and so the identifications of mechanisms to distinguish between CSCs and other tumour cells is critical for CSC-targeted therapy. It has also been noticed that after primary tumour surgery, a tumour in a secondary location can develop years after the treatment. This could be due to quiescent or metastatic CSCs that travel to distant sites from the primary tumour and repopulate a secondary site. Experimental evidence suggests that breast cancer CSCs are intrinsically resilient to conventional therapy and metastatic breast cancer has been found to relapse more than a decade after initial treatment. Overall, with these clinical observations and what we know about the properties of CSCs there is a huge amount of clinical relevance for CSCs as therapeutic targets, because if CSCs are responsible for the maintenance of solid tumours, then removing these cells would result in the regression of tumours.
Potential ways that I believe CSCs could be implemented in therapeutics include:
- Inducing quiescent cells into the cell cycle making them more susceptible to conventional therapy
- Targeting the CSCs via their cell surface markers
- Inhibiting critical CSC pathways
Over the past decade, a number of pathways that regulate the self-renewal of stem cells have been elucidated. These include the Wnt, Notch, and Hedgehog pathways, and the cell division and proliferation pathways NF-kB and Jak/STAT. Interestingly, these pathways are deregulated in many human cancers, leading to uncontrolled self-renewal of CSCs. These pathways may provide excellent targets for developing drugs against CSCs.
Conclusions & Future Directions
A CSC is defined as a cell that has the ability to self-renew, dividing to give rise to another malignant stem cell, as well as to produce the phenotypically diverse, differentiated tumour cells that form the bulk of the tumour.
The cancer stem cell theory is controversial because evidence for the existence of cancer stem cells relies solely on experiments that involve breaking down a tumour, taking out particular cells and then transplanting them, which requires experimental manipulation that could damage the cells or induce different behaviours. This process, termed a xenograft assay, does not exactly mirror natural cancer growth as it involves xenotransplantation of cancer cells into immunodeficient mice; an environment that could be dramatically different from the original tumour niche. Although this assay is seen as a ‘gold standard’, a better alternative that can assess the fate of CSCs in vivo would be preferred.
However, if there is only one thing that we can learn from studying CSCs, I believe it is that cells within a tumour have molecular and proliferative differences and that is something that our current therapies do not currently address. Even if CSCs turn out not to be the small sub-population with unique properties, then they have identified the heterogeneous nature of tumours that our conventional therapies must address. However, potential novel CSC-targeted treatments have many hurdles to overcome before resolving this issue. Nothing is universal, so could require cancer and patient specific therapies, due to different cancers acting to a different growth model and having different cell surface markers that aren’t CSC specific, so targeting via these biomarkers would be difficult due to the lack of specificity.
In conclusion, despite an exponential increase in CSC research over the past few years, this field of CSCs remains in its infancy and many questions and challenges remain. More studies are needed to determine precisely how different cancers grow and how they resist medical therapy. Do all tumours contain cancer stem cells? What type of cell is the cell of origin, or starting point, for different cancers and which growth model do they follow? Researchers are also investigating how cancer stem cells are controlled. What genes, proteins or other molecules are involved in their development and behaviour? Does the tumour’s microenvironment affect how cancer stem cells behave? The answers to these questions will be important for future cancer treatment strategies.
However, this research has helped to resolve a number of controversies regarding identification of these cells and their role in driving tumour growth. Due to these advances, more than a dozen biotechnology and pharmaceutical companies are now vigorously pursuing CSC research and a number of early-phase clinical trials targeting CSCs are in progress. These studies and the later-stage efficacy trials that follow them should indicate whether successful targeting of CSCs significantly improves outcomes in cancer patients. If this is found to be the case, it may usher in the beginning of a new era of cancer therapy.
So, are cancer stem cells ready for prime time??