Recent Developments In The Cancer Stem Cell Theory

Cancer stem cells (CSCs) are an important population of tumour cells. They can self-renew, are thought to contribute to metastasis and are resistant to chemo- and radiotherapy. CSCs’ specific properties mean that new cancer treatments are required to target these cells. This article reviews some recent developments in the field including new therapeutic strategies and techniques that researchers are using to overcome some of the main challenges they face. These studies are proving vital in understanding the biology of CSCs and tumour survival.

Cancer was first suggested to originate from adult stem cells in the nineteenth century. This theory acquired credibility in the twentieth century when acute myeloid leukaemia cells were shown to be able to give rise to new tumours [Bonnet and Dick, 1997]. The ‘cancer stem cell’ theory, as it is now known [reviewed by Behbod and Rosen, 2004], suggests that adult stem cells may play an important part in cancer due to their association with tumour initiation, maintenance and metastasis [Reya et al. 2001; Zhao et al., 2012].  All tumours are thought to contain populations of cancer stems cells (CSCs) that undergo asymmetric division to form phenotypically distinct cells within the same tumour cell population [Castano et al. 2012].

Research has demonstrated that CSCs behave differently from normal stem cells. Their molecular regulation is disrupted, which induces changes in their phenotype. CSCs have deregulated cell cycles, which result in DNA damage, and are suggested to play a key role in the tumour, contributing to its survival through unlimited self-renewal capacity [Baccelli and Trumpp, 2012].

Clinical challenges of cancer stem cells

The CSC concept has accumulated credibility over the past fifteen years or so. However, recent research has also emphasised the clinical challenges provoked by this theory. For example, genetically and phenotypically distinct sub-populations of CSCs can exist within the same tumour. Despite this, non-CSCs have been shown to form the main bulk of the tumour, prompting debate on the roles of the different cell types within a tumour [Zhao, 2012]. CSC phenotypes also vary between individuals [Baccelli and Trumpp, 2012].

An important discovery is that CSCs are resistant to current standard therapies that are used to treat patients. CSCs are not killed by chemotherapy, radiotherapy or surgery. In fact, it has been shown that chemotherapy increases the ability of CSCs to survive [Zhao et al., 2012]. These cells are also capable of entering a dormant or quiescent state before re-entering the cell cycle and rebounding to form new tumours when their environment is more favourable [Castano et al., 2012].

CSCs have also been suggested to originate from progenitors that undergo reverse phenotypic changes due to an accumulation of genetic and epigenetic abnormalities [Baccelli and Trumpp, 2012]. These re-generated stem cells may go on to form CSCs that can differentiate into any cell type the tumour may require [Baccelli and Trumpp, 2012], forming a hierarchy within the tumour’s multiple cell populations.

 The Challenges of working with CSCs

One main hypothesis for treatment is the ‘dandelion phenomenon’ insomuch as treating the visible ‘flower’ (tumour growth) does not treat the underlying problem and you need to aim for the ‘roots’ (CSCs) [Zhao et al., 2012]. Targeting the root of the problem, however, means finding new drug therapies to specifically eradicate CSCs and this has challenged researchers due to the difficulties experienced in culturing CSCs and performing assays. The large quantities of cells required for assays are hard to cultivate. New drugs are routinely screened using high throughput assays that allow thousands of compounds to be tested simultaneously in a small timeframe. Each test requires the use of microtitre plates that contain 1,536 or 3,456 wells. Robotic instruments are usually used for the assay testing due to their reliability and rapidity in dispensing the small volumes needed for these assays. However, cells and especially stem cells are very delicate and require specific growth media, rendering them difficult to work with using laboratory equipment, notably causing blockages in robotic instruments. Due to their fragility and specific growth requirements for culture, all stem cells are very precious and waste needs to be kept to a minimum. To resolve these assay problems, innovative microplate dispensers have been developed, which enables reliable stem cell dispensing.

New therapeutic targets

Recent research has identified new potential targets in CSCs. These include targeting specific receptors and specific molecular pathways. It has been reported that breast CSCs can be selectively eradicated by salinomycin [Gupta et al., 2009]. An important mechanism of CSC drug resistance involves ABC-transporters and in human myeloid leukemia stem cells, salinomycin is thought to overcome ABC-transporter-mediated multidrug resistance. This drug may also prevent apoptosis resistance [Naujokat and Steinhart, 2012]. Recently, salinomycin has also been shown to target CSCs in other types of human cancers including gastric and prostate cancers [Zhi et al., 2011; Ketola et al., 2012].

It has also been shown that microRNAs (miRNAs) are frequently deregulated in human cancer, suggesting that they could be a new means of testing for and diagnosing the disease [Ali et al. 2012]. Research has also targeted molecular pathways used by CSCs. By targeting the functional pathways that CSCs rely upon, it is hoped that CSCs can be eradicated. One problem with this method is that normal stem cells and CSCs share many pathways so any drug would have to be very selective. One main target is the Wnt signalling pathway, which is thought to play a role in self-renewal of mammary tumour stem cells [Behdod and Rosen, 2004]. The hedgehog, notch and hox family pathways have also been successfully inhibited by researchers, eradicating CSCs in some tumour types [Zhao et al., 2012].

In conclusion, current cancer therapies have proved unsuccessful in eliminating CSCs, thought to be the main cause of metastasis and tumour regrowth following treatment. Our understanding of CSCs has improved greatly since the beginning of the century, enabling scientists to explore potential new cancer cures. As explained by the dandelion phenomenon, much research is going into eradicating CSCs as an integral part of cancer therapies. A combination of therapies, which target the tumour as well as the CSCs, could lead to dramatic improvements in cancer therapies and survival rates.

References

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